Conference 2018:

Translating Innovative Technology to Patient Care

May 22 - 25, 2018 Chelsea Hotel, Toronto, ON, Canada

A joint conference of:

Canadian Society for Pharmaceutical Sciences Canadian Society of Pharmacology and Therapeutics Canadian Chapter of Controlled Release Society

Conference Co-Chairs: Catherine Lau, Janssen Inc., Toronto, ON Micheline Piquette-Miller, University of Toronto, Toronto, ON

Conference Organizing Committee: From CSPS: Frank Abbott, University of British Columbia, Vancouver, BC, Christine Allen, University of Toronto, Fakhreddin Jamali (University of Alberta) From CSPT: Kerry Goralski (Dalhousie University), Randee Holmes (CSPT), Brad Urquhart (University of Western Ontario) From CC-CRS: Marc Gauthier (INRS)

Translating Innovative Technology to Patient Care | 1s

Canadian Society for Pharmaceutical Sciences

Welcome to Toronto and to the celebration of the 21st Anniversary of CSPS! We are pleased to once again collaborate with the Canadian Chapter of the Controlled Release Society and also the Canadian Society of Pharmacology and Therapeutics to bring you an exciting program - From Innovation to Patient Solution. We hope you find the conference sessions to be valuable and thought-provoking. The Canadian Society for Pharmaceutical Sciences (CSPS) is a non-profit organization established in 1997 to foster excellence in pharmaceutical research. Our members are scientists and educators involved in all aspects of pharmaceutical sciences including academia, industry and government. A major objective is to build partnerships and develop a strong voice to encourage government, academia, and industry to advance pharmaceutical R&D innovation in Canada. The electronic Journal of Pharmacy and Pharmaceutical Sciences is the official, international journal of CSPS and can be accessed on our website. Enjoy the program while meeting old friends and making new ones! Catherine Lau, Ph.D. President, CSPS (2018-2019)

CSPS Board of Directors includes representatives from industry and academia and government. The 2018 Board is: Catherine Lau, President (2018-2019) (Janssen Inc.), Christine Allen, President-Elect & Treasurer (University of Toronto), Frank Abbott, Past President (University of British Columbia), Noriko Daneshtalab, Secretary (Memorial University of Newfoundland), Directors: Jane Alcorn (University of Saskatchewan), Denis deBlois (Université de Montréal), Ron Boch (BIOTECanada), Arshia Ghani (Pfizer), Emmanuel Ho (University of Waterloo), Fakhreddin Jamali (University of Alberta), Agnes Klein (Health Canada), Elisabeth Kovacs (Apotex), Ted Lakowski (University of Manitoba), Co Pham (Health Canada), Franklyn de Silva, Trainee Rep (University of Saskatchewan)

CSPS 2018 Awards - Congratulations to the following: CSPS Lifetime Achievement Award: Gordon Amidon, University of Michigan CSPS Fellow: Raimar Loebenberg, University of Alberta; Krishnan Tirunellai, Health Canada Gattefossé Canada/CSPS Lipid-Based Drug Delivery Award: Shannon Callender, University of Waterloo GSK/CSPS National Undergraduate Student Research Program Awards: Jonathon Thomson (University of Alberta), Anne Nguyen (University of British Columbia), Kelsey Mann (Dalhousie University), Rachel Ward (Memorial University of Newfoundland), Francis Lefebvre (Université de Montréal), Grace Cuddihy (University of Saskatchewan), Wendy Siu (University of Toronto), Stephanie De Jong (University of Waterloo)

Poster Awards (Winners to be announced Friday afternoon):  Antoine A. Noujaim Award of Excellence, sponsored by the Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta  Servier Canada Poster Awards  Cedarlane Award of Excellence  CSPS Best Poster Awards

Special thanks for the support of our Sustaining Partner: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta.

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Canadian Society of Pharmacology and Therapeutics

On behalf of the Canadian Society of Pharmacology and Therapeutics (CSPT), it is our pleasure to welcome you to our Annual Meeting in Toronto. This year, we are joining forces with our partners of the Canadian Society of Pharmaceutical Sciences (CSPS) and the Canadian Chapter of Controlled Release Society (CC-CRS) to bring together a critical mass of academic researchers, clinicians and industry professionals in offering an outstanding conference program and research forum. CSPT is the voice of Canadian pharmacology. We are a national not-for-profit organization created with the goal of fostering the application of educational and research excellence to drug discovery and therapeutic choices. Our membership is diverse blend of clinicians, academic investigators, industrial partners and trainees interested in the goal of more effective and safer drug therapy. CSPT is the official Canadian member of the International Union of Basic and Clinical Pharmacology (IUPHAR) and as such is an international voice for Canadian science and innovation in drug discovery and therapeutic excellence. This year’s meeting promises to be exceptional with a great slate of speakers and a host of interesting oral and poster presentations. In addition to offering scientific excellence, the meeting will be held in the heart of Toronto, one of the most vibrant and exciting cities in the world. Thank you for your attendance and we look forward to serving you and interacting with you in the coming months! If you’d like to get involved in CSPT, we are always looking for new and motivated individuals to be involved – please contact us! Visit our website at https://pharmacologycanada.org for information on our society and to learn about updates on our activities throughout the year.

Congratulations to the 2017 CSPT award winners: Distinguished Service and Education Award: George Dresser, Western University Senior Investigator Award: Anne-Noël Samaha, Université de Montréal Clinical Fellowship Award: Gavin Sun, Western University Postdoctoral Award: Galen Wright, University of British Columbia Publication Award: Jean-François Trempe, McGill University

CSPT Executive Committee President: Michael Rieder (Western) Vice President: Kerry Goralski (Dalhousie) Secretary: Marc Gauthier (INRS) Treasurer: John McGuire (Memorial) Past President: Emmanuel Escher (Sherbrooke) Scientific Program Chair: Bradley Urquhart (Western) Education Committee Chair: Cindy Woodland (Toronto) Outreach Committee Chair: Bruce Carleton (UBC) Royal College Liaison: Doreen Matsui (Western)

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Canadian Chapter of Controlled Release Society

On behalf of the Canadian Chapter of the Controlled Release Society (CC-CRS), it is my pleasure to welcome you to our Annual Chapter Symposia in Toronto. This year, we once again join forces with our colleagues at CSPS and CSPT to bring together a critical mass of academics and industry professionals to offer an outstanding conference program. The topic of this meeting “Translating Innovative Technology to Patient Care” is a fundamental motivation of our Society, and one that we hope to achieve through the research we showcase at this Meeting. CC-CRS represents over 250 Canadian academics and industry professionals across scientific, engineering, and medical fields. We are involved in the science and technology of controlled delivery of drugs and therapeutic agents in human and animal health, and of other active agents in environmental, consumer, and industrial applications. We encourage you to join our Society (membership is free!) and to participate in the networking opportunities we organize across Canada. In particular, we would welcome you to attend our regional events that bring together local students, professionals, and industry leaders in the area of controlled release – in the past, we have held events in Winnipeg, Toronto, and Montreal and plan to broaden these events in the coming year across Canada. This year, for the second time in our history, we are also please to invite you to our pre- conference workshop entitled ‘Formulation and Delivery of Biologics: Vaccines, Peptide/Protein, and Gene Therapeutics’, which provides an opportunity to learn for academic and industry leaders on this important topic. Finally, we encourage you to attend the Annual Meeting & Exposition of our parent body, the international Controlled Release Society (CRS), taking place in New York City, July 22–24, 2018 – an ideal spot to access the latest in delivery science worldwide!

Thank you for your attendance and we look forward to serving you and interacting with you in the coming months! If you’d like to get involved in CC-CRS, we are always looking for new and motivated individuals to be involved – please contact us! Visit our website at http://cc-crs.com for updates on all our activities throughout the year.

CC-CRS Board of Directors President: Marc A Gauthier (INRS) Secretary: Marta Cerruti (McGill) Treasurer: Larry Unsworth (Alberta) Past President: Emmanuel Ho (Waterloo) Webmaster: Michael Majcher (McMaster) Members-at-Large: Brian Amsden (Queen’s), Jake Barralet (McGill), Michael R. Doschak (Alberta), Azita Haddadi (Saskatchewan), Afsaneh Lavasanifar (Alberta), Davide Brambilla (Montreal), Shyh-dar Li (British Columbia), Shirley X.Y. Wu (Toronto), Todd Hoare (McMaster) Student Board Members: Soudeh Tehrani (UdeM)

Sincerely,

Marc A. Gauthier

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CSPS / CSPT / CC-CRS 2018 Conference Program

TUESDAY, MAY 22, 2018 Industry Day: Innovation and Management of Modern Pharmaceuticals 1:00 ‐ 5:00 PM (Chairs: Andrew Casey, BIOTECanada, and Christine Allen, University of Toronto) Room: Churchill Ballroom Opening and Welcome: Catherine Lau, CSPS President & Conference Co‐Chair 1:00 PM Introductory Remarks: Andrew Casey, BIOTECanada 1:10 ‐ 2:00 PM PLENARY: Mary Haak‐Frendscho, Blueline Bioscience & Versant Ventures The View From Here: Innovation Canadian Style 2:00 ‐ 2:15 PM MaRS Innovation: Raphael (Rafi) Hofstein, President & CEO MaRS Innovation: Modern Approaches to Bridging the Valley of Death

2:15 ‐ 2:30 PM JLABS: Allan Miranda, Head of JLABS @ Canada JLABS @ Canada Catalyzing Innovation 2:30 ‐ 2:45 PM Avicanna: Aras Azadian, President & CEO Avicanna and Evidenced Backed Delivery of Medical Cannabinoids 2:45 ‐ 3:00 PM Cyclica Inc.: Stephen MacKinnon, Director of Research and Development, Cyclica Inc. Structure‐Based and AI‐Augmented Proteome Screening for Drug Discovery 3:00 ‐ 3:15 PM Coffee & Tea Break

3:15 ‐ 3:30 PM Pendant Biosciences: Shawn Glinter, CEO From the Bench to the Board Room: The Things Nobody Tells You! 3:30 ‐ 3:45 PM Panag Pharma, Halifax: Melanie Kelly, Chief Scientific Officer, and Tetra Bio Pharma, Montreal: Guy Chamberland, Chief Scientific Officer Navigating the Cannabis Pharma Space 3:45 ‐ 4:00 PM Mirexus Inc.: John Dutcher, Founder Phytoglycogen Nanoparticles in Nanomedicine: Novel Drug Delivery, Anti‐Infective & Immunomodulatory Agents Encycle Therapeutics: Jeffrey Coull, CEO 4:00 ‐ 4:15 PM Nacellins: New Therapeutic Entities for Challenging Targets ImmunoBiochem Inc.: Anton Neschadim, CEO 4:15 ‐ 4:30 PM Targeting the Cancer Cell Secretome to Overcome Tumor Heterogeneity IMV Inc.: Genevieve Weir, Director of Research 4:30 ‐ 4:45 PM Improving Immune Responses to Cancer Antigens Using a Nanoparticle Formulation that Targets Lymph Node Cells Session Summary 4:45 PM Christine Allen, University of Toronto

5:30 ‐ 7:00 PM Welcome Reception: CSPS, CSPT, CC‐CRS Churchill Court

Translating Innovative Technology to Patient Care | 5s WEDNESDAY, MAY 23 ‐ MORNING SESSIONS

7:00 AM Registration & Poster Set‐Up

7:00 ‐ 9:00 Trainee Breakfast & Session: Nana Lee, Faculty of Medicine, University of Toronto AM Creating Your Career Path with your Grad Degree Trainee Breakfast 7:00 ‐ 7:30 AM, Session 7:30 ‐ 9:00 AM Room: Rosetti

8:30 AM Coffee & Muffins

9:00 ‐ 9:05 Welcome from: ‐ CSPS ‐ Cathy Lau, President AM ‐ CSPT ‐ Kerry Goralski, Vice President ‐ CC‐CRS ‐ Marc Gauthier, President

9:00‐10:00 PLENARY SESSION: David Juurlink, Sunnybrook Health Sciences Centre AM The North American Opioid Crisis from 30,000 Feet Chair: Tuan Trang, University of Calgary Room: Churchill Ballroom

10‐10:30 AM Coffee & Tea Break: Posters, Exhibitors, & Networking

10:30 AM ‐ SESSION 1A: OPIOID CRISIS SESSION 1B: REGULATORY REFORMS SESSION 1C: CROSSING BIOLOGICAL 12:30 PM MEMBRANES Chair: David Juurlink, Sunnybrook Health Chair: Cathy Parker, Director General, Sciences Centre BGTD, Health Canada Co‐Chairs: Emmanuel Ho, Univ. of Waterloo, and Kerry Goralski, Dalhousie University

Room: Churchill Ballroom Room: Rosetti Room: Wren 10:30 Opioid Use and Adverse Events: Improving Access to Innovative Improving Predictions of Renal Anionic Emerging Trends and Policy Impacts Medicines: Health Canada’s Regulatory Drug Transport Tara Gomes, Li Ka Shing Knowledge Reform Initiative Ryan Pelis, Dalhousie University Institute of St. Michael's Catherine Parker, Health Canada 11:00 Pharmacological Strategies for Harm CADTH in 2018: Crossroads, Inflection Disruption of Model Membranes by Reduction in Opioid Use Disorder: An Points, and Partnerships Surfactants used in Gene Delivery Overview Heather Logan, Canadian Agency for Shawn Wettig, University of Jessica Leen, University of Toronto Drugs & Technologies in Health Waterloo (CADTH) 11:30 Nudges, Pushes, Policy and St Francis: PMPRB Framework Modernization Medicating the Brain: The Challenges of Perspectives on the Opioid Crisis Doug Clark, Patented Medicine Getting Drugs Past the Blood‐Brain Shawn Bugden, Memorial University Prices Review Board, Govt. of Canada Barrier of Newfoundland Donald Miller, University of Manitoba 12:00 HPFB Activities in Support of the Federal Panel Discussion: Speakers plus: Optimizing Nanoparticle Interactions Action on Opioids Ed Dybka, QIV Capital (Past with Macrophages and Endothelial Cells Emma Spreekmeester, Health President, AstraZeneca Canada Inc.) for Improved Site‐Specific Delivery Canada Joy Wolfram, Mayo Clinic Durhane Wong‐Rieger, Consumer Advocare Network 12:30 ‐ 1:00 CSPS Lifetime Achievement Award: Presentation & Lecture: CSPT Distinguished Service and Education Award: Gordon Amidon, University of Michigan George Dresser, Western University Don’t Throw the BA/BE out with the Bathwater: Translating Health Technology at the most Challenging Interface: (Mechanistic Oral BE) The Physician/Patient Interaction Chair: Fakhreddin Jamali, University of Alberta Room: Rosetti Room: Wren

1:00 ‐ 1:30 Lunch break (on your own) Posters, Exhibitors, and Networking

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WEDNESDAY, MAY 23 ‐ AFTERNOON SESSIONS

1:30 ‐ 2:30 Poster Session, Exhibitors

2:30 ‐ 5:10 SESSION 2A: KNOWLEDGE SESSION 2B: PHARMACEUTICAL SESSION 2C: CSPT TRAINEE ORAL TRANSLATION – FROM REAL WORLD POTENTIAL OF STEM CELL & CRISPR‐ PRESENTATIONS EVIDENCE TO CANADIAN HEALTH CARE MEDIATED GENE MODIFICATIONS Chair: Tuan Trang, University of Calgary NEEDS Chair: Jeffrey Henderson, University of

Chair: George Wells, University of Ottawa, Toronto and University of Ottawa Heart Institute Room: Wren Room: Rosetti Room: Churchill Ballroom 2:30 Public Payer Perceptions of the Value of Stem Cell Activation to Promote Self‐ Galen Wright, University of British Real World Evidence repair of the Injured Nervous System Columbia Don Husereau, University of Ottawa, Cindi Morshead, Donnelly Centre for Cellular and Biomolecular Research Khaled Adb‐Elrahman, Ottawa School of Epidemiology and Public University Health 3:00 Improving the Use of Real World A Stemness‐based Drug Screen to Britt Drögemöller, University of British Evidence in the Regulatory Environment: Target Acute Myeloid Leukemia Stem Columbia Where are we Heading? Cells Anish Engineer, Western University Rhonda Kropp, Marketed Health Jean Wang, Princess Margaret Products Directorate, Health Canada Cancer Centre, Univ. Health Network Elizabeth Greco, Western University Shrinidh Joshi, North Dakota State University

3:30 Coffee & Tea Break: Posters, Exhibitors, & Networking 4:00 Canadian Network for Observational Opening the Gate for Pluripotent Stem Anette Surmanski, Western University Drug Effect Studies: Using Real‐World Cell‐based Therapies Markus Gulilat, Western University Evidence to Inform Regulatory Andras Nagy, Lunenfeld‐ Eliza McColl, University of Toronto Decisions Tanenbaum Research Institute, Sinai Robert Platt, CNODES and DSEN Health System Kamelia Mirdamadi, University of Toronto 4:30 Life‐Cycle HTA: Unlocking the Potential Network Analysis of Cell Death for Real World Evidence Signaling Pathways via CRISPR‐ Tessa Bendyshe‐Walton, University of Tammy Clifford, CADTH mediated Modification in Embryonic British Columbia Stem Cells and Derivatives Jay Fang, Western University Jeffrey Henderson, University of Toronto Pierre Thibeault, Western University Yong Jin (James) Lin, Western University 5:00 ‐ 5:10 Selected CSPS trainee abstract PM presentation: Investigating the Role of the IKKβ Protein Kinase in Vascular Remodeling Events Francis Lefebvre, Université de Montréal 5:15 ‐ 6:15 Launch of CSPS Young Scientist PM Network We are building a community known as the CSPS Young Scientist Network to bring together trainees pursuing pharmaceutical sciences across the country. This meeting will be an oppor‐ tunity for anyone who is interested in joining to offer feedback about how they would like the network to operate and to establish points of contact at the various schools across the country.

[Free Evening] ‐ Toronto Blue Jays Game 7:00 PM

Translating Innovative Technology to Patient Care | 7s THURSDAY, MAY 24 ‐ MORNING SESSIONS

7:00 AM Registration & Poster Set‐Up

8:00 AM Coffee & Muffins

8:30 ‐ 9:30 PLENARY SESSION: Tak Mak, Ontario Cancer Institute, Princess Margaret Hospital, Toronto AM The Fourth Pillar of Cancer Treatment: It Takes a Village Chair: Catherine Lau, Janssen Inc. Room: Churchill Ballroom 9:30 ‐ 10:00 AM Coffee & Tea Break: Posters, Exhibitors, & Networking

10:00 AM ‐ SESSION 3A: IMMUNO‐ONCOLOGY SESSION 3B: THE GUT MICROBIOME SESSION 3C: PRACTICAL 12:00 PM AS A NOVEL THERAPEUTIC TARGET PHARMACOLOGY: CASE STUDIES FROM Chair: Pamela Ohashi, Princess Margaret ACROSS THE COUNTRY Cancer Centre Chair: Brad Urquhart, Western University Chair: George Dresser, Western University Room: Churchill Ballroom Room: Rosetti SPONSORED BY: CDRD Room: Wren 10:00 10:00 ‐ 10:20 Overview of the Microbiome and its 10:00: Clearing Up Controversies CAR Therapy: The CD19 Paradigm and Potential Role in Therapeutics Around Carfentanil Beyond Michael Surette, McMaster Jessica Leen, University of Toronto Michel Sadelain, Memorial Sloan‐ University Kettering Cancer Center, NYC 10:15: A Case of Unilateral Adrenal Adenoma with Resistant Hypertension 10:30 10:20 ‐ 10:40 Microbial Effects on Innate and Marc Chretien, Western University A Trans‐Canada Highway for CAR‐T Cells Adaptive Immunity 10:30: Improving Outcomes for Brad Nelson, BC Cancer Agency ‐ Deeley Kathy McCoy, University of Calgary Research Centre Childhood Cancer Patients Using Genomics‐guided Treatment 11:00 10:40 ‐ 11:00 ‐ Fecal Microbial Transplants: Treatment Optimization A New Generation CAR Containing a of C. Difficile and Beyond Catrina Loucks, University of British JAK–STAT Signaling Domain Mediates Michael Silverman, Western Columbia Superior Antitumor Effects University Naoto Hirano, Princess Margaret 10:45: Choosing the Right Antihypertensives for your Pregnant Cancer Centre, UHN Patient 11:30 11:00 ‐ 11:20 Unexplained Atherosclerosis and Albayada Medhar, Western Immuno‐Oncology Combinations in Metabolic Products of the Intestinal University Clinical Development Microbiome 11:00: Genetic Screening and Cannabis Lillian Siu, Princess Margaret Cancer Ctr David Spence, Western University Induced‐Psychosis: Who, What and When? Gavin Sun, Western University 11:20 11:15: CSPT Clinical Fellowship Award Panel Discussion with: Lecture: Session Speakers + Gavin Sun, Western University Jian Wang, Health Canada Ismael Samudio, CDRD 12:00 ‐ 12:30 11:45: CSPT Post‐Doctoral Award Lecture: Galen Wright, University of British Columbia Room: Wren 12:30‐1:30 Annual General Meetings: CSPS (Churchill), CSPT (Wren), CC‐CRS (Rosetti) Lunch break (on your own) following AGMs Posters, Exhibitors, and Networking

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THURSDAY, MAY 24 ‐ AFTERNOON SESSIONS

1:30 ‐ 2:30 Poster Session

2:30 ‐ 5:10 SESSION 4A: TRANSLATIONAL SESSION 4B: CANNABINOIDS SESSION 4C: INNOVATIVE MEDICINE BIOMATERIALS FOR DRUG DELIVERY

Co‐Chairs: Ming Tsao, Ontario Cancer Chair: Rachel Tyndale, CAMH Co‐Chairs: Todd Hoare, McMaster University, Institute; Janet Dancey, Canadian Cancer Marta Cerruti, McGill University Trials Group & Queens University Room: Rosetti Room: Wren Room: Churchill Ballroom 2:30 2:30‐2:50 Therapeutic Potential of CB1 Allosteric Trigger‐Amplifying Self‐Immolative Opening Pandora’s Genome: Rethinking Modulators Nanoparticles for Drug Delivery Molecular Diagnostics Ruth Ross, University of Toronto Elizabeth Gillies, Western University Aly Karsan, BC Cancer Agency 3:00 2:50‐3:10 Growing up High: Long‐Term Polymer‐ Based Protein Delivery Biomarker Testing in Lung Cancer Consequence of Adolescent Cannabis Systems Ming Tsao, Ontario Cancer Institute Use ‐ Preclinical Studies Sankaran Thayumanavan, 3:10‐3:30 Jibran Khokhar, University of University of Massachusetts Tumor Mutational Burden as a Biomarker Guelph for Cancer Immunotherapy Caitlin Connelly, Foundation Medicine 3:30 Coffee & Tea Break: Posters, Exhibitors, & Networking 4:00 4:00‐4:20 Adolescent Cannabis Use: Risk for Controlled‐Release Nano‐Therapeutics: Molecular Diagnostic Advancement in Mental Health and Drug Dependence The Status of Translation Oncology Marcus Munafò, University of Subramanian Venkatraman, Alan Spatz, McGill University & Bristol, UK NTU Singapore Jewish General Hospital 4:30 4:20‐5:00 Opioid Sparing Effects of Cannabinoids: Biomimetic Nanoparticles for Targeted Panel Discussion: Myth or Reality? Drug Delivery and Detoxification All Speakers + Bernard Le Foll, University of Liangfang Zhang, UC San Diego Janet Dancey, Canadian Cancer Toronto Trials Group, and Queens University Raffi Tonikian, Merck 5:00 PM 5:00‐5:10 PM 5:00‐6:00 PM ‐ Panel Discussion 5:00‐5:10 PM Selected CSPS oral abstract Selected oral abstract presentation: presentation: The Future of Medical Cannabis in Hyperthermia‐mediated Drug Delivery Combining Statins with Radio‐ Canada Increases Cisplatin Sensitivity and immunotherapy as a Novel Therapeutic Moderator: James Evans, University of Accumulation Resulting in improved Strategy for Colorectal Cancer Toronto Efficacy in Triple Negative Breast Vessie Vassileva, Imperial College Cancer London Participants: Michael Dunne, University of  Beleave (Peter Chen, VP of Science Toronto and Technology)  Avicanna (Aras Azadian, President)  CannTrust (Kaivan Talachian, VP, Presentation of CC‐CRS Poster Awards Professional Services)  University of Toronto (Lakshmi Kotra)

6:30 PM Conference Gala and Awards Dinner (6:30 PM Cash Bar, 7:30 PM Dinner) Churchill Ballroom

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FRIDAY, MAY 25 ‐ MORNING SESSIONS

7:30 AM Registration

8:00 AM Coffee & Muffins

8:30 ‐ 9:30 PLENARY SESSION: Richard Weinshilboum, Mayo Clinic Pharmacogenomics: Clinical Implementation and Future Challenges Chair: Micheline Piquette‐Miller, University of Toronto Room: Churchill Ballroom

9:30‐‐ Coffee & Tea Break: Networking 10:00 SESSION 5A: PHARMACOGENOMIC IMPLEMENTATION SESSION 5B: DRUG THERAPY IN CHILDREN 10:00 ‐ 12:00 Chair: Micheline Piquette‐Miller, University of Toronto Chair: Michael Rieder, Western University Noon Room: Churchill Ballroom Room: Rosetti 10:00 PRIME: Implementing Pharmacogenomic Testing into Nephrotoxic Acute Kidney Injury in Hospitalized Children and Pharmacy Practice ‐ Focus on Mental Health Description of a National Cisplatin Pediatric Cohort Pharmacotherapy Mike Zappitelli, The Hospital for Sick Children, Toronto Natalie Crown, University of Toronto 10:30 Clinical Pharmacogenomics Program in Pediatric Novel Approaches to Improving Pharmacotherapy in Epilepsy: Oncology: 225 Patients and Counting Machine Learning and Human Organoids Bruce Carleton, University of British Columbia Peter Carlen, University of Toronto 11:00 Clinical Utilization of Pharmacogenomic Testing – The Vaccinating Children Against Pain and Fear Evolving Canadian Environment Anna Taddio, University of Toronto Christopher Trevors, Dynacare 11:30 Pharmacogenetics in the Benefits Arena – Baby Steps; Giant CSPT Senior Investigator Award: Opportunities Addiction to Cocaine: How you Take the Drug is More Important Wayne Murphy, Prudent Benefits Administration Services than how Much Anne‐Noël Samaha, Université de Montréal

12:00 PM Trainee Poster Awards ‐ Announcement and Presentation of Awards Room: Churchill Ballroom 12:30 PM Conference Concludes

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Table of Contents

CSPS / CSPT / CC-CRS 2018 CONFERENCE PROGRAM ...... 5

TUESDAY, MAY 22 INDUSTRY DAY: INNOVATION AND MANAGEMENT OF MODERN PHARMACEUTICALS ...... 24

PLENARY SESSION 1 The View from Here: Innovation Canadian Style ...... 24 Mary Haak-Frendscho, CEO, Blueline Bioscience; and Venture Partner, Versant Ventures, Toronto

INDUSTRY DAY: PRESENTATIONS Session Chair: Andrew Casey ...... 24

MaRS Innovation: Modern Approaches to Bridging the Valley of Death ...... 25 Raphael (Rafi) Hofstein, President & CEO, MaRS Innovation JLABS @ Canada Catalyzing Innovation ...... 25 Allan Miranda, Johnson & Johnson Innovation, JLABS in Canada Avicanna and Evidence Backed Delivery of Medical Cannabis ...... 26 Aras Azadian, Chief Executive Officer and Co-Founder, Avicanna, Toronto, ON Structure-Based and AI-Augmented Proteome Screening for Drug Discovery ...... 26 Stephen MacKinnon, PhD, Director of Research and Development, Cyclica Inc. From the Bench to the Board Room: The Things Nobody Tells You ...... 27 Shawn H. Glinter, Founder & CEO, Pendant Biosciences Navigating the Cannabis Pharma Space ...... 28 Melanie E.M. Kelly1 & Guy Chamberlain2, 1Panag Pharma Inc. Halifax, Nova Scotia and 2Tetra Bio-Pharm, Orleans, Ontario Phytoglycogen Nanoparticles in Nanomedicine: Novel Delivery, Anti-infective and Immuno-modulatory Agents ...... 29 John Dutcher, Founder, Mirexus Biotechnologies/ Glysantis Nacellins: New Therapeutic Entities for Challenging Targets ...... 29 Jeffrey Coull, President and CEO, Encycle Therapeutics Targeting the Cancer Cell Secretome to Overcome Tumor Heterogeneity ...... 29 Anton Neschadim, PhD MBA, CEO, ImmunoBiochem Corporation Improving Immune Responses to Cancer Antigens Using a Nanoparticle Formulation that Targets Lymph Node Cells ...... 30 Genevieve Weir, Director of Research, IMV Inc.

WEDNESDAY, MAY 23

TRAINEE BREAKFAST Creating Your Career Path with your Grad Degree ...... 31 Nana Lee, PhD, Departments of Biochemistry and Immunology, Lead Coordinator, Faculty Development Program, Graduate Life and Science Education, Faculty of Medicine, University of Toronto

Translating Innovative Technology to Patient Care | 11s PLENARY SESSION 2 The North American Opioid Crisis from 30,000 Feet ...... 32 David Juurlink, Sunnybrook Health Sciences Centre

SESSION 1A: OPIOID CRISIS Opioid Use and Adverse Events: Emerging Trends and Policy Impacts ...... 33 Tara Gomes, St. Michael’s Hospital Pharmacological Strategies for Harm Reduction in Opioid Use Disorder: An Overview ...... 33 Jessica L.S. Leen, MD, FRCPC, University of Toronto Nudges, Pushes, Policy and St Francis: Perspectives on the Opioid Crisis ...... 34 Shawn Bugden, Memorial University of Newfoundland / University of Manitoba HPFB Activities in Support of the Federal Action on Opioids ...... 34 Emma Spreekmeester, PhD., Manager / Health Products and Food Branch, Health Canada

SESSION 1B: REGULATORY REFORMS Improving Access to Innovative Medicines: Health Canada’s Regulatory Reform Initiative ...... 35 Catherine Parker, Director General, Biologics and Genetic Therapies Directorate, Health Canada CADTH in 2018: Crossroads, Inflection Points, and Partnerships ...... 35 Heather Logan, Vice-President, Pharmaceutical Reviews (Acting), Canadian Agency for Drugs and Technologies in Health (CADTH) PMPRB Framework Modernization ...... 36 Douglas Clark, Executive Director of Patented Medicine Prices Review Board Panel Discussion: Panel Members Ed Dybka ...... 36 Durhane Wong-Rieger ...... 37

SESSION 1C: CROSSING BIOLOGICAL MEMBRANES Improving Predictions of Renal Anionic Drug Transport ...... 38 Ryan M. Pelis, PhD, Associate Professor, Department of Pharmacology, Dalhousie University Disruption of Model Membranes by Surfactants used in Gene Delivery ...... 39 Shawn Wettig, Ph.D., C.Chem., Associate Professor and Associate Director, Graduate Studies and Research, School of Pharmacy, University of Waterloo, Waterloo, ON Medicating the Brain: The Challenges of Getting Drugs Past the Blood-Brain Barrier ...... 39 Donald W. Miller, Department of Pharmacology and Therapeutics, University of Manitoba Optimizing Nanoparticle Interactions with Macrophages and Endothelial Cells ...... 40 Joy Wolfram, PhD, Assistant Professor, Department of Transplantation and Department of Physiology and Bioengineering, Mayo Clinic, Jacksonville, Florida, United States

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CSPS LIFETIME ACHIEVEMENT AWARD LECTURE Don’t Throw the BA/BE out with the Bathwater (Mechanistic Oral BE) ...... 41 Gordon L. Amidon Ph.D., University of Michigan, College of Pharmacy; Department of Pharmaceutical Sciences, Ann Arbor, Michigan

SESSION 2A: KNOWLEDGE TRANSLATION - FROM REAL WORLD EVIDENCE TO CANADIAN HEALTH CARE NEEDS Session Chair: ...... 42 George A. Wells, MSc, PhD, University of Ottawa, and Cardiovascular Research Methods Centre, University of Ottawa Heart Institute Public Payer Perceptions of the Value of Real World Evidence ...... 42 Don Husereau, University of Ottawa, School of Epidemiology and Public Health Improving the Use of Real World Evidence in the Regulatory Environment: Where Are We Heading? ..... 43 Rhonda Kropp, Director General, Marketed Health Products Directorate, Health Products and Food Branch, Health Canada Canadian Network for Observational Drug Effect Studies: Using Real-World Evidence to Inform Regulatory Decisions ...... 44 Robert Platt, McGill University Health Centre Research Institute, Montreal, QC Life-Cycle HTA: Unlocking the Potential for Real World Evidence ...... 44 Tammy Clifford, Chief Scientist & Vice President, Evidence Standards, CADTH

SESSION 2B: PHARMACEUTICAL POTENTIAL OF STEM CELL & CRISPR-MEDIATED GENE MODIFICATIONS Stem Cell Activation to Promote Self-Repair of the Injured Nervous System ...... 46 Cindi M Morshead, PhD, Professor and Chair, Anatomy, Department of Surgery, Donnelly Centre, University of Toronto, Toronto, ON A Stemness-based Drug Screen to Target Acute Myeloid Leukemia Stem Cells ...... 46 Jean Wang MD PhD, Princess Margaret Cancer Centre, University Health Network Opening the Gate for Pluripotent Stem Cell-based Therapies ...... 47 Andras Nagy, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada Network Analysis of Cell Death Signaling Pathways via CRISPR-mediated Modification in Embryonic Stem Cells and Derivatives ...... 48 Jeffrey Henderson, Faculty of Pharmacy, University of Toronto, Toronto, Ontario Selected CSPS Trainee Abstract Oral Presentation Investigating the Role of the IKKβ Protein Kinase in Vascular Remodeling Events ...... 49 Francis Lefebvre, Université de Montréal

SESSION 2C: CSPT TRAINEE ORAL PRESENTATIONS ...... 49 Galen Wright, University of British Columbia Khaled Adb-Elrahman, Ottawa University Britt Drögemöller, University of British Columbia Anish Engineer, Western University

Translating Innovative Technology to Patient Care | 13s Elizabeth Greco, Western University Shrinidh Joshi, North Dakota State University Anette Surmanski, Western University Markus Gulilat, Western University Eliza McColl, University of Toronto Kamelia Mirdamadi, University of Toronto Tessa Bendyshe-Walton, University of British Columbia Jay Fang, Western University Pierre Thibeault, Western University Yong Jin (James) Lim, Western University

THURSDAY, MAY 24

PLENARY SESSION 3 The Fourth Pillar of Cancer Treatment: It Takes a Village ...... 50 Tak-Wah Mak, OC, PhD, DSc (Hons), FRSC, FRS, Ontario Cancer Institute, Princess Margaret Hospital, Toronto

SESSION 3A: IMMUNO-ONCOLOGY CAR Therapy: The CD19 Paradigm and Beyond ...... 51 Michel Sadelain, MD, PhD, Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA A Trans-Canada Highway for CAR-T Cells ...... 51 Brad Nelson, Ph.D., Distinguished Scientist and Director, Deeley Research Centre, Co-Director, Immunotherapy Program, BC Cancer, Victoria BC, Canada A New Generation CAR Containing a JAK–STAT Signaling Domain Mediates Superior Antitumor Effects . 52 Naoto Hirano, Princess Margaret Cancer Centre, University Health Network, Toronto, ON Immuno-Oncology Combinations in Clinical Development ...... 53 Lillian L. Siu, MD, BMO Chair in Precision Genomics, Professor of Medicine, Princess Margaret Cancer Centre, Toronto, Canada PANEL MEMBERS ...... 54 Jian Wang, MD, PhD, Biologics and Genetic Therapies Directorate, Health Canada Ismael Samudio, CDRD

SESSION 3B: THE GUT MICROBIOME AS A NOVEL THERAPEUTIC TARGET Overview of the Microbiome and its Potential Role in Therapeutics ...... 55 Michael G Surette, Interdisciplinary Microbiome Research, Farncombe Family Digestive Health Research Institute, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton ON Microbial Effects on Innate and Adaptive Immunity ...... 55 Kathy D. McCoy, University of Calgary

14s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

Fecal Microbial Transplants: Treatment of C. Difficile and Beyond ...... 56 Michael Silverman, Western University Unexplained Atherosclerosis and Metabolic Products of the Intestinal Microbiome ...... 56 J. David Spence M.D., Professor of Neurology and Clinical Pharmacology; Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute; Western University, London, Ontario

SESSION 3C: PRACTICAL PHARMACOLOGY: CASE STUDIES FROM ACROSS THE COUNTRY Clearing Up Controversies around Carfentanil ...... 58 Jessica L.S. Leen, MD, FRCPC, University of Toronto A Case of Unilateral Adrenal Adenoma with Resistant Hypertension ...... 58 Marc L Chretien, George K Dresser, Division of Clinical Pharmacology and Toxicology, Department of Medicine, Western University Improving Outcomes for Childhood Cancer Patients Using Genomics-Guided Treatment Optimization ... 59 Catrina M Loucks, Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada Choosing the Right Antihypertensives for your Pregnant Patient ...... 59 Albayada Medhar, Western University

CSPT CLINICAL FELLOWSHIP AWARD LECTURE Genetic Screening and Cannabis Induced-Psychosis: Who, What and When? ...... 60 Gavin Sun, Division of Clinical Pharmacology and Toxicology, Western University, London, ON CSPT POST-DOCTORAL AWARD LECTURE Pharmacogenomics for Neurological Conditions and Related Phenotypes ...... 60 Galen Wright, Canadian Pharmacogenomics Network for Drug Safety (CPNDS), University of British Columbia, Vancouver, BC

SESSION 4A: TRANSLATIONAL MEDICINE Opening Pandora’s Genome: Rethinking Molecular Diagnostics ...... 62 Aly Karsan, MD, FRCPC, Centre for Clinical Genomics, Genome Sciences Centre, British Columbia Cancer Agency, and Professor, Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC Biomarker Testing in Lung Cancer ...... 63 Ming S. Tsao, MD, FRCPC, Consultant Pathologist, University Health Network and Professor, Department of Laboratory Medicine and Pathobiology, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Tumor Mutational Burden as a Biomarker for Cancer Immunotherapy ...... 63 Caitlin Connelly, Ph.D., Scientist, Foundation Medicine, Cambridge, MA Molecular Diagnostic Advancement in Oncology ...... 64 Alan Spatz, McGill University, McGill University Health Center & Jewish General Hospital Panel for Discussion Janet Dancey (Panel & Session Co-Chair) ...... 65 Raffi Tonikian, Merck Canada ...... 66 Selected CSPS Oral Abstract Presentation Combining Statins with Radio-immunotherapy as a Novel Therapeutic Strategy for Colorectal Cancer .... 66 Vessie Vassileva, Imperial College London

Translating Innovative Technology to Patient Care | 15s

SESSION 4B: CANNABINOIDS Session Chair: ...... 67 Rachel Tyndale Therapeutic Potential of CB1 Allosteric Modulators ...... 67 1 1 2 1 1 1 Catharine A. Mielnik , Vincent M Lam , Iain R. Greig , Ali Salahpour , Amy J. Ramsey , Ruth A. Ross , 1University of Toronto, Faculty of Medicine, Department of Pharmacology & Toxicology; 2University of Aberdeen, UK, institute of Medical Sciences Growing up High: Long-Term Consequence of Adolescent Cannabis Use - Preclinical Studies...... 68 Jibran Khokhar, Assistant Professor, Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON Adolescent Cannabis Use: Risk for Mental Health and Drug Dependence ...... 69 Marcus Munafò, Professor of Biological Psychology, School of Experimental Psychology, University of Bristol Opioid Sparing Effects of Cannabinoids: Myth or Reality? ...... 69 Bernard Le Foll, Medical Head, CAMH; Professor University of Toronto

PANEL DISCUSSION: THE FUTURE OF MEDICAL CANNABIS IN CANADA ...... 70 PANEL MEMBERS Avicanna: Aras Azadian, President Beleave: Peter Chen, Vice President of Science and Technology CannTrust: Kaivan Talachian, Vice President, Professional Services University of Toronto: Lakshmi P. Kotra, B. Pharm.(Hons), Ph.D.

SESSION 4C: INNOVATIVE BIOMATERIALS FOR DRUG DELIVERY Trigger-Amplifying Self-Immolative Nanoparticles for Drug Delivery ...... 72 Elizabeth Gillies, Department of Chemistry, Department of Chemical and Biochemical Engineering, The University of Western Ontario, London, Canada Polymer-Based Protein Delivery Systems ...... 72 S. Thayumanavan, Department of Chemistry, University of Massachusetts, Amherst, MA Controlled-Release Nano-Therapeutics: The Status of Translation ...... 73 Subbu Venkatraman, School of Materials Science and Engineering, Nanyang Technological University; Singapore Biomimetic Nanoparticles for Targeted Drug Delivery and Detoxification ...... 74 Liangfang Zhang, Professor, Department of Nanoengineering and Moores Cancer Center, University of California San Diego Selected oral abstract presentation: Hyperthermia-mediated Drug Delivery Increases Cisplatin Sensitivity and Accumulation Resulting in improved Efficacy in Triple Negative Breast Cancer ...... 75 Michael Dunne, University of Toronto

16s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

FRIDAY, MAY 25

PLENARY SESSION 4 Pharmacogenomics: Clinical Implementation and Future Challenges ...... 76 Richard Weinshilboum, Professor of Pharmacology and Medicine and Dasburg Professor of Cancer Genomics Research, Mayo Clinic

SESSION 5A: PHARMACOGENOMIC IMPLEMENTATION Session Chair: ...... 77 Micheline Piquette-Miller PRIME: Implementing Pharmacogenomic Testing into Pharmacy Practice - Focus on Mental Health Pharmacotherapy ...... 77 Natalie Crown, Leslie Dan Faculty of Pharmacy, University of Toronto Clinical Pharmacogenomics Program in Pediatric Oncology: 257 Patients and Counting ...... 78 Bruce Carleton, PharmD, FISPE, Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia; Senior Clinician Scientist, BC Children’s Hospital Research Institute; Director, Pharmaceutical Outcomes Programme, BC Children’s Hospital, Vancouver, BC Clinical Utilization of Pharmacogenomic Testing – The Evolving Canadian Environment ...... 79 Christopher Trevors, MS, CGC National Director, Genetic Health Solutions, Dynacare Pharmacogenetics in the Benefits Arena – Baby Steps; Giant Opportunities ...... 79 Wayne Murphy, Prudent Benefits Administration Services Inc.

SESSION 5B: DRUG THERAPY IN CHILDREN Nephrotoxic Acute Kidney Injury in Hospitalized Children and Description of a National Cisplatin Pediatric Cohort ...... 81 Mike Zappitelli, The Hospital for Sick Children, Toronto Novel Approaches to Improving Pharmacotherapy in Epilepsy: Machine Learning and Human Organoids . 81 Peter L. Carlen MD, FRCPC; Krembil Research Institute; Toronto Western Hospital, University Health Network; Departments of Medicine (Neurology), Physiology, and IBBME, University of Toronto Vaccinating Children Against Pain and Fear ...... 82 Anna Taddio, University of Toronto CSPT Senior Investigator Award Addiction to Cocaine: How you Take the Drug is More Important than how Much ...... 83 Anne-Noël Samaha, PhD, Université de Montréal

Translating Innovative Technology to Patient Care | 17s POSTER SESSION 1 - CSPS AND CC-CRS WEDNESDAY, MAY 23

Biomedical Sciences

1. Wrinkled Microparticles as new Microcarriers for Cell Culture Applications in Vaccine Production . 85 2. S-Enantiomer of 19-Hydroxyeicosate-traenoic Acid Preferentially Protects Against Angiotensin II- Induced Cardiac Hypertrophy ...... 85 3. Potential Neuroprotective Effects of Wild Blueberries: A Pilot Study ...... 86 4. Alpha-2C Adrenergic Receptor Expression in Rat Caudal Arteries ...... 86 5. Upregulation of Reduced Folate Carrier (RFC) by Vitamin D Enhances Folate Uptake at the Blood- Brain Barrier (BBB) ...... 87 6. Examining the Cholesterol Synthetic Pathway in the Search for New Druggable Targets for Glioblastoma ...... 87 7. Role of Peroxisome Proliferator-activated Receptor-γ (PPARγ) in Regulating Inflammatory Signalling in Acute and Chronic Rodent Models of HIV-1 Associated Brain Inflammation ...... 88 8. Vascular Endothelial Growth Factor a Diagnostic Test for POEMS Syndrome ...... 89 9. Investigating the Role of the IKK Protein Kinase in Vascular Remodeling Events ...... 89 10. Quantitative and Qualitative Analysis of a Bioluminescent BRCA Deficient Model of Serous Ovarian Cancer ...... 90 11. Injectable, Covalently In Situ-Gelling Block Copolymers for the Improved Loading and Prolonged Release of Hydrophilic Drugs ...... 90 12. Using PD-1 Knockout Mice to Test the Potential of Green Tea Extract and (-)-epigallocatechin-3- gallate (EGCG) to Cause Idiosyncratic Drug-induced Liver Injury ...... 91 13. Combining Statins with Radioimmuno-therapy as a Novel Therapeutic Strategy for Colorectal Cancer . 91 14. Effect of Female Sex Hormones and Their Derivatives on Amyloid Beta Aggregation ...... 92

Clinical Sciences & Pharmacy Practice

15. Aspirin and Other Non-Steroidal Anti-Inflammatory Drugs Interactions: A Systematic Review ...... 92 16. Needs Assessment and Online Program for Physiotherapists in Alberta Regarding Physical Function and Drugs ...... 93 17. Nocturnal Hypoglycemia Associated with Bedtime Insulin Mixture Administration in Hospitalized Patients ...... 93

Drug Delivery and Pharmaceutical Technology

18. Cytotoxicity Profiles of Lanthanide Compounds within Human Kidney (HEK-293), Liver (HEPG2), and Osteoblast (HOb) Cells in addition to Murine Pre-osteoclast (RAW 264.7) Cells ...... 94 19. Preparation and Solidification of Esculetin Nanocrystal: Towards an Innovative Approach for Hyperuricemia ...... 95 20. Core-Shell Spray Dried Dry Powder Vaccines for Controlled Enteric Delivery ...... 95 21. Repetitive On-demand Drug Delivery by External Triggering of Injectable Magnetic Hydrogels Incorporated with Glass Transition (Tg) Switchable Nanoparticles ...... 96 22. Dynamic PEGylation Reduces the Viscosity of Concentrated Protein Solutions ...... 96 23. The Enhancement of the Poor Oral Bioavailability of Cefotaxime Sodium using Nano-mixed Micelles Formulation ...... 97 24. A Mucoadhesive Lipidic Delivery System of the Adjuvant Innate Defense Regulator (IDR)-1002 ...... 97 25. In vivo Wound Healing Effect of G-CSF Loaded Nanofiber/Nanoparticle Composite ...... 98 26. Segmented Intravaginal Ring for Dual Delivery of siRNA-encapsulated Nanoparticles and Hydroxychloroquine as a Prevention Strategy for HIV Infection ...... 98

18s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

27. Pharmacokinetics and Biodistribution of Traceable Poly(ethylene oxide)-block-poly(ester) Based Micellar Formulations of Diclofenac: The Effect of Poly(ester) Structure ...... 99 28. Development of Mycophenolate Mofetil (MMF) Immunosuppressant as Sustained Release Oral Nanoparticles ...... 100 29. Fluorescence De-quenching and Albumin-induced Fluorescence Enhancement Assays to Measure Liposomal Drug Release of Camptothecins and Protein Kinase Inhibitors ...... 100 30. Pilot Scale-up and Evaluation of Starch-based Spray Dried Microcapsules as Controlled Drug Delivery and Taste Masking Device ...... 101 31. Determination of the Effect of Patient Posture and Fasting State on Digital Pulse Wave Features using a Novel Computational Technique, Non Invasive Vascular Risk Prediction System (NIVAR), and Potential Application for Assessment of Raynaud Phenomenon ...... 101 32. Microemulsions: A Cure for All Ills? ...... 102 33. Development of Novel Polymeric Micellar DACHPt for Enhanced Platinum Based Chemotherapy in Colorectal Cancer ...... 102 34. Protein-triggered Sustained Release of FITC-dextran from Microspheres Modified with Aptamer- containing DNA Oligomers ...... 103 35. Effect of Synthesis Conditions on the Properties of Bone-Targeting Bisphosphonate- Conjugated Superparamagnetic Iron Oxide Nanoparticles (BP-SPIONs) ...... 104 36. Striking a Balance: Interactions of Pluronics and Gemini Surfactants for Gene Therapy Nanoparticles . 104 37. Modulating Physiochemical Properties of a Small Peptide Drug by Chemical Conjugation ...... 105 38. Application of Design of Experiments for Optimizing Critical Quality Attributes of Scored Controlled Released Tablet ...... 105 39. Bisphosphonate Drug Alveolar Bone Burden in Osteoporosis ...... 106

Pharmaceutical & Analytical Chemistry

40. Lipid based Liposomal Formulation of Phytosterols and Tocopherols into Functional Food ...... 106 41. The Quantitative Analysis of Titanium Dioxide in Commonly used Sunscreen Cosmetics by Ultraviolet-visible Spectroscopy ...... 107 42. FOXM1 Inhibitors: A Structural Activity Relationship Study ...... 107

Pharmacokinetics & Pharmacodynamics

43. Assessing Cardiovascular Toxicity of Doxorubicin and Isoproterenol by Hemodynamics and in vivo Catabolism of Adenosine 5-‘triphosphate ...... 108 44. Effects of Tacrolimus on Mycophenolic Acid Exposure in de novo, Steroid-Free Adult Kidney Transplant Patients ...... 108 45. Comparison of Population PK and Non-compartmental Analyses for Tailoring PK in Hemophilia A with Limited Sampling ...... 109 46. Impact of Inflammation on the Expression of Renal Drug Transporters in Pregnancy ...... 109 47. The Impact of Diet Induced Obesity on the Microsomal Glucuronidation of Propofol in Rats ...... 110

POSTER SESSION 1 - CSPT WEDNESDAY, MAY 23

48. Using the Wet Bridge Transfer System to Assess Exogenous Surfactant as a Pulmonary Drug Delivery Vehicle ...... 112 49. Gene Expression of Solute Carrier Transporters in Multidrug Resistant Breast Cancer Cells ...... 112 50. Gene-specific Epigenetic Modifications May Contribute to Postnatal Neurodevelopmental Deficits in OGG1 KO Mice Exposed to Ethanol in utero ...... 113 51. An Investigation into T-cell-mediated Drug Hypersensitivity Reactions ...... 113

Translating Innovative Technology to Patient Care | 19s 52. The Role of the Dopamine D3 Receptor in Alcohol Use Disorder ...... 114 53. BRCA1 Protects the Embryo from Oxidative DNA Damage in Brca1 Knockout Mice ...... 114 54. The Effects of War Stress on Pregnancy Outcomes During the Conflict in Tripoli, Libya ...... 115 55. Optimizing Chronic Hepatitis C Treatment in a Canadian Cohort ...... 115 56. Towards Reducing the Burden of Hepatitis C-related Complications through Genomics-guided Treatment Optimization ...... 116 57. Targeting Metabotropic Glutamate Receptor 5 (mGluR5) Ameliorates Huntington’s and Alzheimer’s Disease Pathology via Activating Conserved Mechanisms of Autophagy ...... 116 58. Aldehyde Dehydrogenase – A Real Pharmacogenomic and Toxicogenomic Crossroad ...... 117 59. Development and Implementation of Pharmacogenomic Risk Prediction Models in Pediatric Oncology . 118 60. Association of Nicotine Metabolism Ratio with [11C]-(+)-PHNO PET Binding in Tobacco Smokers .. 118 61. Careful Investigation of Pharmacogenomic Phenotypes to Uncover the Roles of ACYP2 and WFS1 in Cisplatin-induced Ototoxicity...... 119 62. Sapropterin Prevents Coronary Artery Malformations Induced by Pregestational Diabetes ...... 119 63. Expression of Hepatic Cytochrome P450 Drug-Metabolizing Enzymes in Diabetes and Diabetic Nephropathy ...... 120 64. The Effect of Maternal Nicotine Exposure on Fetal Heart Development ...... 120 65. 4-Beta Hydroxycholesterol as a Predictor of Observed Apixaban Plasma Concentration among Atrial Fibrillation Patients ...... 121

POSTER SESSION 2 - CSPS AND CC-CRS THURSDAY, MAY 24

Biomedical Sciences

66. Scavenger Receptor Class B Type I (SR-BI) Mediates the Cellular Uptake of CPX-351 into K562 Leukaemia Cells ...... 123 67. Effects of Diet-induced Diabetes on β-cell Specific Aryl Hydrocarbon Receptor Nuclear Translocator/Hypoxia-inducible Factor-1β (ARNT/HIF-1β) Knockout Mice ...... 123 68. Fluconazole Protects Against Angiotensin II-induced Cellular Hypertrophy through Inhibiting Cytochrome P450 1B1 and its Associated Arachidonic Acid Metabolites in the Heart ...... 124 69. Modeling the Dynamic Gating Mechanism and Small-molecule Binding in the CaV1.2 Channel ...... 124 70. Molecular Mechanisms of Mammalian Lignan Enterolactone in Modulating Cellular Lipid Homeostasis ...... 125 71. DOX-Vit D, A Novel Doxorubicin Derivative, Inhibits Human Osteosarcoma Cell Proliferation by Inducing Apoptosis while Inhibiting Akt and mTOR Signaling Pathways ...... 125 72. Loss of Cation Channels of the TRPC Family Protects against the Development of Diabetic Retinopathy in the STZ Model and Accumulation of Reactive Metabolites ...... 126 73. Effect of Polyphenols on Markers of Neurodegenerative Disease ...... 127 74. Macro- and Micro-fabrication of Chitosan Hydrogels with Anisotropic Pores for Biomedical Applications ...... 127 75. Apoptotic vs. Necroptotic Cell Death Analysis in an Endothelin-1 Model of Cerebral Ischemia ...... 128 76. Binge Drinking During Adolescence Causes Persistent Behavioral Impairments and Elevated Pro- Inflammatory Proteins in a Rodent Model ...... 128 77. Arginine and Glutamate Rich 1 Knockdown is Protective Against High-fat Diet Induced Obesity and Metabolic Dysfunction ...... 129

Clinical Sciences & Pharmacy Practice

78. Developing and Evaluating a Patient Decision Aid for Managing Surgical Menopause: The Story Behind the “SheEmpowers” Patient Decision Aid (PDA) ...... 129

20s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

79. Phytotherapy-induced Hepatocytotoxicity ...... 130 80. Modulation of the Tumor Microenvironment with Manganese Dioxide Nanoparticles to Re-educate Macrophages and Enhance Doxorubicin Efficacy ...... 131 81. Identification and Evaluation of the Prevalence of the Practice of Drugs and Opioids Abuse in Community Pharmacy ...... 131 82. Implementing Pharmacogenomics Testing in Paediatric Care ...... 132

Drug Delivery and Pharmaceutical Technology

83. Are Excipients Inert? Phenytoin: A Follow-up Half a Century Later with New Incompatibility Insights ...... 132 84. Transnasal Mucosal Delivery of Brain-Derived Neurotrophic Factor AntagoNATs in Rat Brain using Cationic Liposomal Formulation ...... 133 85. Engineering Functionalized Diamond Nanoparticles for Drug/Gene Delivery: Biodistribution Studies . 133 86. Additive Polyplexes as a Non-viral Delivery System for Combinational siRNA Therapy against CDC20 and Survivin in Breast Cancer and Non-malignant Cells ...... 134 87. Nano-sized Droplets of Self-Emulsifying System for Enhancing Oral Bioavailability of Etoposide in Rats ...... 135 88. Microwave Enhanced Protein Folding ...... 135 89. Phenylbutyrate Loaded Solid Lipid Nanoparticles could Improve Cognition in Alzheimer’s Disease Induced Animal Model ...... 136 90. Precise Orientation of Thermally-sensitive Biomolecules using DNA Nanostructures: An Exploration of Non-thermal Techniques for Controlling DNA Nanoassemblies ...... 136 91. Biomimetic Vector (BMVTM): An Innovative Skin Delivery System ...... 137 92. Photocleavable Hydrogel-Coated Upconverting Nanoparticles for On-Demand Drug Delivery of Ultra- small Gold-Doxorubicin Conjugates ...... 137 93. Hyperthermia-mediated Drug Delivery Increases Cisplatin Sensitivity and Accumulation Resulting in Improved Efficacy in Triple Negative Breast Cancer ...... 138 94. Liposomal Delivery of a Doxorubicin and Niraparib combination for the treatment of High Grade Serous Ovarian Cancer ...... 138 95. Stimuli-sensitive Theranostic Nanoparticles for Targeted Imaging-Guided Drug Delivery ...... 139 96. Optimization of a New pH-Responsive Pore Former for Controlled Release Coating ...... 139 97. Microemulsion-based System for Transdermal Drug Delivery of Methimazole in Cats ...... 140 98. Affinity Based Release of Protein Therapeutics to Treat Retinitis Pigmentosa ...... 140

Pharmaceutical and Analytical Chemistry

99. Investigating the Correlation between Miscibility and Physical Stability of Solid Phospholipid Dispersions Using Fluorescence-Based Techniques ...... 141 100. Use of Confocal Fluorescence Imaging Techniques to Understand Phase Separation Behaviour during Dissolution of Amorphous Solid Dispersions ...... 142 101. Investigation into the Factors Associated with Anesthetic Failure of Hyperbaric Bupivacaine, including the Potential Role of Cold Exposure on Bupivacaine Degradation ...... 142 102. Developing an Assay to Quantify Nuclear Receptors by Mass Spectrometry ...... 143

Pharmacokinetics and Pharmacodynamics

103. In silico, in vitro and in vivo Pharmaceutical Investigations of a Novel Skeletal Muscle Regenerator . 143 104. A Physiologically-based Approach to the Pharmacokinetics of Anti-TNF Agents in Pediatrics ...... 144 105. Correlating Protein Expression of Human Hepatic Uridine Diphosphate Glucuronosyltransferases (UGTs): Implications for UGT Protein Co-regulation ...... 144

Translating Innovative Technology to Patient Care | 21s 106. In silico Homology Modeling of Human UDP-glucuronosyltransferase 1A6 (UGT1A6) reveals new Insights into Structural Folding and Binding of Substrate and Co-substrate ...... 145 107. Role of Elevated sFLt-1 on the Regulation of Placental Transporters in Women with Pre-eclampsia 146

POSTER SESSION 2 - CSPT THURSDAY, MAY 24

108. Quantification of NSAIDs in Human Tissues with a Novel UHPLC/MS/MS Method ...... 148 109. Investigating the Mechanisms of Bile Acid-mediated Organ Toxicity in Ntcp (Slc10a1) Knockout Mice . 148 110. Genome-wide Association Study of Anthracycline-induced Cardiotoxicity in Adult Cancer Patients 149 111. Physician Feedback and Antibiotic Prescribing Patterns ...... 149 112. Safety of laninamivir Octanoate, a Neuraminidase Inhibitor, in Lactating Women with Influenza ... 150 113. Single Time Point Sampling for Assessment of Fexofenadine as an In Vivo Drug Transporter Probe 150 114. Development of a Novel Cellular Reporter Assay to Measure Anticholinergic Activity ...... 151 115. Swelling-induced Chloride Current in Glioblastoma Proliferation, Migration and Invasion ...... 151 116. Hypoxic Stimulation of Vasoreparative Functions in Human CD34+ Cells is Mediated by Angiotensin Converting Enzyme-2 and Mas Receptor ...... 152 117. Characterization of the Metabolome and Renal Tubular Cisplatin Disposition in Cisplatin Induced Acute Kidney Injury ...... 152 118. Viral Mimetic Imposes a Dysregulation of Nutrient and Neurotransmitter Transporter Expression in Rat Placenta ...... 153 119. Impact of MS-induced Systemic Pro-inflammatory Cytokines on the Regulation of Human Placental Transporters ...... 153 120. Low-dose, Low-fluctuation Dihydropyridine Concentrations as Delivered by Nifedipine- Extended-release Tablets Do not Perturb Heart Rate ...... 154 121. Identifying the role of G-Protein Signalling Modulator 3 in GPCR signalling ...... 154 122. Comparing Pharmacokinetics of All-trans Retinoic Acid Between Adults and Children with Acute Promyelocytic Leukemia ...... 155 123. Insights into PAR4 Signaling and Biased Agonism ...... 155 124. Pharmacogenomics of Vincristine-induced Peripheral Neuropathy Implicates Pharmacokinetic snd Inherited Neuropathy Genes ...... 156

INDEX ...... 157

22s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

Invited Speaker Abstracts & Bios

Translating Innovative Technology to Patient Care | 23s Tuesday, May 22 Industry Day: Innovation and Management of Modern Pharmaceuticals

PLENARY SESSION 1 Mary Haak-Frendscho, Blueline Bioscience

Chairs: Andrew Casey, BIOTECanada, and Christine Allen, University of Toronto

Mary Haak-Frendscho The View from Here: Innovation Canadian Style Mary is CEO of Blueline Bioscience in Toronto and a Venture Partner with Versant Ventures. Mary Haak-Frendscho, CEO, Blueline Bioscience; Previously, she established and served as Chairman and Venture Partner, Versant Ventures, Toronto of Compugen, Inc., was CEO and member of the Board at Igenica Biotherapeutics, Inc., and This presentation will provide an investor established and was President, Chief Scientific perspective on the Canadian innovation ecosystem, Officer and Board member of Takeda San Francisco. as seen through a US biotech lens. What we see, Mary began her industry career at Genentech, where filling the gaps and leveraging our unique strengths. she played a key role in the development of The talk will wrap up with a Q&A session. omalizumab (Xolair®) for the treatment of severe asthma and CIU.

Presentations

Research in Immunology and Cancer, Session Chair: Andrew Casey Commercialization of Research (IRICoR) • Director, Board of Directors, Arthritis Alliance Andrew Casey became president and CEO of of Canada (AAC) BIOTECanada in August, 2012. In his role as Prior to joining BIOTECanada, Andrew served President & CEO of BIOTECanada Andrew is from 2004-2012 as Vice President, Public Affairs responsible for the strategic operations of the and International Trade with the Forest Products Association representing Canada’s biotechnology Association of Canada (FPAC). From 1993-2004 he sector. As the head of BIOTECanada, he is the lead was the Assistant Vice-President, Government spokesperson for Canada's biotechnology industry Relations with the Canadian Life and Health communicating on the industry's behalf with Insurance Association. Between 1989 and 1993 government, regulators, international bodies, media Andrew worked on Parliament Hill as a political and the Canadian public. advisor in the office of the Federal Ministry of In his capacity as head of BIOTECanada Finance. Andrew also serves as: Andrew Casey is a native of Montreal, Quebec. • Director, Board of Directors, BIOTECanada After attending Loyola High School (Montreal) and • Vice Chair, International Council of St. Lawrence CEGEP (Quebec City) he graduated Biotechnology Associations (ICBA) from Carleton University (Ottawa) with degree in • Director, Board of Directors, Institute for Political Science.

24s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

MaRS Innovation: Modern Approaches to Raphael (Rafi) Hofstein Bridging the Valley of Death Dr. Hofstein joined MaRS Innovation in 2009 after past positions that include Scientific Director of Raphael (Rafi) Hofstein, President & CEO, MaRS Biotechnological Applications Ltd.; Manager R&D Innovation and Chief of Immunochemistry at the International Genetic Scientific Partnership; Scientific Director of MaRS Innovation (www.marsinnovation.com; the Israeli office of Ecogen Inc.; Vice President, @marsinnovation) is a leading provider of Business Development for Ecogen in Langhorne, commercialization services, early-stage funding, and Pa.; and President and CEO of Hadasit, the deal-brokering with industry and private investors. commercialization company of Hadassah, the largest As a member-based organization made up of 15 teaching hospital in Israel. member institutions, our mandate is to drive the Dr. Hofstein received his PhD and Master of commercialization of their most promising research Science degrees in Life Sciences and Chemistry breakthroughs. MaRS Innovation’s portfolio consists from the Weizmann Institute of Science in Rehovot, of early-stage assets and companies, and we leverage Israel. our deep expertise and experience to mature this portfolio via important global and strategic partnerships. With an active portfolio of more than JLABS @ Canada Catalyzing Innovation 40 companies which have raised in excess of $250M from global investors, and with the creation of more Allan Miranda, Johnson & Johnson Innovation, than 400 direct jobs, MaRS Innovation is truly a JLABS in Canada leader in the commercialization field. MaRS Innovation provides the important – and JLABS represents a new type of incubator in the unfortunately, most often non-existing – bridge Canadian ecosystem. Located in the heart of Toronto between initial concept development and the it provide emerging companies the opportunity to acceleration towards a more mature market-ready access state-of-the-art technology, venture capital state. Nascent scientific technologies have very few investors, unique programming and mentorship. This avenues of assistance in crossing the “valley of is all accomplished with a no-strings attached model death” – this is where we come in, by addressing this in that intellectual property rights are neither shared challenge through company creation and formation nor are there any rights of first refusals. Biotech of an ideal R&D platform that is attractive to entrepreneurs are afforded the opportunity to reach industry. their development milestones and grow their MaRS Innovation is finding novel ways to companies unfettered by ties to a larger corporate ensure a faster and more certain path to better entity. Increasing the number of biotechnology commercialization of these young scientific companies in Canada will have a benefit to the discoveries. By creating meaningful collaboration, economy by providing jobs and the next wave of locally and globally, with industry partners – such as cutting edge technologies. Ensuring these LAB150 with Evotec AG, and UTEST with technologies get to patients faster means that University of Toronto (www.lab150.com and biotechnology companies and regulators need to www.utest.to) to name but two examples of recent work together earlier in development to ensure partnerships – MaRS Innovation is laying the innovation, patient safety and value are adequately foundation to successfully launch start-up captured in clinical development programs. companies. To this end, we have developed a “Venture Builder” process as a means to attain Allan Miranda improved technology development, post ideation. As Head of Johnson & Johnson Innovation, JLABS Dr. Hofstein will discuss these and other novel in Canada, Allan is responsible for external and innovative commercialization initiatives engagement, innovation sourcing, company undertaken by MaRS Innovation as the organization onboarding, portfolio management, operational continues to find ways to navigate an ever- changing excellence, educational programming and P&L. He start-up landscape with the aim to bringing its catalyzes and supports the translation of science and member discoveries to market quickly and fruitfully. technology into valuable solutions for patients and consumers across the pharmaceutical, medical device, consumer and healthtech sectors.

Translating Innovative Technology to Patient Care | 25s

Allan joined the JLABS team from Janssen Network (UHN) and Dr. Christine Allen's Research Canada, where he has spent the last 12 years in Group (CARG) at the University of Toronto, positions of increasing responsibility in business Avicanna's team of expert scientists are studying the development, marketing and market access. His medical properties of cannabinoids and the potential most recent role was Therapeutic Lead Immunology benefits they may provide to specific indications. and Primary Care where he was responsible for Avicanna is also using its collaborative relationships market access strategy for a complex product to explore and develop advanced cannabinoid portfolio exceeding $1 billion. Allan started his formulations and delivery mechanisms. Finally, career at PARTEQ Innovations, the technology Avicanna is entering clinical development stage transfer arm of Queen's University at Kingston where several of their products will be undergoing where he was responsible for technology assessment human trials with some of the major hospitals and and new company start-up. He then moved to institutions across three countries. Avicanna is Paladin Labs, where he successfully completed uniquely positioned to address the current gaps in numerous in-licensing transactions for specialty the medical cannabis industry due to its rigorous pharmaceutical products for the Canadian market. evidence and scientific-based approach that bring Allan subsequently worked in business development rationally designed and clinical meaningfulness to for two early stage biotechnology companies in their cannabinoid products. Canada leading their business development and partnering initiatives prior to joining Janssen. Aras Azadian Allan received his Ph.D. in Neuropharmacology Aras is the chief executive officer and a co-founder from Queen's University at Kingston, Ontario and of Avicanna, and brings with him extensive senior his MBA from McGill University in Finance and management experience in the biotechnology and Strategy. financial sectors including his involvement in several successful start-ups. In addition to his international experience in corporate development Avicanna and Evidence Backed Delivery of his diverse roles included his position as the Medical Cannabis president of an investment corporation in the cannabis space and former COO of an oncology Aras Azadian, Chief Executive Officer and Co- company. Aras has degree in economics from York Founder, Avicanna, Toronto, ON University in Toronto and MBA from EADA Business School in Barcelona. With a strictly scientific and medical focus, Avicanna has optimized its vertically integrated value chain and has positioned itself for the future of Structure-Based and AI-Augmented Proteome the medical cannabis industry. This presentation will Screening for Drug Discovery take a brief look into Avicanna's four major divisions including i) the organic cultivation project Stephen MacKinnon, PhD, Director of Research and in Colombia; ii) the research and product Development, Cyclica Inc. development at JLABS @ Toronto and the University of Toronto; iii) the clinical development Cyclica has developed Ligand Express, an partnerships in Canada; Jamaica and Colombia, and innovative and patented AI-augmented platform that iv) Avicanna's commercial product offerings. efficiently screens small molecule drugs against the Avicanna's cultivation projects take advantage of the entire known proteome via cloud computing to optimal growing conditions of Santa Marta, determine on- and off-target protein-drug Colombia where selective breeding and genetic interactions thereby enabling in silico techniques are used to cultivate plants expressing polypharmacology. The platform is used by specific cannabinoids of varying proportions for medicinal chemists, biologists, drug screening medical purposes. The proprietary extraction and groups, and others to identify drug targets, to isolation processes used, result in purified natural investigate the mechanism of drug action, to and organic cannabinoids that are further prioritize leads, and to reposition / repurpose assets. characterized to pharmaceutical grade quality. In Ligand Express can securely incorporate proprietary collaboration with several leading research and structure- and bioassay data from clients to augment medical institutions including, the University Health findings that are generated using large public

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datasets. The company has recently developed a likely leave with some great advice and pearls of patented biophysical and AI-assisted Multi Targeted wisdom…whether you’re pursuing industry, Drug Discovery (MTDD) technology to generate academia, and most definitely the startup life. new chemical entities (NCE) in silico using a differential drug design strategy, and they have also Shawn H. Glinter developed structural pharmacogenomic (SPGx) For over 20 years, successful serial entrepreneur capabilities that enable the mapping of genetic Shawn Glinter has been in love with helping information onto protein structures, which will lead students, faculty & entrepreneurs with their startups to a better integration between genomics and drug and early stage company’s. His background reveals discovery. With developments such as MTDD and a vast experience and explains the passion he's SPGx Cyclica has evolved from a company with a shown as he has helped, advised, and worked with "proteome screening" technology into one with an over 9 dozen first time founders of startups and integrated network of technologies to support a mentored over 1000’s of companies. design --> screen --> personalize workflow based on Shawn’s career began in emergency medicine a foundation of polypharmacological profiling. and hospital administration (George Washington University Health System and MedStar Health in Stephen MacKinnon Washington, DC, and Vanderbilt University in Stephen received his PhD in Biochemistry from the Nashville, TN). University of Toronto, using structural Most recently, Shawn was a co-founder & CEO bioinformatics to study systemic trends in protein of a life sciences (water technology) company for an structures to reveal new mechanistic insights. At entity located in the USA, Canada, and Europe. In Cyclica, he designed and led the development of just over 3.5 years he successfully grew that computational proteome screening technologies. company from $600K to 11M (which eventually Stephen now oversees the prototype stages of new sold). Shawn is currently the Founder & CEO of the scientific computing solutions and partnered biotechnology startup Pendant Biosciences (formerly research projects using predictive informatics. Nanoferix) an advanced materials company developing innovative surface coating and drug delivery technologies using a unique, polymer-based From the Bench to the Board Room: The Things platform. Pendant is currently a Johnson & Johnson Nobody Tells You Innovations JLABS Company. Shawn recently received a Faculty appointment Shawn H. Glinter, Founder & CEO, Pendant at the University of Louisville, Schools of Medicine, Biosciences in the Department of Neurological Surgery, as the Director of Innovation & Entrepreneurship. Shawn You’re gonna want to hear this one! Come listen to is currently the Entrepreneur in Residence at Shawn Glinter, a successful serial entrepreneur in Belmont University and a Mentor in Residence at the healthcare, technology, and life sciences space. Vanderbilt University in Nashville, TN. Shawn has Shawn will share his journey that started over 20 spent the last 10 years as one of the Master Mentors years ago and the roller coaster ups & downs of at the Nashville Entrepreneur Center. He also a launching startups. You will hear Glinter share his mentors for the Life Science Tennessee Mentor current startup journey, the decision to launch the Program, the JumpStart Foundry, the Co.Lab business; along with some of the ‘crazy things’ that accelerator program in Chattanooga, and is a Master you never believe will happen. Mentor for Launch TN (a state wide accelerator Shawn will discuss his challenges as an program). entrepreneur, along with both the successes and Shawn is married to his wife Nicole and they hurdles that he and his team have encountered. have a 10-year-old boy, Jordan. “I love being a Dad, You’ll hear about the “Oh-Sh*t” moments of Husband, and Entrepreneur every day of my life.” starting a life science’s company and some of the current success that the company has achieved to date. It’s a jam packed 15-minutes, so come out and meet Shawn and learn more about the exciting times he’s pursuing with Pendant Biosciences. You’ll

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Navigating the Cannabis Pharma Space discovery. Her research specifically addresses the pharmacology of the endocannabinoid system and Melanie E.M. Kelly1 & Guy Chamberlain2 how cannabis and cannabinoids can modify disease. 1Panag Pharma Inc. Halifax, Nova Scotia and 2Tetra She has published more than 100 publications in the Bio-Pharm, Orleans, Ontario area of pharmacology, cannabinoids and the endocannabinoid system and holds several patents in Panag Pharma Inc. (Panag) was formed in 2014. The the area of cannabinoid drugs for therapeutic founders of Panag, all clinician researchers and management of disease. Professor Kelly has scientists, have built on their experience and participated in and developed curriculum in foundation in the cannabinoid space since the middle medicine and pharmacy at undergraduate and of the 90’s and leveraged that experience into a graduate levels as well as content for continuing series of innovative pharmaceutical products that fill medical education and postgraduate professional a niche in the chronic pain market. Current pain education. She contributes as an expert consultant to management therapies lack efficacy and safety and industry with regard to drug development in the have proved inadequate for treatment of chronic pain cannabis/cannabinoid space and in the development and neuropathic pain conditions. The emergence of of scientific material for public dissemination and cannabis-based research demonstrating efficacy in knowledge translation. Dr. Kelly’s recent work has chronic pain management and a changing regulatory focused on development of new therapies to environment have opened up significant alleviate pain and inflammation. As one of the opportunities to address this medical need. The goal founders of a small drug company based in Halifax, of Panag is to develop safe and effective products she is working to leverage research discoveries into for chronic pain and inflammation to a proof of Health Canada approved medicines for those concept stage and then licence to a qualified partner. suffering from chronic neurodegenerative diseases. An example of this is the current partnership between Panag and Tetra Bio-Pharma (Tetra), the Guy Chamberland licensing partner for Panag’s topical and ocular Dr. Guy Chamberland, M.Sc., Ph.D., M.H., has been cannabinoid pain products. In the Panag-Tetra Chief Scientific Officer & Regulatory Affairs of partnership, Tetra provides non-dilutive funds to Tetra Bio-Pharma since June 2016. He has been develop the licensed drugs to proof of concept and a Vice President of Regulatory Affairs & Product commitment to cover costs tor each Development at Biotanika Health Group Inc. since commercialization. Importantly, Tetra brings a team March 2007. He served as Vice President of Clinical of people who know the regulatory space extremely & Regulatory Affairs at Victhom Laboratory Inc. well and understand the ability to work with from 2005 to 2007. He developed a specialty in regulatory agencies. This presentation examines how regulatory affairs (drugs, biologics, medical device, partnerships between academic start-up drug combination products, botanicals). He works closely companies and industry partners can pool with physicians and naturopathic physicians in these complimentary expertise to exploit current clinical areas. He spent 6 years as the Co-Chair and regulatory and market opportunities in the member of Health Canada's Expert Advisory development of cannabinoid drugs for areas of Committee for Veterinary Natural Health Products medical need. and Low Risk VHP. He was the Program Director of MDS Pharma Services. Dr. Chamberland has over Melanie Kelly 10 years experience in the development of clinical Dr. Melanie Kelly is Professor of Pharmacology, research protocols for botanical medicines and the Ophthalmology & Visual Sciences, Anesthesia, management of these clinical studies in the areas of Perioperative Medicine and Pain Management, anxiety, sleep, pain, depression, inflammation and Dalhousie University, Nova Scotia, Canada. wound healing. He has over 23 years’ experience in Professor Kelly is also the Executive Director of the the development of new drugs in the pharmaceutical International Cannabinoid Research Society, a industry (Canada and USA). He was a member of Canadian Consortium for the Investigation of the Investment Committee of Fonds Bionovation for Cannabinoids Board Member and Director and Chief 7 years. Since 2007, Dr. Chamberland developed an Scientific Officer, Panag Pharma Inc. Halifax, Nova expertise in the development of botanical medicines. Scotia, Canada. Dr. Kelly’s primary research expertise is in translational pharmacology and drug

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Phytoglycogen Nanoparticles in Nanomedicine: generated at sizes greater than 500 Da without Novel Delivery, Anti-infective and Immuno- compromising properties including permeability and modulatory Agents oral bioavailability. Dr. Coull will discuss the emergence of this new technology and how Encycle John Dutcher, Founder, Mirexus Biotechnologies/ is applying it to challenging protein targets. Glysantis Jeffrey Coull Dr. Jeffrey Coull is the President and CEO at Phytoglycogen is a highly branched polymer of Encycle Therapeutics. Prior to holding this position, glucose that is produced in the form of dense, he was head of operations at the Ontario Brain monodisperse nanoparticles by some varieties of Institute, and before this, held the position of plants such as sweet corn. Its special tree-like or President and CEO at Chlorion Pharma. He is dendrimeric structure combined with its natural, safe trained as a pharmacologist and has made significant profile make the particles highly desirable for contributions to the field of pain neuroscience. applications involving the human body, such as personal care, nutrition and biomedicine. I will describe promising results for the use of the Targeting the Cancer Cell Secretome to NanoDendrix technology as novel delivery, anti- Overcome Tumor Heterogeneity infective and immunomodulatory agents, and our journey from the initial serendipitous discovery of Anton Neschadim, PhD MBA, CEO, the particles to the commercialization of this natural, ImmunoBiochem Corporation sustainable nanotechnology in our Guelph-based spinoff companies Mirexus Biotechnologies and Surface-expressed tumor targets tend to have Glysantis. distributed and heterogeneous expression in solid tumors, subject to both intra-patient and inter-patient John Dutcher heterogeneity. This heterogeneity is limiting the John Dutcher is the Senior Canada Research Chair in efficacy of targeted biologics and leading to rapid Soft Matter & Biological Physics at the University generation of resistance. In contrast, the tumor of Guelph and a Fellow of the American Physical microenvironment is a rich, under-explored source Society. He has held leadership roles at the of tumor targets that are present in various solid University of Guelph (Director, Centre for Food and tumors more consistently and homogenously than Soft Materials; Director, Nanoscience Program) and surface-expressed targets. Of particular interest to in the national Networks of Centres of Excellence ImmunoBiochem are targets that are amplified in (Theme Leader, Advanced Foods and Materials tumor cell secretomes. The endosomal-lysosomal Network). He is a Founder of Mirexus system of cancer cells undergoes striking changes on Biotechnologies and its biomedical subsidiary transformation, such as failure by cancer cells to Glysantis, which are commercializing a natural, properly organize their intracellular compartment sustainable nanotechnology for use in personal care, and acidify lysosomes. These changes underlie nutrition and biomedical applications. For the tumor progression and metastasis in advanced development of this technology, he received the cancers. As a result, the secretomes of cancer cells 2017 University of Guelph Innovation of the Year are often enriched in proteins and protein variants award. that are only found in the tumor microenvironment and are distributed homogenously throughout the tumor mass. They are also interacting with various Nacellins: New Therapeutic Entities for components of the tumor microenvironment in Challenging Targets addition to the tumor cells, including tumor- supporting stroma and tumor-infiltrating Jeffrey Coull, President and CEO, Encycle macrophages. These secretome-based proteins Therapeutics engender a novel class of selective tumor targets that could be leveraged to eradicate tumors with Encycle Therapeutics is a Toronto-based drug potentiated biological therapeutics, such as the discovery company exploiting a proprietary highly potent antibody-drug conjugates (ADCs). chemistry to synthesize more drug-like peptide ImmunoBiochem’s novel therapeutics are tumor- macrocycles. These so-called “nacellins” can be microenvironment-targeted armed antibodies

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capable of targeting many different solid tumors and Improving Immune Responses to Cancer are not constrained by the expression of the target on Antigens Using a Nanoparticle Formulation that cancer cells like conventional antibodies and ADC Targets Lymph Node Cells therapeutics. They have highly selective activity in vitro and in vivo, damaging tumors but sparing Genevieve Weir, Director of Research, IMV Inc. normal, healthy tissues, and are capable of addressing the challenge of inherit and acquired IMV Inc. has developed a novel lipid in oil based tumor heterogeneity in cancer therapy. delivery platform that can specifically target immune cells. This technology, called DPX, has been used to Anton Neschadim develop DPX-Survivac, which contains short Anton is a biomedical professional, scientist, peptide epitopes derived from the tumour associated innovator, entrepreneur and venture capitalist with antigen survivin. Treatment with DPX-Survivac 15 years of industry and academic experience in results in robust and sustained T cell responses in research and drug development. At ImmunoBiochem ovarian cancer patients. DPX-Survivac is being Corporation, Anton is leading the development of a evaluated in Phase 1 and 2 clinical trials in new class of tumor microenvironment-targeted anti- combination with other immune modulating agents, cancer therapeutics. Anton was formerly the such as Incyte’s IDO inhibitor (epacadostat) and Director of Drug Development at Armour Merck’s anti-PD-1 (pembolizumab). Based on Therapeutics Inc., a biopharmaceutical company preclinical testing, these combinations have the developing a new class of anti-cancer therapeutics potential to improve patient outcome by for prostate, breast and ovarian cancers. Throughout programming the immune system and activating a his career, Anton worked on R&D and consulting targeted T cell mediated immune response towards projects with several biopharmaceutical companies the tumour. The unique mechanism of action of developing biological therapeutics and DPX has been explored using magnetic resonance immunotherapies in oncology. Anton has expertise imaging (MRI) to monitor the clearance of various in cancer research, immunology, chemistry, components of the treatment which can be labeled regenerative medicine and gene therapy, and with SPIO. This work has shown that DPX does not authored more than 25 peer-reviewed publications support passive release of components in the and patents. formulation, rather they are held at the site of Anton obtained his PhD, MSc, and Hon. BSc injection and actively removed up by immune cells, degrees in medical biophysics, immunology, and which bring them directly to the lymph nodes. biological chemistry at the University of Toronto, Ultimately this results in potent T cell activation and where he also completed postdoctoral work and his infiltration of tumours with these T cells. This has MBA at the Rotman School of Management. Anton been recognized as a key step for successful immune is also a graduate of the CIHR Training Program in therapy of cancer, and is complimentary to many Regenerative Medicine (TPRM), Toronto General other forms of immune therapies. Hospital, University Health Network. Anton was a founding board member, and former CCO and Genevieve Weir organizing committee member of the Canadian Genevieve Weir, PhD, is the Director of Research at Science Policy Centre (Toronto, ON) – a national IMV Inc. and has been with the company for 12 organization promoting science policy in Canada. years. Dr. Weir oversees translational research activities at IMV, bringing discoveries from concept to clinical development. She works closely with the Product Development and Clinical teams at IMV to conduct translational research. Her work involves developing new models and assays, preclinical testing of treatments, evaluation of immune responses in preclinical and clinical testing. Dr. Weir received her PhD from Dalhousie University in Microbiology and Immunology, and she has co- authored several patents and publications through her work with IMV.

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Wednesday, May 23 Trainee Breakfast

Chair: Nana Lee, University of Toronto

over 1000 students, faculty and industry Creating Your Career Path with your Grad professionals with her GPD curriculum-embedded Degree course featured in Science Careers, the National Post, Conference Board of Canada, and the Council Nana Lee, PhD, Director and Lecturer of Graduate of Graduate Schools. Professional Development, Departments of Biochemistry and Immunology, Lead Coordinator, Nana Lee Faculty Development Program, Graduate Life and Dr. Nana Lee holds a PhD from U of Toronto, a Science Education, Faculty of Medicine, University visiting scholar experience from MIT, and a of Toronto postdoctoral fellowship from the University of Michigan. She brings her years of experience and How do you develop core competency skills during expertise from the biotech industry (Ellipsis graduate school which empower you to be market- Biotherapeutics, DNA Software) into the classroom ready? with her internationally recognized (Science Careers, How do you find the hidden job market? Council of Graduate Schools\NSF, Conference How do you strengthen strategic communications to Board of Canada) graduate-level professional create the job? development curriculum-embedded course in the These are the highlights of this trainee workshop, led Departments of Biochemistry and Immunology. She by the internationally recognized Dr. Nana Lee, has spoken to over 1000 students, postdocs, faculty Director of Graduate Professional Development and curriculum administrators in empowering (GPD) programs at the Departments of trainees to be market-ready for any career. Biochemistry, Immunology, and Faculty of Medicine, University of Toronto. She has spoken to

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Wednesday, May 23 PLENARY SESSION 2 David Juurlink¸ Sunnybrook Health Sciences Centre

Chair: Tuan Trang, University of Calgary

David Juurlink The North American Opioid Crisis from 30,000 Dr. Juurlink is the Eaton Scholar and Professor of Feet Medicine, Pediatrics and Health Policy at the University of Toronto. He is head of the Division of David Juurlink, Sunnybrook Health Sciences Centre Clinical Pharmacology and Toxicology at both Sunnybrook Health Sciences Centre and University Objectives: of Toronto, and a medical toxicologist at the Ontario  To review the genesis and recent evolution of Poison Centre. He is also a senior scientist at the the opioid crisis Institute for Clinical Evaluative Sciences, where he  To discuss its current scope maintains an active research program in the field of  To review ways in which the crisis might be drug safety. mitigated

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Wednesday, May 23 SESSION 1A: Opioid Crisis

Chair: David Juurlink, Sunnybrook Health Sciences Centre

Michael’s Hospital and the Institute for Clinical Opioid Use and Adverse Events: Emerging Evaluative Sciences and an assistant professor at the Trends and Policy Impacts University of Toronto. Her research is focused on pharmacoepidemiology, drug safety and drug policy Tara Gomes, St. Michael’s Hospital research leveraging large, administrative databases, and she has published over 125 peer-reviewed Canada and the United States have the highest articles and over 50 policy reports in this area. prescription opioid consumption per capita in the Dr. Gomes has worked closely with the Ontario world, which has been attributed to widespread Ministry of Health and Long-Term Care and the overprescribing of this class of medications for Canadian Network for Observational Drug Effect decades. In parallel with increasing opioid Studies (CNODES) to develop evidence to inform prescribing, rates of opioid-related overdoses have policies related to opioid use and abuse in Ontario climbed across North America, leading to many and more broadly across Canada. She has also characterizing the opioid-related harms as the most served as an expert for the US Food and Drug important public health issue of our time. In 2017, it Administration and the US Department of is anticipated that there will be more than 4000 Transportation in discussions related to opioid opioid-related deaths in Canada; however, as policy policies and regulations. In 2014, the ODPRN was and clinical response to this issue has evolved over awarded the Institute for Public Administration of the past decade, so have the drivers of this epidemic. Canada’s Bronze Public Sector Leadership Award in In particular, as prescription opioids become more Health and Education. difficult to access, several provinces across Canada have demonstrated rising rates of fatal overdoses from illicitly manufactured opioids, such as fentanyl Pharmacological Strategies for Harm Reduction and its analogues. This presentation will review in Opioid Use Disorder: An Overview patterns of opioid prescribing and related harms across Ontario, and will speak to the impacts of Jessica L.S. Leen, MD, FRCPC, University of recently introduced policies designed to address this Toronto issue, focusing both on intended and unintended consequences. Finally, the implications of the This talk will provide a brief overview of the shifting opioid environment will be discussed, along pharmacologic harm reduction strategies currently with suggestions for how future policies and used in the management of opioid use disorder. responses to this issue can be designed to effect These include, but are not limited to, opioid agonist positive change. therapies (methadone, buprenorphine, sustained release oral morphine, intravenous prescription Tara Gomes grade heroin and hydromorphone) and opioid Dr. Tara Gomes is an epidemiologist and Principal antagonists (naloxone and naltrexone). Other Investigator of the Ontario Drug Policy Research objectives include reviewing basic harm reduction Network (ODPRN), a provincial network of principles and the neurobiologic model of addiction. researchers with expertise in pharmaceutical Attendees will develop a working knowledge and utilization, outcomes and policy who rapidly understanding of the key pharmacological principles conduct research for drug decision-makers in supporting these strategies. Ontario and across Canada. She is also a Scientist in the Li Ka Shing Knowledge Institute of St.

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Jessica L.S. Leen and has taken further post-graduate training at Jessica L S Leen is a Royal College of Physicians Oxford University, and the University of and Surgeons of Canada certified general internist Washington. who completed her core training and medical school at the University of Toronto. She is currently completing her final year of her internal medicine HPFB Activities in Support of the Federal Action subspecialty fellowship in Clinical Pharmacology on Opioids and Toxicology. Her areas of focused interest include addiction medicine, specifically opioid Emma Spreekmeester, PhD., Manager / Health substitution therapies, therapeutic use of Products and Food Branch, Health Canada cannabinoids as opioid-sparing agents, and adverse drug reactions. Her career goals include improving The growing number of overdoses and deaths caused the care of the patient with addictions and promoting by opioids is a national public health crisis. The the value of clinical pharmacology in the opioid crisis can be linked to the rapid rise in rates of community. drug overdoses and death involving both prescription opioids and increasingly toxic illegal drugs due to the increased presence of powerful Nudges, Pushes, Policy and St Francis: illegal substances, such as fentanyl, a drug 50-100 Perspectives on the Opioid Crisis times more potent than morphine. The Federal Minister of Health has made addressing this crisis a Shawn Bugden, Memorial University of top priority. This is a complex health and social Newfoundland / University of Manitoba issue that needs a response that is comprehensive, compassionate and evidence-based. Health Canada The opioid crisis rightly dominates the headlines as is working with provinces, territories and other clinicians, policy makers and politicians all struggle partners across the country to take a collaborative to find solutions. Linked administrative databases approach to the crisis. Under the ‘Joint Statement of give us the ability to assess aspects of the impact Action to Address the Opioid Crisis’, Health Canada policy changes on opioid prescribing. This committed to take new action across the Health presentation will review impact of a variety of policy Portfolio related to prevention, treatment, harm changes and the apparent impact on practice in reduction and enforcement measures, all supported Manitoba. Manitoba has had one of the most by a strong evidence base. regulated opioid prescribing environments in the country for more than 20 years. Consideration will Emma Spreekmeester be given to the impact of tamper resistant products Emma Spreekmeester is the manager of the Central policy, exempted codeine products policy, drug Nervous System Division 1 (CNSD1) at the safety warnings and opioid guidelines. Perhaps Therapeutic Products Directorate (TPD) of Health there is some positive news to share, as we continue Canada. She joined Health Canada in 2005 and to address this dire crisis. worked as a drug reviewer until 2014, when she assumed the manager position in the CNS Division. Shawn Bugden During her career at Health Canada, Emma has Shawn is Dean of the School of Pharmacy at participated actively on several internal regulatory Memorial University of Newfoundland. He is a committees, addressing topics such as Women in recent transplant from the Rady Faculty of Health Clinical Trials, Orphan Drugs, the Importation of Sciences at the University of Manitoba where he Drugs for an Urgent Public Health Need and various taught ethics, biostatistics and critical appraisal. His aspects of Health Canada’s Opioid Action Plan. research focusses on drug evaluation, evidence- Emma completed both her Ph.D. in Neurology and based healthcare, pharmacoeconomics and Neurosurgery and her M.Sc. in Psychiatry at McGill pharmacoepidemiology. Shawn is a graduate of the University, in Montreal, Quebec. College of Pharmacy at the University of Manitoba

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Wednesday, May 23 SESSION 1B: Regulatory Reforms

Co-Chairs: Catherine Parker, Health Canada

Improving Access to Innovative Medicines: Catherine Parker Health Canada’s Regulatory Reform Initiative Catherine Parker was appointed Director General of the Biologics and Genetic Therapies Directorate Catherine Parker, Director General, Biologics and (BGTD) of the Health Canada in June 2015. Ms. Genetic Therapies Directorate, Health Canada Parker was previously the Director of its Office of Policy and International Collaboration where she In 2016, Canadian provincial, territorial and federal played a key role in the development of several health ministers committed to work together to major regulatory initiatives. improve the affordability, accessibility and appropriate use of prescription drugs. The government commitment to improving drug access CADTH in 2018: Crossroads, Inflection Points, has been reinforced by significant funding in the and Partnerships 2017 federal budget to Health Canada (the federal drug regulator), the Canadian Agency for Drugs and Heather Logan, Vice-President, Pharmaceutical Technologies in Health (a health technology Reviews (Acting), Canadian Agency for Drugs and assessment organization), and the Patented Technologies in Health (CADTH) Medicines Price Review Board (which ensures that prices on patented medicines are not excessive). Part [Abstract not available] of this investment is driving a large-scale Health Canada transformation over the next five years of Heather Logan how the various systems and players work together Heather Logan is CADTH’s Vice-President, to bring therapeutic products to market. Pharmaceutical Reviews (Acting), with This initiative, called the Regulatory Review of responsibility for the CADTH Common Drug Drugs and Devices (R2D2), consists of regulatory Review, the pan-Canadian Oncology Drug Review, and policy changes to improve timely access to safe therapeutic class reviews, and optimal use projects, drugs for patients, including accelerated market as well as drug-related Environmental Scans, access to innovative technologies coming to market. Horizon Scans, and Rapid Response. Heather and R2D2 began in 2017, and a variety of projects her team deliver high-quality, relevant, and timely attacking the problem of drug access have been assessments of drugs using the best available developed, under the pillars of expanded science, tools, and methodologies. collaboration with health partners, more timely With more than 20 years of experience working availability of drugs and devices, and enhanced use with local, provincial, national decision-makers, she of real world evidence. Expected outcomes of this is known for her facilitative leadership style and for initiative include agile regulatory pathways that being results-driven. With a background as a support the drugs needed most by the healthcare Nursing Officer in the Canadian Armed Forces, a system coming to market, better alignment and health care administrator, and a systems leader, she partnerships between the various players involved in brings a unique and collaborative perspective. bringing therapeutic products into the healthcare Heather is married with two children. She has a system and better support for the health needs of Bachelor of Science in Nursing and a Masters of Canadians. An overview of the R2D2 projects, Health Science from the University of Toronto. future directions, and progress made to date will be provided.

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PMPRB Framework Modernization 2010 Vancouver Winter Olympics. In 2009, Doug joined the Competition Bureau as Assistant Deputy Douglas Clark, Executive Director of Patented Commissioner, Civil Matters, where he led a number Medicine Prices Review Board of high profile prosecutions under the Competition Act. Patented drug prices in Canada are among the Doug became Executive Director of the PMPRB highest in the world and per capita spending on in October 2013. prescription drugs is second only to the United States. In addition, an influx in very high cost drugs is driving growth in pharmaceutical spending at Panel Discussion: Panel Members alarming rates. Over the past decade, the average annual cost of the top ten selling drugs in Canada Ed Dybka increased by over 1500% and the number of drugs Ed Dybka is the President of QIV Capital with annual per-patient treatment costs of at least Management working with the biopharmaceutical $10,000 leapt from 20 to 135. Fully 25% of public industry, academia and government. Previously he and private insurer spending is allocated to these was President & CEO of AstraZeneca Canada Inc., drugs, which cover only 1% of beneficiaries. part of AstraZeneca PLC, one of the world’s leading Excessive pharmaceutical spending can limit biopharmaceutical companies. access to innovative drugs by straining the budget Mr. Dybka has worked in the Canadian envelope of public and private insurers, place a pharmaceutical industry for over 30 years. In 2012, financial burden on those who pay out of pocket for he led the Canadian establishment of Almirall their medicines, and mean fewer resources for other Canada Inc., a start-up biopharmaceutical company critical areas of the health care system. As part of the focused on the treatment of respiratory diseases. federal government’s commitment to improve the Prior to establishing Almirall in Canada, Mr. affordability of prescription drugs in Canada, it is Dybka held a number of executive roles at advancing major reforms to the Patented Medicine GlaxoSmithKline Canada including Vice Prices Review Board (PMPRB) a federal regulator President of Marketing, Sales and Public Affairs & that protects consumers from excessively priced Reimbursement. During this time, he was patented drugs These reforms would enable the accountable for the marketing and sales of all GSK PMPRB to benchmark Canadian prices to a less pharmaceutical products, including specialty care, expensive grouping of OECD member countries and oncology and vaccines, achieving strong commercial consider value (cost effectiveness) and affordability performance and employee engagement. Earlier in (market size) when setting ceiling prices for new his career, Mr. Dybka held progressively senior roles patented drugs in Canada. in product management and product development, as well as sales, at Glaxo Wellcome Canada Inc. and Douglas Clark Zeneca Pharma Inc. Doug has a background in international trade law, Mr. Dybka is currently Co-Chair of Life intellectual property policy, competition law Sciences Ontario, a Director of Clinical Trials enforcement and pharmaceutical pricing and Ontario and he is also the Chair of the Acute reimbursement. Coronary Treatment (ACT) Foundation. He is a Doug attended McGill University, the current member of the Life Science Working Group University of New Brunswick and l'Université de advising the Ministry of Research & Innovation for Moncton. He obtained his law degree in1997 and the Province of Ontario on it’s Life Sciences was called to the Ontario Bar in 1999 after a Economic Strategy. He is also a member of the clerkship with the Federal Court of Appeal. Health/Biosciences Economic Strategy Table for the In 2000, Doug was hired by the federal Federal Ministry of Health and Ministry of government to help defend against two WTO Innovation, Science and Economic Development. challenges to Canada’s drug patent regime. In 2006, He has served on a number of other Boards he became Director of Patent and Trademark Policy including Innovative Medicines Canada, the at Industry Canada where he was responsible for Pharmaceutical Advertising and Advisory Board, the Canada’s Access to Medicines Regime, changes to Canadian Pharmaceutical Distribution Network, The the Patented Medicines (Notice of Compliance) Mississauga Board of Trade and The George Hull Regulations and special trademark legislation for the Centre for Children and Family.

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Durhane Wong-Rieger Technology Assessment International Patient Durhane Wong-Rieger, PHD, is President & CEO of /Citizen Involvement Interest Group. She is a the Canadian Organization for Rare Disorders (the certified Health Coach and licensed T-Trainer with umbrella organization of patients and patient groups) the Stanford-based Living A Healthy Life with and chair of the Consumer Advocare Network (a Chronic Conditions. national network for patient engagement in Dr. Wong-Rieger has served on numerous health healthcare policy and advocacy). She is also policy advisory committees and panels and is a President & CEO of the Institute for Optimizing member of the Ontario’s Rare Disease Health Outcomes (providing training and direct Implementation Working Group, member of service on health coaching and patient self- Genome Canada Steering Committee for the Rare management) and Chair of the Canadian Heart Disease Precision Health Initiative and member of Patient Network. Internationally, Durhane is Chair the Patient Liaison Forum for the Canadian Drugs of Rare Disease International (the global alliance of and Technologies in Health. rare disease patient organizations), Past-Chair of the Durhane has a PhD in psychology from McGill International Alliance of Patient Organizations, University and was professor at the University of member of the Editorial Board of The Patient- Windsor, Canada from 1984-1999. She is married Patient Centred Outcomes Research, member of the and has two children. She is a trainer and frequent Global Commission to End the Diagnosis Odyssey lecturer and author of three books and many articles. for Rare Diseases and member of Health

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Wednesday, May 23 SESSION 1C: Crossing Biological Membranes

Co-Chairs: Emmanuel Ho, University of Waterloo, and Kerry Goralski, Dalhousie University

where drug is allowed to fully equilibrate across the Improving Predictions of Renal Anionic Drug plasma membrane prior to performing saturation Transport kinetic studies. The kinetic constants from the zero- trans and equilibrium exchange experiments were Ryan M. Pelis, PhD, Associate Professor, then input into the Mechanistic Kidney model within Department of Pharmacology, Dalhousie University the Simcyp Simulator for PK predictions. Our data show that there is a significant effect of time on Jmax, The kidney is important for eliminating from the Km and IC50 values, and that the time chosen body a structurally diverse array of small molecular profoundly influences PK and DDI predictions at weight drugs that carry a net negative charge at OAT1 by PBPK modeling. physiological pH, i.e., anionic drugs. The renal elimination of anionic drugs is accomplished in part Ryan M. Pelis by tubular secretion mediated by organic anion The Pelis laboratory studies drug transport transporters. My laboratory is focused on using in energetics and how it influences tissue drug vitro transport kinetic data and physiologically- concentration-time profiles – i.e., pharmacokinetics. based pharmacokinetic (PBPK) modeling to predict His major research focus is on using in vitro drug the involvement of renal organic anion transporters transporter kinetics and physiologically-based in drug disposition and drug-drug interactions. One pharmacokinetic (PBPK) modeling to predict drug major hurdle in generating accurate PK predictions concentration-time profiles. With in vitro data and with PBPK modeling is the generation of PBPK modeling we are moving toward predicting physiologically-relevant transport kinetic constants interindividual variability in drug exposure and in vitro. Much of our recent work has focused on response due to factors such as disease, genetics and studying ligand interactions with the organic anion drug-drug interactions. This information is essential transporter 1 (OAT1), an anionic drug uptake for the clinical registration of investigational drugs transporter expressed at the basolateral membrane of with the major pharmaceutical regulatory agencies renal proximal tubule cells. Here I will discuss our (FDA & EMA). With this information we will help recent studies that aim to find the most make more cost-effective and safer pharmaceutical physiologically-relevant condition in vitro for therapies for individualized medicine. accurate PK predictions with OAT1 by PBPK Dr. Pelis graduated from the University of modeling. The first kinetic studies that I will Massachusetts with a Bachelor of Science in Animal describe are those conducted under ‘zero-trans’ (i.e., Science and a Master of Science in Biology. He ‘sink’) conditions, where upon initiation of transport received his Ph.D. in Physiology and Neurobiology the concentration of substrate inside of the cells is from the University of Connecticut and completed zero. Saturation kinetic studies were performed at his Postdoctoral Fellowship in the Department of various time-points, from initial-rate to steady-state, Physiology at the University of Arizona. Much of to examine the influence of time on the kinetic his training was spent with the US Geological constants, maximal transport rate (Jmax) and Survey (Turners Falls, MA) and the Mount Desert Michaelis constant (Km). We also performed Island Biological Laboratory (Bar Harbor, ME). inhibition studies at various incubation times under From 2009-2012 Ryan was a Senior Investigator and zero-trans conditions to determine the effect of time Laboratory Head in the Drug-Drug Interactions on inhibition potency (IC50 determination). The Section in the Department of Drug Metabolism and second set of studies that will be described are those Pharmacokinetics at the Novartis Institutes for conducted under ‘equilibrium exchange’ conditions, Biomedical Research in East Hanover, NJ. At

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Novartis he managed an in vitro drug metabolism self-assembling systems. While self-assembly is a and drug transport laboratory whose purpose was to readily recognized tool in the design of systems for support Investigational New Drug Applications drug delivery applications, the use of self-assembly (INDs) and New Drug Applications (NDAs). From in the so-called “bottom-up” construction of nano- 2012-2018 he was an Assistant and then an particulate systems for drug delivery applications is Associate Professor in the Department of an emerging field. A key aspect of this research is Pharmacology in the Faculty of Medicine at the design of novel surface-active compounds Dalhousie University in Halifax, NS, Canada. He (surfactants) that, in addition to providing the recently joined the Department of Pharmaceutical desired characteristics of self-assembly and control Sciences in the newly-established Pharmacy of particle dimensions on the nanometer size scale, program at the State University of New York in can also provide enhanced pharmaceutical Binghamton, NY. applications such as targeted delivery and/or I am looking for students and postdocs, so please enhanced bio-distribution of an active compound. come see me! For more details on his research program see Dr. Wettig’s research website at uwaterloo.ca/wettig- research-group/. Disruption of Model Membranes by Surfactants used in Gene Delivery Medicating the Brain: The Challenges of Getting Shawn Wettig, Ph.D., C.Chem., Associate Professor Drugs Past the Blood-Brain Barrier and Associate Director, Graduate Studies and Research, School of Pharmacy, University of Donald W. Miller, Department of Pharmacology and Waterloo, Waterloo, ON Therapeutics, University of Manitoba

Gene delivery relies on the delivery of a specific The brain microvessel endothelial cells that form the gene of interest to target cells. One of the major blood-brain barrier (BBB) have an important role in barriers to successful gene therapy is the transport of maintaining the proper extracellular environment for the DNA across cellular membranes into the central nervous system (CNS) function. This same cell. Synthetic gene therapy vectors rely on the use cellular barrier also presents a formidable obstacle to of various cationic agents (polymer, lipid, or the delivery of many drugs to the brain. The surfactant) to condense and package DNA, and to expression of a wide variety of transporter systems facilitate its transport across cellular membranes. In that allow for selected transcellular passage through this talk I will discuss studies of lipid monolayers the BBB and the presence of complex tight junctions (used as a simplistic model for a cellular membrane) that limit paracellular diffusion across the BBB which were treated with a nanoparticle based gene encompass the two most prominent features that therapy. Langmuir isotherms were obtained for each distinguishes the brain microvasculature from system, along with images obtained using Brewster microvasculature in peripheral tissues. They also Angle Microscopy. The results are interpreted based represent the two extremes of efforts to enhance upon the effect that the components of the drug penetration across the BBB. With over 200 nanoparticle formulation has on the compressibility different solute carriers (SLCs) and 38 different of the model membrane systems. ATP-binding cassette (ABC) proteins expressed in human brain microvessel endothelial cells, there is a Shawn Wettig diverse array of uptake and efflux systems for Dr. Wettig obtained his Ph.D. studying the physical moving selected drugs into and out of the brain. In chemistry of novel mixed surfactant/polymer this regard, much emphasis has been placed on the systems with Dr. Ron Verrall in the Department of importance of drug efflux transporters, such as P- Chemistry at the University of Saskatchewan. His glycoprotein, in the BBB. From a paracellular research interests lie in the general areas of diffusion standpoint, there is growing interest in biophysical chemistry and nanotechnology; in capitalizing on transient changes in tight junction particular at the interface of these two broadly complexes within the brain endothelial cells that defined areas. This research involves aspects of provide therapeutic windows for enhanced drug physical chemistry, solution thermodynamics, delivery to the brain. Studies highlighting both biochemistry and cell biology applied to the study of transporter-based and paracellular approaches to

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CNS delivery and the challenges inherent in each to tumor endothelial cells through exploitation of approach will be discussed. hemodynamics. Nanoparticles display increased interactions with the vessel wall due to tumor blood Donald Miller flow characteristics, resulting in enhanced exposure Dr. Miller received his PhD in Pharmacology and of cancer cells to therapeutic agents. Specifically, Toxicology from the University of Kansas. After large discoidal nanoparticles display preferential completing a postdoctoral fellowship in the binding to cancer vasculature. Additionally, the laboratory of Dr. Ronald Borchardt in the microenvironment of the mononuclear phagocyte Department of Pharmaceutical Chemistry at the system can be altered with pharmacological agents University of Kansas, he accepted a position as to reduce nanoparticle clearance by macrophages. Assistant Professor in the Department of Notably, systemically injected nanoparticles Pharmaceutical Sciences at the University of accumulate preferentially in tissue-resident Nebraska Medical Center. In 2006 he was recruited macrophages of the liver and spleen, thereby to the Department of Pharmacology and limiting site-specific delivery. In fact, drug- Therapeutics at the University of Manitoba where he repurposing strategies, such as the use of is currently a Professor and Principal Investigator in chloroquine, are promising for modulating the Kleysen Institute for Advanced Medicine. Dr. macrophage activity to obtain reduced nanoparticle Miller’s research focus is on understanding the endocytosis. The encouraging preclinical results of cellular signalling pathways influencing blood-brain the abovementioned nanoparticle design and barrier (BBB) permeability under normal and microenvironmental preconditioning strategies will pathological conditions and on the development of be discussed, as well as ongoing strategies for approaches for enhancing drug delivery to the brain. clinical translation. In conclusion, optimization of Using both cell culture and animal models, Dr. nanoparticle interactions with biological membranes Miller has mechanistically examined drug efflux is promising for improving the treatment of disease. transporters and their impact on BBB permeability. In addition to transcellular routes of drug penetration Joy Wolfram, PhD in the BBB, his laboratory is also examining Dr. Joy Wolfram is an Assistant Professor of methods for transiently modulating the paracellular Medicine at the Mayo Clinic in Florida, where she pathways for delivery of drugs and nanomaterials to leads the Nanomedicine and Extracellular Vesicles the brain with a primary focus on improved group. She also holds affiliate faculty positions in treatment of brain tumors. He has participated on the Department of Nanomedicine at the Houston grant review panels for CIHR, NIH, European Methodist Hospital in Texas, the Department of Union, and Austrian Science Federation, and is Biology at the University of North Florida in currently a member of the scientific advisory board Florida, and the Wenzhou Institute of Biomaterials for Vireo Systems LLC (Nashville, TN). and Engineering at the Ningbo Institute of Industrial Technology in China. She received her bachelor’s and master’s degrees in biology from the University Optimizing Nanoparticle Interactions with of Helsinki in Finland. In 2016, she completed her Macrophages and Endothelial Cells Ph.D. in nanoscience and technology at the University of Chinese Academy of Sciences in Joy Wolfram, PhD, Assistant Professor, Department China. In the past five years, she has authored over of Transplantation and Department of Physiology 40 publications and received more than 25 scientific and Bioengineering, Mayo Clinic, Jacksonville, awards from seven different countries. She was Florida, United States included in the Amgen Scholars Ten to Watch List, which highlights the best and brightest up-and- The ultimate goal of drug delivery is to direct and comers in science and medicine across 42 countries. confine therapeutic agents to specific locations in the She has developed several nanoparticles for the body in order to reduce side effects and increase treatment of various diseases, including cancer. Her therapeutic efficacy. Site-specific delivery goal is to bring new nanomedicines with increased necessitates implementation of nanoparticle design therapeutic efficacy and safety to the clinic. Her and microenvironmental modification strategies to mission is also to inspire and support achieve favorable interactions with biological underrepresented minorities in science. She is membranes. In particular, the shape and size of actively involved in community outreach and nanoparticles can be optimized to increase binding scientific education.

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Wednesday, May 23 CSPS Lifetime Achievement Award Lecture Gordon Amidon, University of Michigan

Chair: Fakhreddin Jamali, University of Alberta

variability in oral drug product plasma levels is due Don’t Throw the BA/BE out with the Bathwater to gastrointestinal variation, since we dose subjects (Mechanistic Oral BE) randomly relative to this GI variation. Our recent results imply that we need to update and revise our Gordon L. Amidon Ph.D., William I. Higuchi FDA and USP product regulatory standards to Distinguished University Professor of ensure continued product efficacy. Pharmaceutical Sciences; Charles R. Walgreen Jr. Professor of Pharmacy and Pharmaceutical Sciences; Gordon L. Amidon University of Michigan, College of Pharmacy; Dr. Gordon L. Amidon received his B.S. degree Department of Pharmaceutical Sciences, Ann Arbor, from the State University of New York, Buffalo Michigan (1967), an M.A. degree in Mathematics (1970) and Ph.D. in Pharmaceutical Chemistry (1971) from The Bioequivalence (BE) is usually taught as a relative University of Michigan. From 1971 to 1981 Dr. Bioavailability (BA) science…which it Amidon was a member of the faculty at the unquestionably is! However, the fact that BE is a University of Wisconsin. He was appointed test of product differences with the same drug (API) Professor of Pharmaceutics at The University of is often overlooked. This implies that the ‘A’ part Michigan in 1983 and was named the Charles R. of ADME is responsible for the differences in in Walgreen, Jr., Professor of Pharmacy in 1994. Dr. vivo BE, since the ‘DME’ of the two products is the Amidon is internationally known for his research in same, with some exceptions. Consequently, for the field of drug absorption, transport phenomena, most drug products it is the interaction of the drug solubility, dissolution, and prodrugs. He has product with the absorbing site where the difference published 375 papers and 370 abstracts, and has18 in drug product in vivo performance occurs. US patents. Professor Amidon has mentored more This mechanistic approach to oral product than 120 doctoral and postdoctoral students with performance and bioequivalence, which led to the over 20 selecting academic careers. Dr. Amidon has widely accepted Biopharmaceutics Classification received numerous awards, including, in September System (BCS) will be further elaborated in this of 2017, the William I. Higuchi Distinguished seminar through recent studies simultaneously University Professor of Pharmaceutical Sciences at measuring gastrointestinal events and oral plasma the University of Michigan. Dr. Amidon developed levels. These in vivo studies, in normal subjects, a Biopharmaceutics Classification System (BCS), have revealed the very low buffer capacity of the with the FDA, impacting bioequivalence standards gastrointestinal tract and a very significant effect worldwide. He currently continues his dissolution (correlation) of gastrointestinal motility on oral drug work with the FDA, with current contract funding. plasma levels. These results imply that much of the

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Wednesday, May 23 SESSION 2A: Knowledge Translation - From Real World Evidence to Canadian Health Care Needs

Chair: George Wells, University of Ottawa, and University of Ottawa Heart Institute

Session Chair: Public Payer Perceptions of the Value of Real World Evidence George A. Wells, MSc, PhD, University of Ottawa, and Cardiovascular Research Methods Centre, Don Husereau, University of Ottawa, School of University of Ottawa Heart Institute Epidemiology and Public Health

Dr. Wells is a Professor in the School of Canada has a long history of the use of research Epidemiology, Public Health at the University of evidence to support healthcare decision-making. Ottawa and Director of the Cardiovascular Research Although there have been recent improvements in Methods Centre at the University of Ottawa Heart data holdings and analytic capacity in Canada, there Institute. He is also a Professor in the Department of remain questions about the perceptions of the value Medicine and a Senior Investigator at the Ottawa of real-world evidence in reimbursement and Hospital Research Institute at the Ottawa Hospital. decision-making barriers to its optimal use in pricing His research interests are in the design and and reimbursement, current initiatives that may lead analysis of clinical trials, statistical methodology to its increased use, and what role the related to health care delivery, systematic reviews pharmaceutical industry may play in this. and meta-analysis, economic evaluations and the Methods: To capture stakeholder perceptions, 91 development and assessment of decision support participants identified as key stakeholders were technologies for patients and practitioners. Dr. Wells identified according to background roles and is the author or co-author of over 800 published geography and invited to participate in four round articles and 900 scientific abstracts. He has been the table discussions conducted under Chatham House principal investigator or co-investigator on over 270 rule. Important themes emerging from these research projects. He has taught at the University discussions included: 1) The need to understand graduate and undergraduate level for 36 years and what "real world" evidence means; 2) Barriers to has supervised over 90 graduate students. using real world evidence from differences in access, Dr. Wells has worked extensively with national governance, inter-operability, system structures, and international government and non-government expertise and quality across Canadian health research organizations, as well as private systems; 3) Differing views on industry's role. pharmaceutical and biotechnology industries. He has Conclusions: The use of real-world data in Canada been on the executive and steering committees of to inform pricing and reimbursement decisions is far national and international research programs, from routine but nascent and slowly increasing. The external safety and efficacy monitoring committees, federated structure of Canada’s health system and scientific grant review committees, editorial the lack of universal public insurance for drugs have committees and, scientific advisory committees. He led to initiatives that have been focused on the is currently an Associate Editor of the Journal of networking of healthcare administrative data Clinical Epidemiology and on the Editorial acrossprovincial jurisdictional boundaries. There Committee of the Canadian Medical Association also appears to be a desire to see better use of Journal. pragmatic trials linked to these administrative data sets. Emerging initiatives have been funded to use real world evidence more broadly.

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Don Husereau the product life cycle. The project is expected to Don Husereau is the Senior Economic Advisor to result in enhanced monitoring of the performance of the CPhA. He is an Adjunct Professor of Medicine health products in Canada, which will contribute to at The University of Ottawa and Senior Associate improved access to health products, especially those with the Institute of Health Economics. He has products and for populations for which assessment expertise in health technology and policy through randomized clinical trials is less feasible. assessment, and was a former Director and Senior This work will also improve our ability to share Advisor for the Canadian Agency for Drugs and information on health product safety and Technologies in Health. Don is currently Chair of an effectiveness which is important for the decision International Task Force that has developed making of health care providers, patients and others consolidated health economic evaluation reporting in the health care system. This presentation will standards (CHEERS) that is now endorsed by outline the plans and provide a status update for this leading biomedical and health policy journals. Don work. is currently an Editorial Advisor for the biomedical journals, Value in Health and BMC Medicine. He is Rhonda Kropp also Senior Scientist at the University for Health Rhonda Kropp is currently the Director General for Sciences, Medical Informatics and Technology in the Marketed Health Products Directorate in the Hall in Tirol, Austria. Most recently, Don served on Health Products and Food Branch of Health Canada. the pan-Canadian Oncology Drug Review (pCODR) She is responsible for the oversight of the vigilance Expert Review Committee (pERC) and currently of marketed health products in Canada, including serves on the Ontario Committee to Evaluate Drugs. ensuring Canadians and health professionals are Don received both his BSc and MSc from the informed of important issues impacting the safety University of Alberta's faculty of Pharmacy and and effectiveness of health products in a timely Pharmaceutical Sciences. fashion. Rhonda has been working in health policy, programs and surveillance for over 20 years as a Improving the Use of Real World Evidence in the nurse, microbiologist, researcher and infectious Regulatory Environment: Where Are We disease epidemiologist. She started her career as a Heading? microbiologist in an industry laboratory. After returning to school to get her degree in Nursing, she Rhonda Kropp, Director General, Marketed Health worked as a paediatric oncology nurse at British Products Directorate, Health Products and Food Columbia Children’s Hospital before pursuing Branch, Health Canada graduate school in public health at the University of California, Berkeley. After a few years directing Health Canada has recently launched an initiative to public health research projects in California for the improve the regulatory review of drugs and devices state government, Stanford University and the with an eye towards making the system more University of California, San Francisco, Rhonda efficient, supporting more timely access to joined the Government of Canada through the therapeutic products and building better linkages Recruitment of Policy Leaders program in 2003. within the healthcare system as a whole. As part of During her fourteen years with the Government of this initiative, Health Canada is working in Canada, Rhonda has taken on a diversity of roles collaboration with its key partners to improve how it from technical expert and epidemiologist to policy can access and analyze Real World Data (RWD) manager before joining the Executive cadre. Within with the objective of optimizing decision-making her last five years in the federal public service, she across the life cycle of health products. This project, served as the Chief Health Surveillance Officer and called “Enhancing the Use of Real-World Evidence the Director General of the federal immunization (RWE) Throughout the Life Cycle of Health program at the Public Health Agency of Canada Products”, will explore the key information gaps before joining Health Canada in December 2017. impacting our ability to monitor performance of Rhonda was the proud recipient of the Chief Public marketed health products across their life cycle, and Health Officer of Canada medal in 2017 for the role RWE can play in filling those gaps. We are outstanding performance. also assessing the existing use of RWE to better understand how we can optimize its use throughout

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Canadian Network for Observational Drug Effect faculty at McGill University. His main research Studies: Using Real-World Evidence to Inform interests are statistical methods and applications for Regulatory Decisions administrative data, pharmacoepidemiology, perinatal epidemiology, and methods for causal Robert Platt, McGill University Health Centre inference from epidemiological studies. His Research Institute, Montreal, QC methodological interests center on marginal structural models for analyses of large administrative The Canadian Network for Observational Drug data cohorts, in particular the specification and Effect Studies (CNODES) was formed in 2011 as a optimization of the propensity score and inverse component of the Drug Safety and Effectiveness probability weights. Network, a collaborative venture between CIHR, Dr. Platt is principal investigator on a number of Health Canada, and other stakeholders. CNODES grants, including a Foundation Grant from the addresses queries from Health Canada and other Canadian Institutes of Health Research (CIHR) and groups on drug utilization, safety, and effectiveness, a Discovery Grant from the Natural Sciences and using administrative data-based cohorts from most Engineering Council of Canada. He is co- Canadian provinces, the US, and the investigator/subcontractor on several other CIHR UK. CNODES’ work has addressed safety concerns and National Institutes of Health grants. In 2005, Dr. associated with several frequently-used medications Platt received the Prix d’Excellence from the including statins, proton-pump inhibitors, Québec Foundation for Research on Children’s antipsychotic medications, and anti-acne Diseases. Dr. Platt is a 2016 Thomson Reuters medications. CNODES has had significant impact Highly-Cited Researcher. on regulatory policy. CNODES develops protocols Dr. Platt is on the editorial board of the in close collaboration with query submitters, and American Journal of Epidemiology, involves decision-makers at several points in the Pharmacoepidemiology and Drug Safety and query development and research process. Recently Current Epidemiology Reports, and is Associate CNODES researchers have implemented a common Editor of Statistics in Medicine and the International data model across the Canadian databases, which Journal of Biostatistics. He has published over 300 will enable rapid-response analyses for articles, one book and several book chapters on straightforward queries using semi-automated epidemiology. computer programs, and faster turn-around for decision-makers. I will describe CNODES processes and interactions with Health Canada and Life-Cycle HTA: Unlocking the Potential for Real other stakeholders, and provide several examples of World Evidence CNODES’ work. Tammy Clifford, Chief Scientist & Vice President, Robert Platt Evidence Standards, CADTH Robert Platt is Professor in the departments of Pediatrics in addition to Epidemiology, Biostatistics, Traditionally, CADTH and other Health Technology and Occupational Health (EBOH) at McGill Assessment (HTA) organizations have focused their University, and Director of Graduate Programs in assessments on new drugs and other health the department of EBOH. He holds the Albert technologies, at the point of their adoption into the Boehringer I endowed chair in health care system. These decisions are often binary Pharmacoepidemiology. in nature (e.g., adopt or not, fund or not) and are Dr. Platt is the Executive Co-Lead of the often made with considerable uncertainty. Quality Canadian Network for Observational Drug Effect and efficiency are not simply a function of whether a Studies (CNODES). He has been the leader of the technology is available; it is equally important to Methods team of CNODES since its inception. In manage how, how often and how well the this role, he has led a methods research and training technology is used in the real world. program for the network and has participated as With the launch of its new strategic plan, methods liaison (senior methods author) in CADTH aims to support the transformation of how numerous CNODES studies. our system manages health technologies. Integral to After completing his PhD in Biostatistics at the this shift from health technology assessment (HTA) University of Washington in 1996, he joined the to health technology management (HTM) is a move

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away from one-time decisions, made at the time of a Tammy Clifford technology’s adoption, to supporting decisions at all Dr. Tammy Clifford is CADTH’s Chief Scientist phases of the technology life-cycle, from pre-market and Vice President, Evidence Standards. Over the to adoption, to actual use in real-world setting, past decade, she has served in a number of senior through to disinvestment and decommissioning. In leadership roles at CADTH, with responsibility for order for HTM to be a success, we need greatly the agency’s Health Technology Assessment (HTA), expanded and continuous evaluative capacity to Horizon Scanning, Rapid Response, Scientific ensure the health care system effectively manages Advice and Patient Engagement programs. Tammy the entry, ongoing use, and exit of technologies. received her PhD in Epidemiology & Biostatistics at Many decisions about health technologies are the University of Western Ontario, and her BSc and made with considerable uncertainty at product MSc from McGill. Through her role as an adjunct launch. CADTH will establish guidelines and professor with the School of Epidemiology, Public processes for the reassessment of drugs, devices and Health & Preventive Medicine at the University of interventions already in use within the system. This Ottawa, Tammy is building awareness of and will allow for new recommendations to be made, capacity in HTA through her active involvement facilitate adjustments to both pricing and practice with the graduate program where she both teaches guidelines, and promote disinvestment in and supervises MSc and PhD students. She has been technologies that provide low value to Canadians actively involved with national and international (thereby enabling re-investment elsewhere). To be HTA activities, including having served on the effective, this will require coherent mechanisms for Board of Directors of Health Technology identifying technologies amenable to reassessment Assessment international (HTAi), the international and will rely, in part, on the use of RWE. society for the promotion of HTA, and having This session will provide insights into CADTH’s participated in the development of the scientific new strategic plan, highlighting opportunities for programmes for many HTAi annual meetings. collaboration with others in the RWE space so as to Tammy is internationally recognized for her passion enable the effective management of health and commitment to advancing the science of HTA, technologies within a living healthcare system. and to mentoring the next generation of HTA producers

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Wednesday, May 23 SESSION 2B: Pharmaceutical Potential of Stem Cell & CRISPR-mediated Gene Modifications

Chair: Jeffrey Henderson, University of Toronto

questions regarding the behaviour and Stem Cell Activation to Promote Self-Repair of characterization of neural stem cells and applying the Injured Nervous System this knowledge to regenerative medicine strategies. Her team is actively pursuing the role of endogenous Cindi M Morshead, PhD, Professor and Chair, stem cells in models of neurodegenerative disease Anatomy, Department of Surgery, Donnelly Centre, such as stroke, cerebral palsy, acquired brain injury University of Toronto, Toronto, ON and spinal cord injury.

The discovery of neural stem cells has led to significant interest in their use for neural repair. We A Stemness-based Drug Screen to Target Acute are interested in developing therapeutic interventions Myeloid Leukemia Stem Cells that can harness the potential of resident neural stem cells and their progeny (together termed neural Jean Wang MD PhD, Princess Margaret Cancer precursor cells, NPCs) to promote tissue repair and Centre, University Health Network functional recovery. Herein, I will focus on our work using the drug Metformin, a drug typically Acute myeloid leukemia (AML) is an aggressive used to treat type II diabetes, which we have shown hematologic malignancy with poor prognosis, to expand the size of the NPC pool and promote especially for older patients. Although conventional neurogenesis and oligogenesis. Moroever, the intensive chemotherapy reduces bulk disease and administration of Metformin promotes motor induces morphologic remissions in most patients, the recovery in a model of neonatal stroke. Chronic disease frequently recurs due to the persistence of administration of metformin also leads to a rescue of leukemia stem cells (LSCs), which possess stem cell cognitive deficits in this same model, but this only properties such as self-renewal and quiescence that occurs in females, and not males. I will discuss our are linked to therapy resistance and relapse. Novel recent work investigating how the factors of age, sex therapies that eradicate L SCs through disruption of and brain region modulate the response of NPCs to pathways required for stemness have the potential to metformin in the intact and injured brain. Our produce durable responses and improve clinical findings indicate that the stem cell niche plays an outcomes. Previous drug discovery approaches in important role in regulating the NPC response to leukemia have been largely unsuccessful, in no small metformin, which has important implications for the part due to the use of established AML cells lines development of therapeutics to treat the injured that do not retain the functional hierarchy of primary brain. AML clones, and the use of surrogate endpoints such as bulk cell viability or proliferation that poorly Cindi Morshead reflect drug activity against LSCs. Thus, many drugs Dr. Morshead did her PhD at the University of that move forward from such screens ultimately fail Toronto and joined the Department of Surgery in to improve patient outcomes in clinical trials. The 2003. She is currently a tenured Professor and Chair best functional assay for studying LSC properties is of the Division of Anatomy, Department of Surgery. xenotransplantation of patient samples into Dr. Morshead’s expertise is in stem cell biology and immunocompromised mice. However, labour- specifically, in the field of adult neural stem cells. intensive xenotransplantation assays are impractical Her lab is interested in exploring fundamental to perform on a large scale and are prohibitively

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costly for drug discovery studies. To address these these two kinases were connected with a viral 2A issues, we have developed a next-generation high- sequence. Using mouse and human embryonic stem throughput drug discovery approach designed to cell lines with the above homozygous modification, identify novel compounds with activity against we showed an extremely efficient and reliable LSCs, using a functionally-validated LSC-specific ablation of proliferating cells both in vitro and in gene signature that captures the core transcriptional vivo by ganciclovir treatment, the pro-drug for HSV- programs associated with stemness. TK. Using published and our experimental measures Jean Wang of forward mutation rates, we defined Jean Wang is a Clinician Scientist and Staff mathematically the level of safety of therapeutic Hematologist at the University Health Network in batches of these cells. Our general approach to Toronto, and an Affiliate Scientist at Princess assess and quantify the safety will be critical to Margaret Cancer Centre. Her research currently make informed decisions by the regulators, doctors, focuses on acute myeloid leukemia (AML), one of and patients to advance the modern medicine- the most deadly types of leukemia and the most transforming cell therapies. common type of acute leukemia in adults. Through Building on the fail-safe technology, we the use of xenotransplantation models of AML, Dr. addressed the next hurdle faced by cell therapies; a Wang studies the biology of the leukemia stem cells solution for induced allograft tolerance. We showed (LSC) that underlie therapy resistance and relapse, that the expression of eight local-acting, and evaluates the efficacy of novel anti-leukemia immunomodulatory transgenes introduced into agents against LSCs, with parallel development of embryonic stem cells is sufficient to protect cell drug response biomarkers for patient stratification in derivatives against rejection in allogenic, immune- clinical trials. Her group recently developed a robust competent recipients. Allografts survive long-term, LSC gene signature for rapid determination of risk in in different MHC-mismatched recipients, and newly-diagnosed AML patients, and she is currently without immunosuppressive drugs. Most working with colleagues at Princess Margaret to importantly, the recipients of these engineered cells bring her research findings to the clinic. do not have suppressed systemic immune function. The combination of the fail-safe and immune tolerance genome editing makes the One4All cell Opening the Gate for Pluripotent Stem Cell- line and therapeutic cell development a reality. based Therapies Andras Nagy Andras Nagy, Lunenfeld-Tanenbaum Research Dr. Nagy is currently a Shawn Kimel Senior Institute, Sinai Health System, Toronto, Canada Scientist at the Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Professor in the Pluripotent stem cells have accelerated the Department of Obstetrics & Gynaecology and development of new avenues for targeting Institute of Medical Science at the University of degenerative diseases and cancer with cell-based Toronto, Investigator at the McEwen Centre for therapies. Numerous human therapies are currently Regenerative Medicine and Professor at the on their way to treat devastating conditions. Australian Regenerative Medicine Institute in However, concerns about the cell-safety hold back Monash University, Melbourne. He holds a Tier I the full utilisation of these promising new Canada Research Chair in Stem Cells and treatments. Here we introduce a concept and show Regeneration. He also has a Fellowship of the the associated genome engineering strategy that Royal Society of Canada in the Life Sciences addresses this issue and provides a solution for “fail- Division of the Academy of Science and recently safe” cell therapies. became a Foreign Member of the Hungarian To ensure the reliable expression of a suicide Academy of Sciences. Dr. Nagy has made transgene system in proliferating cells, we significant breakthroughs in the development of transcriptionally linked it to a cell division essential mouse and human pluripotent stem cells (both endogenous locus (CDEL) in a homozygous manner. embryonic and induced) that could accelerate Our prototype suicide gene was the herpes simplex research in regenerative medicine and lead to future virus-thymidine kinase (HSV-TK), and the therapies for currently incurable diseases, such as prototype CDEL was CDK1. The coding regions of blindness, diabetes, arthritis, spinal cord injury and

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many others. His team created the first two Canadian with competitive, cooperative and antagonistic human embryonic stem cell lines and developed a signaling models observed in vitro and in vivo. We novel method for generating non-viral induced have further validated these findings using pluripotent stem cells. His current research focuses pharmacologic approaches in wild-type animals, on understanding the process of reprogramming to adding a new layer of complexity to caspase-8/RIP-1 stem cells at the molecular level and using signaling. sophisticated genome editing methodology to pave the way leading to safe and effective cell based Jeffrey Henderson therapies of diseases. Dr. Henderson received his doctorate in Physical Biochemistry at the University of Illinois. Following post-doctoral work in molecular neuroscience and Network Analysis of Cell Death Signaling transgenics he joined the Faculty of the Lunenfeld- Pathways via CRISPR-mediated Modification in Tanenbaum Research Institute, Mount Sinai Embryonic Stem Cells and Derivatives Hospital where his laboratory examined mechanisms of regulated cell death and axon guidance relevant to Jeffrey Henderson, Faculty of Pharmacy, University CNS injury. In conjunction with Drs. R. Hakem and of Toronto, Toronto, Ontario T. Mak he provided the first demonstration of the in vivo role of caspase-9 in the CNS; as well as EphB2, Programmed cell death (PCD) plays a critical role in ShcB and ShcC with the laboratory of Dr. T. the proper development and homeostasis of a Pawson. In 2002 he joined the University of number of cellular systems in mammals. As such, Toronto, Faculty of Pharmacy the where he heads aberrant execution of PCD has been shown to play a the Murine Imaging and Histology Core Facility and role in a number of human pathologies ranging from the Antibody-Epitope Recognition Database. He is cancer to autoimmune disease to neurodegeneration. the designer of NeuroMouse and developed the first Modulation of PCD signaling is therefore of key 3D surgical atlases of the murine brain and skull for interest to a number of clinical and biomedical strains 129Sv/IMJ and C57Bl/6J. In conjunction applications. Analysis of complex PCD signaling with the laboratory of Dr. M.R. Henkelman he interactions in mammalian cells and tissues has developed the first probabilistic CNS atlases for traditionally been hampered both by the kinetic murine strains 129Sv, C57Bl and CD1 and the limitations of small molecule and sh/siRNA expert systems utilized for cross-comparative approaches, and the difficulty in generating probabilistic analyses. His current research focuses genetically comparable sets of null/conditional on three principle themes: Regulation of mutations encompassing the systems of interest. programmed cell death signaling in the mammalian However recent advances in gene modification CNS, EphB-family mediated control of axon technologies have vastly altered the general guidance and development of small molecule applicability of network approaches toward the therapeutics modifying PCD signaling. His present analysis of cell signaling systems. Using a Crispr- studies aim to elucidate PCD signaling in the CNS in mediated gene targeting approach in embryonic stem response to a variety of cellular stressors using gene- (ES) cells, we have presently developed multiple modification methods such as Crispr to identify key individually validated guides toward a number of identify molecule interactors in mammals. Dr. key members of the apoptotic, necroptotic and Henderson currently serves on the Board of macro-autophagic PCD signaling networks. Using Advisors for the Toronto Centre for Phenogenomics clonally related Crispr-targeted cell lines in Transgenic Core, Executive and Academic conjunction with in vitro cellular differentiation and committees for the University of Toronto’s cellular transplantation in vivo, we have examined Collaborative Program in Neuroscience, the the role of apoptotic-necroptotic signaling for Collaborative program in Cardiovascular Sciences several forms of cell death. The presence of such cell and the Centre for Collaborative Drug Research. His lineages allows for the rapid profiling of a number of work is generously supported by funding from the different toxicologic agents with respect to cell death CIHR, NIH, NSERC and NARSAD. He is a three mechanisms. Our studies demonstrate that despite time awardee of the Rick Hansen Fellowship in expression of key PCD regulators the influence and spinal cord research. regulation of apoptotic/necroptotic signaling can vary markedly as a function of both cellular context,

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Selected CSPS Trainee Abstract Oral Presentation

Investigating the Role of the IKKβ Protein Kinase in Vascular Remodeling Events . Francis Lefebvre, Université de Montréal

(See Poster Abstract # 9)

Wednesday, May 23 SESSION 2C: CSPT Trainee Oral Presentations

Chair: Tuan Trang, University of Calgary

Galen Wright, University of British Columbia Eliza McColl, University of Toronto Khaled Adb-Elrahman, Ottawa University Kamelia Mirdamadi, University of Toronto Britt Drögemöller, University of British Columbia Tessa Bendyshe-Walton, University of British Anish Engineer, Western University Columbia

Elizabeth Greco, Western University Jay Fang, Western University

Shrinidh Joshi, North Dakota State University Pierre Thibeault, Western University

Anette Surmanski, Western University Yong Jin (James) Lim, Western University . Markus Gulilat, Western University

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Thursday, May 24 PLENARY SESSION 3 Tak Mak, Princess Margaret Hospital

Chair: Catherine Lau, Janssen Inc.

chain. This finding not only solved a problem The Fourth Pillar of Cancer Treatment: It Takes plaguing scientists for decades but also opened up a Village novel research avenues and provided the basis for new genetic tools used to study how T cells operate Tak-Wah Mak, OC, PhD, DSc (Hons), FRSC, FRS, and develop, to dissect mechanisms of autoimmunity Ontario Cancer Institute, Princess Margaret and tumor cell survival, and to formulate new Hospital, Toronto pathways to cancer eradication.

Tumorigenesis involves more than oncogene Tak-Wah Mak activation or tumor suppressor inactivation, and the Dr. Tak W. Mak is the Director of the Campbell cancer cell genome contains many more alterations Family Institute for Breast Cancer Research at the than can be targeted at once. A key function of the Princess Margaret Cancer Centre in Toronto. He immune system is to prevent incipient tumor cells received a bachelor’s of science in biochemistry in from establishing but these cells deploy numerous 1967 and a master of science in biophysics in 1968 tactics to evade and neutralize the immune responses from the University of Wisconsin. He earned his they provoke. Techniques of immunotherapy have Ph.D. in Biochemistry from the University of been devised to stimulate specific components of the Alberta in 1971. He is also senior scientist in the immune system to increase cancer cell killing division of Stem Cell and Developmental Biology, (costimulation) and to render tumor cells once more Ontario Cancer Institute. Since 1984, he has been a vulnerable to immune attack (checkpoint blockade). Professor in the Departments of Medical Biophysics About 30% of cancer patients around the world can and Immunology at the University of Toronto. now benefit from these immunotherapies, including Dr. Mak co-discovered the t-cell receptor, a key those suffering from non-small cell lung component of the immune system. His research is cancer, urothelial cancer, renal cell carcinoma, concentrated on gaining fundamental knowledge of melanoma, head and neck squamous cell carcinoma, the biology of cells in normal and disease settings, and Hodgkin lymphoma. Ongoing clinical trials are and in particular on the mechanisms underlying exploring combinations of checkpoint inhibitors, immune responses and tumorigenesis. His lab has although the enhanced efficacy of this approach initiated several complementary programs, many of produces increased adverse effects. Thus, new which have evolved from the production and avenues beyond checkpoint inhibition are under analysis of genetically engineered mouse strains. investigation, including manipulation of the tumor Dr. Mak has received several awards and honors microenvironment. A key goal is to undo the for his work. He is a member of the Order of Ontario immune-privilege created by the infiltration of and was elected as a foreign associate to the regulatory and coopted effector T cells expressing National Academy of Sciences in the discipline of immunosuppressive molecules. Techniques of immunology in 2002. Dr. Mak has received the King adoptive T cell transfer (receipt of T cells expanded Faisal Prize for Medicine, the Gairdner Foundation and activated ex vivo) and T cell vaccination may International Award, the Paul Ehrlich Prize, the fulfill the promise of personalized medicine, as Novartis Prize in Immunology, the Killam Prize by may CAR-T cell immunotherapy with its T cells the Canada Council for the Arts, and the Sloan Prize expressing engineered anti-tumor receptors. These of the General Motors Cancer Foundation, and the exciting new frontiers in medical innovation would Robert L. Noble Prize by the National Cancer not have been possible without the cloning of the Institute of Canada. gene encoding the human T cell receptor (TCR) beta

50s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

Thursday, May 24 SESSION 3A: Immuno-Oncology

SPONSORED BY: AstraZeneca, CDRD, Merck, Roche

Chair: Pamela Ohashi, Princess Margaret Cancer Centre

development of CAR T cells for other cancers. CAR Therapy: The CD19 Paradigm and Beyond Michel Sadelain Michel Sadelain, MD, PhD, Center for Cell Michel Sadelain, MD, PhD, is the Director of the Engineering, Memorial Sloan Kettering Cancer Center for Cell Engineering and the incumbent of Center, New York, NY, USA the Stephen and Barbara Friedman Chair at Memorial Sloan-Kettering Cancer Center. He is a Chimeric antigen receptors (CARs) are synthetic Member of the Immunology Program and the receptors that redirect and reprogram T cells to Departments of Medicine and Pediatrics. mediate tumor rejection. The most successful CARs Dr. Sadelain’s research focuses on human cell used to date are those targeting CD19, which offer engineering and cell therapy to treat cancer and the prospect of complete remissions in patients with hereditary blood disorders. His laboratory has made chemorefractory/relapsed B cell malignancies, several seminal contributions to the field of chimeric especially acute lymphoblastic leukemia (ALL). We antigen receptors (CARs), from their have treated 53 adult patients with refractory and conceptualization and optimization to their clinical relapsed ALL with autologous peripheral blood T translation for cancer immunotherapy. His group cells manufactured to express the 19-28z CAR. was the first to publish dramatic molecular Despite a high complete remission rate (83%), a remissions in patients with chemorefractory acute number of patients will eventually relapse, pointing lymphoblastic leukemia following treatment with to the need to further improve CAR design and T autologous CD19-targeted T cells. cell engineering. To enhance the intrinsic (function, Dr. Sadelain is the recipient of the Cancer persistence) and extrinsic (action on the tumor Research Institute’s Coley Award for Distinguished microenvironment) potency of adoptively transferred Research in Tumor Immunology, the Sultan Bin T cells, we have designed novel CARs to delay the Khalifa International Award for Innovative Medical onset of T cell exhaustion and recruit tumor- Research on Thalassemia and NYPLA Inventor of infiltrating T cells via trans-costimulation. Using the Year award. He previously served on the NIH CRISPR/Cas9, we found that directing a CAR to the Recombinant DNA Advisory Committee and as T cell receptor alpha chain (TRAC) locus not only President of the American Society for Gene and Cell results in uniform CAR expression in human Therapy. peripheral blood T cells, but enhances T cell potency by attenuating CAR tonic signaling and further postponing T cell exhaustion, enabling TRAC-CAR A Trans-Canada Highway for CAR-T Cells T cells to vastly outperform conventionally engineered CAR T cells. We also recently succeeded Brad Nelson, Ph.D., Distinguished Scientist and in modeling cytokine release syndrome (CRS), one Director, Deeley Research Centre, Co-Director, of the major complications of CD19 CAR therapy, Immunotherapy Program, BC Cancer, Victoria BC, pinpointing macrophages as the major source of Canada pathogenic cytokines such as interleukin-6. In aggregate, these findings hold the promise for The striking clinical successes of cancer further improving CD19 CAR therapy and the immunotherapy are transforming oncology, yet they

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also bring significant clinical and fiscal challenges refractory B cell malignancies. Late 2017, FDA for publicly funded healthcare systems in Canada approved tisagenlecleucel-T (Kymriah™, Novartis) and beyond. In particular, a new cell-based therapy and axicabtagene ciloleucel (Yescarta™, Kite involving Chimeric Antigen Receptor (CAR) T cells Pharma) for the treatment of refractory and relapsed is yielding up to 90% complete response rates pediatric acute lymphoblastic leukemia and against B cell leukemias yet comes at a commercial advanced non-Hodgkin lymphoma, respectively. cost exceeding $500,000 per patient. Fortunately, the However, the therapeutic effects of CAR-T cells that Canadian immunotherapy research community has a target other malignancies have not yet resulted in strong history of innovation and collaboration, significant clinical benefit. which positions the country to excel in this new era. Although suboptimal tumor trafficking and a I will discuss how CAR-T cells work, why they are a variety of immunosuppressive mechanisms can game-changer for oncology, and the opportunities thwart CAR-T cell effector responses, the signals and challenges we face in applying this approach to delivered by the current CAR constructs may still be other cancers. I will describe an exciting new insufficient to optimally activate antitumor T cell initiative to create a national, public sector CAR-T functions. Full T cell activation and proliferation cell program, which will leverage Canadian talent requires multiple signals, including T cell receptor and innovation while enabling greater cost control (TCR) engagement (signal 1), co-stimulation (signal for our healthcare systems. 2) and cytokine engagement (signal 3). However, CAR constructs currently being tested in the clinic Brad Nelson contain a CD3ζ (TCR signaling) domain and co- Dr. Nelson is a native of Vancouver BC. He stimulatory domain(s) but not a domain that received his B.Sc. from the University of British transmits signal 3. Columbia in 1987 and Ph.D. from the University of We have developed a novel CAR construct California at Berkeley in 1991. He completed capable of delivering cytokine signaling in an postdoctoral training with Dr. Phil Greenberg and antigen-specific manner3. Our new-generation CD19 held faculty positions at the Fred Hutchinson Cancer CAR encodes a truncated intracellular domain from Research Center and University of Washington in the interleukin (IL)-2 receptor β-chain (IL-2Rβ) and Seattle. In 2003, he became the founding Director of a STAT3-binding tyrosine-X-X-glutamine (YXXQ) BC Cancer's Deeley Research Centre in Victoria motif, along with the TCR signaling (CD3ζ) and co- BC. He is a Professor of Medical Genetics at the stimulatory (CD28) domains (28-ΔIL2RB- University of British Columbia and a Professor of z(YXXQ)). The 28-ΔIL2RB-z(YXXQ) CAR-T cells Biochemistry/Microbiology at the University of showed antigen-dependent activation of the JAK Victoria. Dr. Nelson’s lab uses genomic and kinase and of the STAT3 and STAT5 transcription molecular approaches to study the immune response factors signaling pathways, which enhanced their to cancer, with an emphasis on ovarian cancer. As proliferation and prevented terminal differentiation Co-Director of BC Cancer’s Immunotherapy in vitro. The 28-ΔIL2RB-z(YXXQ) CAR-T cells Program, he is leading a phase I clinical trials demonstrated better in vivo persistence and program focused on adoptive T cell therapy for antitumor effects in various tumor models as gynecological cancers, leukemia, lymphoma, and compared with CAR-T cells expressing a CD28 or other malignancies. 4-1BB co-stimulatory domain alone. These results suggest that our new-generation CAR has the potential to demonstrate superior antitumor effects A New Generation CAR Containing a JAK– with minimal toxicity in the clinic and that clinical STAT Signaling Domain Mediates Superior translation of this novel CAR is warranted. Antitumor Effects 1. Park JH et al. N Engl J Med. 2018;378(5):449-459 2. Maude SL et al. N Engl J Med. 2018;378(5):439-448 Naoto Hirano, Princess Margaret Cancer Centre, 3. Kagoya Y et al. Nat Med. 2018;24(3):352-359 University Health Network, Toronto, ON Naoto Hirano The adoptive transfer of T cells engineered to Dr. Hirano received his MD and PhD from the express a chimeric antigen receptor (CAR) specific University of Tokyo and did his post-doctoral for the B lymphocyte antigen CD19 has shown training at the Dana-Farber Cancer Institute, Harvard remarkable clinical responses in patients with Medical School with Dr. Lee M. Nadler. Before

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moving to Toronto in 2011, Dr. Hirano was critical to ensure appropriate use of patients, Assistant Professor of Medicine at the Harvard resources and infrastructure. The dearth of Medical School. He is currently Senior Scientist at nonclinical models that can reliably reflect the the Princess Margaret Cancer Centre, and Associate human immune system and microenvironment Professor of Medicine in the Department of further complicates this selection, resulting in Immunology at the University of Toronto. He is also clinical combinations that lack scientific hypothesis Associate Director for Research of the Tumor or are based largely on empiricism. The go-no-go Immunotherapy Program at the Princess Margaret decisions at the end of early evaluations of IO Cancer Centre. combinations represent another challenge as patient The overarching goal of Dr. Hirano's research is populations enrolled are typically heterogeneous and to devise novel anti-tumor immunotherapeutic no validated predictive biomarkers of sensitivity or modalities that can cure cancer. His laboratory is resistance currently exist with IO therapeutics. Using particularly interested in understanding how the examples of IO combinations tested to date, this interactions between T cells and antigen-presenting presentation will focus on present trends and future cells affect priming, expansion, persistence and predictions, providing some key points on how the differentiation of T cells. He also seeks to clarify clinical development of these compounds can be how this leads to the subsequent generation and modernized and streamlined. For instance, adaptive maintenance of T cell memory. design elements to allow enrichment of sensitive Dr. Hirano has received prestigious awards and disease subtypes, and adaptive randomization honors including the American Society of strategies, can be applied to combinatorial studies of Hematology Scholar Award and Ontario Institute for these compounds to accelerate their development. Cancer Research (OICR) Investigator Award (renewed). His research has been supported by Lillian L. Siu multiple funding mechanisms including NIH, CIHR, Dr. Siu is a senior medical oncologist at Princess OICR, Networks of Centres of Excellence Margaret Cancer Centre since 1998, and has been a (BioCanRX), Terry Fox Research Institute, Canada Professor of Medicine at the University of Toronto First Research Excellence Fund (Medicine by since 2009. She is the Director of the Phase I Design), and Princess Margaret Cancer Foundation. Program and Co-Director of the Bras and Family Dr. Hirano has been Editorial Board Member of the Drug Development Program at Princess Margaret Cancer Immunology Research journal. Cancer Centre, and holds the BMO Chair in Precision Genomics (2016-2026). She is also the Clinical Lead for the Tumor Immunotherapy Immuno-Oncology Combinations in Clinical Program at Princess Margaret Cancer Centre. Dr. Development Siu served on the Board of Directors for the American Society of Clinical Oncology (ASCO) for Lillian L. Siu, MD, BMO Chair in Precision a four-year term (2012-2016). She also served as a Genomics, Professor of Medicine, Princess Margaret member of the Nomination Committee for the Cancer Centre, Toronto, Canada American Association for Cancer Research (AACR) (2014-2016). She currently serves on the AACR An emerging pipeline of immuno-oncology (IO) Board of Directors for a three-year term (2017- therapeutics has entered clinical testing, such as 2020). immune checkpoint inhibitors beyond anti-CTLA4 Dr. Siu’s major research focus is in the area of and anti-PD-1/L1 antibodies, costimulatory new anticancer drug development, particularly with molecules, inhibitors of regulatory T cells, cancer respect to phase I trials and head and neck vaccines using individual neoantigens, functional malignancies. She is the Principal Investigator of a modifiers of immunosuppressive enzymes, myeloid phase I cooperative agreement UM1 award (2014- cell modulators, adoptive cell therapy, as well as 2019) sponsored by the United States National conventional therapies inducing antigen release and Cancer Institute. IIn addition to her active research immunogenic cell death, among others. The in early phase clinical trials, she has been leading potential number of combinations using these genomics initiatives and immuno-oncology trials at various IO therapeutics is considerable, such that the the Princess Margaret Cancer Centre. Together, the selection of the most scientifically rational three programs of drug development, cancer combinations to proceed to clinical development is genomics and tumor immunotherapy form a triad of

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synergy that supports the institution’s core vision to postdoctoral training at the Institute of deliver precision cancer medicine. Biotechnology in Houston, Ismael joined the Section Internationally, Dr. Siu was the recipient of the of Molecular Hematology at MD Anderson Cancer US NCI Michaele C. Christian Award in Oncology Center in 2004 as a Research Scientist where he led Drug Development in 2010. Locally, she was investigations on the antileukemic and antitumor awarded the University of Toronto Department of effects of synthetic triterpenoids, guggulipids, bcl-2 Medicine Eaton Scholar Researcher in 2016. She inhibitors, targeted peptides, p53 activators and was the ASCO Conquer Cancer Foundation Grants kinase inhibitors. In 2007 he was promoted to Selection Committee Chair in 2009-10. She was Research Instructor in the Department of Stem Cell Chairperson of the AACR Education Committee, Transplantation and Cellular Therapy at MD Co-Chairperson of the Scientific Committee for the Anderson Cancer Center, where he made the seminal 2012 Annual Meeting and Co-Chairperson for the discoveries that mitochondrial uncoupling was the Clinical Trials Committee 2015-2017. Dr. Siu has basis for the observed Warburg effect in leukemia published over 270 peer-reviewed manuscripts, and cells, and that pharmacological inhibition of fatty she is currently a scientific editor for Cancer acid oxidation was an effective therapeutic strategy Discovery and is on the editorial board for JAMA to sensitize leukemia stem cells to chemotherapy Oncology. induced cell death. In addition, in collaboration with Dr. Michael Andreeff and Dr. Frank Marini, he demonstrated the therapeutic efficacy of gene- PANEL MEMBERS modified mesenchymal stromal cells in animal models of pancreatic and ovarian cancer. Jian Wang, MD, PhD, Biologics and Genetic In 2009 Ismael joined Pontifical Javeriana Therapies Directorate, Health Canada University in his home country of Colombia as an Dr. Jian Wang has been the Chief of Clinical Associate Professor where he continued to pursue Evaluation Division for the past 13 years and metabolic strategies for the treatment of human manages a team of clinical and medical evaluators. cancer, including a compassionate use study of the His division has regulatory responsibility for antidiabetic agent metformin in combination with assessing non-clinical, PK/PD and clinical data for metronomic chemotherapy that revealed a potential biological drugs for the treatment of haematological, immunomodulatory effect of metformin in advanced oncological, and infectious diseases. cancer patients. In 2013 Ismael joined the Radiopharmaceuticals, gene therapies and laboratory of Gerry Krystal at the BC Cancer biosimilars are also regulated by his division. He Agency to receive additional postdoctoral training in actively participates in various Health Canada, ICH, immunotherapy, where he discovered that Herpes WHO, APEC and DIA working groups and expert virus Simplex-1 is a potent activator of NK function committees. and can be an adjuvant in the setting of bone marrow Dr. Wang received his MD from Harbin Medical transplantation for the treatment of leukemia. University, China and was awarded PhD in In 2015 Ismael joined CDRD as an Physiology from the University of British Columbia, Immunotherapy Scientist where he participated in Canada. He joined Health Canada in 1996 with the development of various immunotherapy many years of scientific and clinical research platforms, including a novel targeting arm for CAR- experience in both academic and clinical settings. T cells that can potentially enable therapeutic efficacy against various solid tumors, and in 2016 Ismael Samudio, CDRD assumed the leadership of the Biologics Division. Ismael Samudio obtained his Ph.D. in genetics from Ismael has published over 70 peer reviewed articles Texas A&M University (2002), where he and various book chapters on the use of small investigated the mechanisms of non-canonical molecules, cellular therapeutics, and immunotherapy estrogen receptor signaling in breast cancer cells, strategies for the treatment of cancer, and is a with particular interest in chromatin remodeling and leading expert on tumor metabolism. estrogen receptor/Sp1 interactions. After

54s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

Thursday, May 24 SESSION 3B: The Gut Microbiome as a Novel Therapeutic Target

Chair: Brad Urquhart, Western University

microbiome. Culturing provides access to the rich Overview of the Microbiome and its Potential diversity of the microbiome and facilitates Role in Therapeutics bioprospecting the microbiome for novel therapeutic potential. Michael G Surette, Professor, Canada Research Chair in Interdisciplinary Microbiome Research, Michael G Surette Farncombe Family Digestive Health Research Michael G. Surette is Professor of Medicine and Institute, Michael G. DeGroote Institute for Biochemistry, and Canada Research Chair in Infectious Disease Research, McMaster University, Interdisciplinary Microbiome Research in the Hamilton ON Canada Farncombe Family Digestive Health Research Institute and Michael G. DeGroote Institute for The human body is host to numerous complex Infectious Disease Research at McMaster microbial communities at different body sites that University. His group researches the human comprise the human microbiome. These microbes microbiome of the airways and gut in health and and their dynamic interactions with each other and disease. The lab is focused on high throughput with the host play critical roles in human culturing and phenotyping methods combined with development and health. The microbiome plays next-generation sequencing approaches to critical roles in normal development, investigate infectious disease and the microbiome, digestion/nutrition and maintenance of immune and changes in the microbiome across the life span. homeostasis. However, bacteria within the Specific diseases researched include cystic fibrosis, microbiome also contribute to disease: as pathogens, asthma, pneumonia, ulcerative colitis, and irritable as reservoirs of antibiotic resistance and virulent bowel syndrome. genes and, when these microbial communities become out of sync with their host, as drivers of chronic inflammatory diseases. The study of the Microbial Effects on Innate and Adaptive microbiome has mostly been driven by culture- Immunity independent DNA sequencing approaches. There is a prevailing view that much of the human Kathy D. McCoy, University of Calgary microbiome (and microbial diversity in general) is not readily accessible to cultivation in the laboratory. The intestinal microbiome plays a critical role in Many studies are challenging this dogma and we shaping the development and function of innate have established culture strategies that capture the immune cells at both mucosal and systemic sites. diversity of the microbiota of the gastrointestinal and Although host-microbial interactions throughout life respiratory tracts. Importantly, we demonstrated that are critical for maintaining homeostasis and a greater diversity of microbiota is revealed by regulating the immune system, these interactions are combining culture with molecular methods than by likely to be especially important in early life. The culture-independent methods alone. Moreover, our dynamics of early life microbial colonization plays data has allowed us to define simple conditions for an important role in development of the immune targeted enrichment of specific taxa of interest. We system and can critically influence susceptibility to a are combining these approaches with genomics and variety of immune-mediated diseases later in life. culture-enriched metagenomics to explore the Changes in microbial composition during early life diversity and functionality of the human when the immune system is still developing have

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been demonstrated to be particularly important, but even including endocrinology, cardiology, suggesting a critical window of opportunity for neurology, rheumatology and psychiatry. Fecal proper conditioning of the immune system. While Transplants are both a high tech and extremely low live microbes are very efficiently contained to tech solution to the problem of an altered mucosal sites, systemic exposure to microbial microbiome. We will outline the basic mechanisms products or metabolites is ubiquitous and exposure by which something previously thought of as “just to maternal microbiota-derived metabolites can even crap” can impact diverse physiological processes, occur in utero. We utilize gnotobiotic mouse models and the potential for therapeutic alteration of the gut in an effort to gain greater insight into the multiple microbiome in the treatment and prevention of mechanisms by which the intestinal microbiota human disease. determines the function of innate and adaptive immune cells and promotes homeostasis. A deeper Michael Silverman understanding of the underlying molecular and Training: cellular pathways involved is required in order to Medical School and Internal Medicine harness the power of the microbiome to treat or Residency: University of Toronto. prevent disease. Infectious Diseases Fellowship: University of Manitoba Kathy McCoy HIV Postdoctoral Research Fellowship: Dr. Kathy McCoy, PhD, is a Professor in the Dept. University of California, San Francisco. of Physiology & Pharmacology, Cumming School of Board Certified: Internal Medicine and Infectious Medicine, member of the Snyder Institute for Diseases Chronic Disease, and scientific director of the Clinical and Academic Activities: International Microbiome Centre at the University of Chair/Chief of Infectious Diseases, Western Calgary. Her lab is interested in the dynamic University interplay between the gut microbiota and the innate Medical Director of the HIV Clinic, St Joseph’s and adaptive immune systems. Using germ-free and Hospital gnotobiotic mouse models her research group aims Co-Director of Infection Control, London Health to understand how exposure to intestinal microbes Sciences and St Joseph’s Hospital early in life educates and regulates the developing POEM (Program of Experimental Medicine) immune system and how this impacts on Scientist susceptibility to immune-mediated diseases such as Assistant Professor of Global Health, Dalla Lana allergy and autoimmunity. Her lab studies School of Public Health, University of Toronto microbiome-immune interactions in health and Major Research Interests: diseases and aims to elucidate the molecular Gut Microbiome and Fecal Microbial mechanisms by which the commensal microbiota Transplantation influences host immunity. Prevention of Mother to Child Transmission of HIV Factors Driving Inappropriate Antibiotic Fecal Microbial Transplants: Treatment of C. Prescribing in Community Practice Difficile and Beyond Infections in Marginalized Populations

Michael Silverman, Western University Unexplained Atherosclerosis and Metabolic Historically the organisms within the gut were not Products of the Intestinal Microbiome considered important physiologically. Awareness of the importance of the gut “microbiome” was first J. David Spence M.D., Professor of Neurology and raised by the potentially life threatening problem of Clinical Pharmacology; Stroke Prevention & Clostridium difficile infection which could be Atherosclerosis Research Centre, Robarts Research triggered by antibiotics which damage the normal Institute; Western University, London, Ontario microbiome and allow this pathogen to overgrow. Recently the impact of the gut microbiome on many Background and Aims: There is increasing other common medical problems has been awareness that the intestinal microbiome plays an highlighted; including not just in gastroenterology important role in human health. We investigated its

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role in the burden of carotid atherosclerosis, J. David Spence measured by ultrasound as total plaque area. Professor Spence has focused on stroke prevention Methods: Multiple regression with traditional risk since his second year of Neurology residency with factors was used to identify three phenotypes among Dr. Henry Barnett. He realized then that half of the ~ 316/3,056 patients attending vascular prevention 1000 strokes he had seen were due to hypertension, clinics. Residual score (RES; i.e. the distance off the and therefore entirely preventable. He studied regression line, similar to standard deviation) was Zoology and then Medicine at Western University, used to identify the 5% of patients with much less obtained Royal College Fellowships in both plaque than predicted by their risk factors (Protected, Neurology and Internal Medicine at Western, and RES <-2), the 90% with about as much plaque as completed a fellowship in Clinical Pharmacology at predicted (Explained, RES -2 to 2) and the 5% with the Cardiovascular Research Institute, University of much more plaque than predicted (Unexplained RES California at San Francisco. He then returned to >2). Metabolic products of the intestinal microbiome Western in 1976, opening the third hypertension that accumulate in renal failure – gut-derived uremic Clinic in Canada in 1977. By 1983, due to efforts by toxins (GDUT) – were assayed in plasma by ultra- the Department of Family Medicine in cooperation performance liquid chromatography coupled to with his clinic, strokes in the London area were quadrupole time-of-flight mass spectrometry. down by half. Results: Plasma levels of trimethylamine n-oxide He pioneered the measurement of 2-dimensional (TMAO, derived largely from egg yolk and red carotid total plaque area beginning in 1990, and meat), and p-cresyl sulfate, p-cresyl glucuronide, since 1994 has collaborated with Prof. Aaron Fenster and phenylacetylglutamine (derived from amino and Dr. Grace Parraga at the Robarts Research acids) were significantly lower among patients with Institute in measurement of 3D plaque volume, the Protected phenotype, and higher in those with plaque ulceration and assessment of vulnerable the Unexplained phenotype, despite no significant plaque. He also pioneered a new approach to differences in renal function or in dietary intake of vascular prevention  “treating arteries instead of nutrient precursors of GDUT. In linear regression treating risk factors”, that has markedly reduced risk with a broad panel of risk factors, TMAO (p = among high-risk patients with carotid stenosis. His 0.015) and p-cresyl sulfate (p = 0.016) were research program focuses on measurement of significant independent predictors of carotid plaque atherosclerosis by ultrasound, for patient burden. Plasma levels of GDUT were significantly management, genetic research and for assessing higher with even modest renal impairment, were effects of new therapies. Other areas of expertise associated with higher carotid plaque burden, and include vitamin therapy for homocysteine, the were not related to Mediterranean diet scores. clinical pharmacology of stroke prevention, Conclusions: The intestinal microbiome appears to physiologically individualized therapy for resistant play an important role in atherosclerosis. These hypertension, nutrition in stroke prevention and findings raise the possibility of novel approaches to identification of high-risk asymptomatic carotid treatment of atherosclerosis such as fecal stenosis. He has seen over 40,000 patients at high transplantation and probiotics. Patients with renal risk of stroke, preventing ~ 10,000 strokes impairment, including the elderly, should avoid egg personally, but by his research, publications and yolk and limit intake of animal flesh, particularly red over 600 lectures on stroke prevention to thousands meat. of physicians in 39 countries has been able to *Co-authors: Chrysi Bogiatzi M.D., Gregory Gloor accomplish much more. Despite a busy clinical Ph.D., Emma Allen-Vercoe Ph.D., Gregor Reid practice, his publications include 4 books and over Ph.D., Ruth G. Wong M.Sc., Bradley L. Urquhart 450 peer-reviewed publications, with with an H- Ph.D., Vincent Dinculescu M.D., Kelsey N. Ruetz index of 78 on Google Scholar, i-10 index 263. BMSc., Thomas J. Velenosi PhD, Michael Pignanelli BMSc., Caroline Just M.D.

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Thursday, May 24 SESSION 3C: Practical Pharmacology: Case Studies from Across the Country

Chair: George Dresser, Western University

Clearing Up Controversies around Carfentanil A Case of Unilateral Adrenal Adenoma with Resistant Hypertension Jessica L.S. Leen, MD, FRCPC, University of Toronto Marc L Chretien, George K Dresser Division of Clinical Pharmacology and Toxicology, This talk will provide an overview of our current Department of Medicine, Western University understanding of carfentanil, a specific fentanyl analogue, centred around a case. Topics include the We discuss a case of a 60-year-old gentleman with history of the drug as an animal tranquilizer to its history of resistant hypertension and hypokalemia current role as a potent adulterant of illicit drugs. who was referred to outpatient clinic for workup and Attendees will develop a working knowledge of management of suspected secondary hypertension. carfentanil’s pharmacology based on animal studies Initial interview revealed ~20-year history of and case reports. Controversies to be clarified worsening hypertension, with associated include detection challenges and appropriate first hypertensive nephropathy, and obesity, without responder safety precautions. history of diabetes mellitus, no angina-like symptoms or history of acute coronary syndromes, Jessica L.S. Leen no cerebrovascular accidents, no obstructive sleep Jessica L S Leen is a Royal College of Physicians apnea, no smoking and no alcohol use/abuse. At and Surgeons of Canada certified general internist initial assessment, the patient’s antihypertensive who completed her core training and medical school medications included - chlorthalidone 25 mg daily, at the University of Toronto. She is currently amlodipine 10 mg daily, coversyl 8 mg daily, completing her final year of her internal medicine metoprolol 75 mg bid, spironolactone 25 mg daily. subspecialty fellowship in Clinical Pharmacology Physical examination showed supine blood pressure and Toxicology. Her areas of focused interest 178/84, pulse 68, weight 104.9 kg, with normal heart include addiction medicine, specifically opioid sounds, no enlarged or displaced apex, no abdominal substitution therapies, therapeutic use of bruits, and unremarkable fundoscopy. Initial cannabinoids as opioid-sparing agents, and adverse bloodwork showed serum potassium 3.6, serum drug reactions. Her career goals include improving creatinine 146, serum renin 5.2, serum aldosterone the care of the patient with addictions and promoting 973, serum cortisol 438. CT adrenals showed 1.2 cm the value of clinical pharmacology in the left adrenal nodule. Follow-up venous sampling community. In her off time, she enjoys painting, showed serum aldosterone distal IVC 1,270 yoga and cooking. (pmol/L), proximal IVC 5,820, left renal vein 5,760, left adrenal vein >27,000, right renal vein 974. Sampling from right hepatic vein, near location of right adrenal vein drainage, showed serum aldosterone 682. Serum cortisol sampled at all sites was within normal limits. The patient completed laparascopic left adrenalectomy for left adrenal Conn’s tumor. A review of current literature and treatment guidelines provides a framework for clinical decision making in this scenario.

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Improving Outcomes for Childhood Cancer of drug-related toxicities in the treatment of Patients Using Genomics-Guided Treatment childhood cancer. Optimization Catrina M Loucks Catrina M Loucks, Division of Translational Catrina is a postdoctoral fellow working with Dr. Therapeutics, Department of Pediatrics, Faculty of Bruce Carleton and the Canadian Medicine, University of British Columbia, Pharmacogenomics Network for Drug Safety Vancouver, BC, Canada (CPNDS) to understand how genetic variation contributes to the likelihood of developing drug- While the 5-year survival rates for children with related toxicities, especially in childhood cancer cancer continue to improve, the major problem of treatment. Catrina has experience uncovering genetic drug-related toxicities remains. Drug-related causes for rare disorders from her Bachelor of toxicities resulting from cancer treatment have long Health Sciences (BHSc) and subsequent MSc work been regarded as necessary risks, balanced by the at the University of Calgary, under the supervision hope of curing a potentially fatal disease. of both Dr. Micheil Innes and Dr. Jillian Importantly, pharmacogenomics, the study of how Parboosingh. She then sought to explore functional genetic variability contributes to individual drug impacts of uncovered genetic mutations by pursuing responses, works to identify individual genetic a PhD under the supervision of Dr. Michel Leroux at differences that can help predict a patient’s risk of Simon Fraser University, using the simple developing serious drug-related toxicities before a roundworm, C. elegans, as a model. To understand drug is administered. The Canadian how genetic information can be used to improve the Pharmacogenomics Network for Drug Safety clinical care of patients, Catrina will incorporate (CPNDS) was established in 2004 with a mission to genetic predictors of drug-related toxicities improve drug safety, and through a personalized associated with childhood cancer treatment into medicine project, the CPNDS has successfully predictive genetic tests that can be used by clinicians implemented genomic testing across British and families to assess the risks and benefits Columbia to predict the risk of three drug-related associated with specific drug treatments. toxicities in childhood cancer. The introduction of genomic testing into clinical practice provides clinicians with an additional tool to select the safest Choosing the Right Antihypertensives for your and most effective treatment strategy for patients. Pregnant Patient Knowing who is at higher risk prior to cancer treatment means that alternative treatment strategies Albayada Medhar, Western University can be considered, dosing can be adjusted in some cases, and monitoring for the development of drug- Objectives: Classification and diagnosis of related toxicities can be enhanced. Furthermore, hypertension disorders in pregnancy, and knowing who is at lower risk prior to cancer management of hypertension in pregnancy and treatment can provide reassurance for both clinicians postpartum. and families when considering aggressive therapy. Hypertension is a highly prevalent condition in For example, for a 12-year-old boy treated at BC pregnancy, yet we have a limited data giving the Children’s Hospital who relapsed one year post- challenges of conducting studies on this unique treatment, the treatment that promised the greatest population. chance of survival included anthracyclines that are I will be presenting the new Hypertension often accompanied by the severe drug-related Canada's 2018 Guidelines for the Management of toxicity of cardiac dysfunction (cardiotoxicity). Hypertension in Pregnancy. Upon genomic testing, this boy was found to be at low risk for developing cardiotoxicity based on his Albayda Mehdar individual genetics, providing reassurance to initiate Albayda Mehdar is a current fellow in clinical anthracycline-based therapy, while balancing hope pharmacology and toxicology program at University for survival with risk of toxicities. Importantly, of Western. She finished her internal medicine through this work the CPNDS hopes to further training at the University of Toronto with plans to genomics-based interventions that reduce the burden pursue further training in obstetric medicine.

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CSPT Clinical Fellowship Award Lecture

induced psychosis Genetic Screening and Cannabis Induced- 3. Review genetic screening targets to identify Psychosis: Who, What and When? those at risk for the subsequent development of cannabis induced psychosis Gavin Sun, Division of Clinical Pharmacology and Toxicology, Western University, London, ON Gavin Sun Dr Sun is currently in his final year of fellowship in There is a high likelihood of cannabis being Clinical Pharmacology and Toxicology at Western legalized in Canada. With such a change in policy, it University in London, Ontario. He was born and is expected that there will a subsequent increase in raised in Johannesburg, South Africa and graduated consumption of the substance. In other jurisdictions with an MD from the University of the where legalization permitted a subsequent increase Witwatersrand in 2006. He subsequently completed in usage, an increased incidence of cannabis-related my 2 years of internship and 1 year of community morbidity has been reported. service in South Africa in 2009. He emigrated to Genomic profiling has identified individuals Canada in 2010 and practised in rural Alberta for 3- with higher risks of development of cannabis and-a-half years. A long-term goal was to pursue induced psychosis. While barriers currently exist in specialist medicine and he was accepted into a the availability of such testing, with cannabis medicine residency at the University of Calgary in induced psychosis one of the major worrisome July 2013. He completed his core Internal Medicine sequelae from cannabis use and given the anticipated training in Calgary and subsequently started a increase in consumption, it may be of value to Clinical Pharmacology fellowship in London in implement genetic screening for certain cohorts of 2016. His practice interests include vascular health, potential cannabis consumers. acute toxicology, factors driving prescribing Objectives of presentation behavior and clinical implementation of 1. Review the pathophysiology of cannabis pharmacogenomics. induced psychosis 2. Discuss the clinical presentation of cannabis

CSPT Post-Doctoral Award Lecture

make important advances in identifying genetic variants that contribute towards inter-individual risk Pharmacogenomics for Neurological Conditions to adverse drug reactions. For example, it has and Related Phenotypes recently been shown that a high proportion (i.e. 97%) of individuals carry clinically-meaningful Galen Wright, Canadian Pharmacogenomics pharmacogenomic variants, indicating the important Network for Drug Safety (CPNDS), University of role that genetic variation plays in drug response. British Columbia, Vancouver, BC For over a decade, the Canadian Pharmacogenomics Network for Drug Safety has been involved in Neurological disorders present a high health care various neurological pharmacogenomic studies, burden on society and are becoming of increasing including research into analgesic-related toxicities, concern with an aging global population. Adding to severe cutaneous reactions from antiepileptics, this burden, numerous medications are associated immunomodulatory agents in multiple sclerosis and with adverse drug reactions that influence the neurotoxicities from cancer medications. This nervous system, causing debilitating drug-induced presentation will discuss how pharmacogenomics neurotoxicities. With ready access to genomic can aid in the treatment of neurological conditions technologies, pharmacogenomics is beginning to and related phenotypes by identifying biomarkers of

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clinical relevance, in addition to increasing our research involved characterizing genes that are understanding of the biological mechanisms involved in antipsychotic response in African underlying these reactions. Additionally, the overlap populations. His current research projects include existing between the genes influencing drug-induced investigating serious adverse drug reactions from neuropathies and those that heritable neuropathy chemotherapeutic agents as well as those caused by conditions will be discussed. Ultimately, such medications used to treat neurologic conditions. This research will contribute towards moving work has led to the identification of predictive pharmacogenomic tests into clinical care to provide biomarkers for drug-induced neurotoxicities, liver safer and more effective treatment solutions. injury and severe cutaneous reactions. Dr. Wright has been supported by various funding Galen Wright organizations, including the Canadian Institutes of Galen Wright is a researcher at the Canadian Health Research and the Drug Safety and Pharmacogenomics Network for Drug Safety Effectiveness Cross-Disciplinary Training Program. (CPNDS), University of British Columbia. His To date, he has published 28 peer-reviewed research interests lie in the fields of manuscripts and was recently awarded the 2016 pharmacogenomics, clinical pharmacology and Canadian Society of Pharmacology and Therapeutics bioinformatics. Dr. Wright completed his PhD in Publication Award. Genetics at Stellenbosch University, where his

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Thursday, May 24 SESSION 4A: Translational Medicine

SPONSORED BY: AstraZeneca, Merck, Roche

Co-Chairs:Ming Tsao, Ontario Cancer Institute, and Janet Dancey, Canadian Cancer Trials Group, and Queen's University

discuss some of the issues surrounding Opening Pandora’s Genome: Rethinking implementation of genomic testing. Molecular Diagnostics Aly Karsan Aly Karsan, MD, FRCPC, Medical Director, Centre Aly Karsan is Professor of Pathology and for Clinical Genomics, Genome Sciences Centre, Laboratory Medicine, University of British British Columbia Cancer Agency, and Professor, Columbia, the Medical Director of the Cancer Pathology & Laboratory Medicine, University of Genetics & Genomics Laboratory, and the Medical British Columbia, Vancouver, BC Director for the Centre for Clinical Genomics at the Genome Sciences Centre, at the British Columbia Tumors are currently classified based on tissue or Cancer Agency. The Centre for Clinical Genomics, organ of origin and then further subclassified by which is embedded within the Genome Sciences morphology and immunohistochemistry. Centre comprises pathologists, clinical and basic Increasingly, specific genetic changes are being scientists with genetics and genomics expertise, and associated with tumor subtypes and by extension bioinformaticians, as well as a social scientist and with therapeutic subclasses. As more genetic events health economist. He received his MD from Queen's are being associated with different tumor types, it is University at Kingston, completed his residency in becoming critical to evaluate different genetic events Hematological Pathology at the University of British in order to reveal potential treatments for individual Columbia, which was followed by a research cancers. In some cases identification of specific fellowship at the University of Washington in genetic events define a contraindication to a Seattle. He has a major interest in developing next- particular class of targeted therapy. The ability to generation sequencing approaches for application in select the right patient for the right treatment at the the clinic. This work led to the clinical right time forms the basis of precision medicine. implementation of the first CAP-compliant next- Genetic testing refers to testing a single gene or part generation sequencing test in Canada. of gene, while genomic testing refers to testing the As a Clinician-Scientist of the Canadian entirety of the genome. Use of the term genomic Institutes of Health Research, and a Senior Scholar testing is sometimes coopted to refer to the testing of of the Michael Smith Foundation for Health large numbers of genes simultaneously (not Research, his research interests focus on functional necessarily whole genome), and this is also referred genomics in the myeloid cancers including acute to as gene panel testing. Mutation frequencies vary leukemia. In particular, recent research has revolved more than 1000-fold across different cancers. around the haploinsufficiency of microRNAs and Because genomic testing can identify many different derepression of immune signaling pathways in variants, not all of which have a clinical impact, myeloid cancers. proper interpretation of variants is important. The His research is currently supported by grants ability to test many genes for variants has become from the Canadian Institutes of Health Research, clinically tractable through the use of next- Canadian Cancer Society Research Institute, the generation sequencing. In this presentation I will Heart and Stroke Foundation, Genome Canada, focus on the use of next-generation sequencing in Genome BC, the Terry Fox Research Institute and diagnosis and prediction of treatment response, and

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the BC Cancer Foundation. University Health Network, Princess Margaret Cancer Centre in Toronto. He is a Professor of Biomarker Testing in Lung Cancer Laboratory Medicine and Pathobiology, and Professor of Medical Biophysics at the University of Ming S. Tsao, MD, FRCPC, Consultant Pathologist, Toronto. University Health Network and Professor, Dr. Tsao is the co-chair of the Correlative Department of Laboratory Medicine and Science and Tumor Biology Committee of the Pathobiology, Department of Medical Biophysics, Canadian Cancer Clinical Trials Group (CCTG). He University of Toronto, Toronto, Ontario, Canada. is a current member (and Past Chair 2011-13) of the International Association for the Study of Lung Lung cancer accounts for approximately 30% of Cancer (IASLC) Pathology Committee, IASLC deaths from all cancer types in Canada, with an Staging and Prognostic Factor Committee, standing overall 5-year survival of 16%. Eighty percent of member of the Editorial Board for WHO Blue lung cancer belong to non-small cell lung cancer Books on Classification of Tumours 5th edition, and (NSCLC), with small cell lung cancer (SCLC) the Canadian Cancer Society Advisory Committee making up the remaining 20%. Up until 2004, on Research. He was a past Associate Editor for the chemotherapy has been the main systemic therapy Journal of Thoracic Oncology and a member (2010- available for patients with advanced stage lung 17) of the Editorial Board of Journal of Clinical cancer, which account for two-thirds of all lung Oncology. He was the lead co-editor of the IASLC cancer patients. Chemotherapy has response rates of Atlases of ALK and ROS1 Testing and of PD-L1 30-40%, yet there is no biomarker that can guide the testing in Lung Cancer. He led several multi-centre selection of patients for this toxic therapy. The studies that resulted in pan-Canadian standardization discovery of oncogenic mutations in the tyrosine of lung predictive biomarker assays, including tests kinase domain of the epidermal growth factor for EGFR, ALK, ROS1, PD-L1 and circulating receptor (EGFR) gene has revolutionized the tumor-derived EGFR T790M mutation. management of NSCLC patients, which now Dr. Tsao received the 2011 O. Harold represents the poster child of personalized cancer Warwick Award from the Canadian Cancer Society, medicine in solid tumours. Subsequent discoveries the 2016 IASLC Mary Matthew Pathology Award, of rearrangement involving the ALK and ROS1 and the CCTG 2017 Dr. Joseph Pater Founder's genes, which generated oncogenic fusion tyrosine Award for Excellence in Clinical Trials Research. kinases, have led to the development of additional He has published slightly more than 500 manuscripts therapies, which are highly effective for lung cancer and 10 book chapters. He was the Principle patients whose tumours harbour these driver Investigator and Director of the CIHR/Terry Fox oncogenes. More recently, efficacious drugs with Foundation Specialized Training Initiative for high response rates have been identified and Health Research (STIHR) Program for clinician approved for the treatment of patients with BRAF scientists in molecular pathology of cancer, a V600E mutation. With ALK, ROS1, BRAF and program focused on training of next generation other upcoming novel targets being present in 1-5% academic pathologists in Canada. of NSCLC patients, lung cancer is becoming a constellation of rare diseases, the treatment of which depends on the execution of complex biomarker Tumor Mutational Burden as a Biomarker for testing algorithm requiring rapid turnaround time, as Cancer Immunotherapy these patients could experience rapid clinical deterioration when treatment is delayed. New tests Caitlin Connelly, Ph.D., Scientist, Foundation such as those for immune oncology therapies are Medicine, Cambridge, MA rapidly being added to the testing strategy for lung cancer patients. Issues and challenges of biomarker Biomarkers capable of predicting response to testing in lung cancer will be discussed. checkpoint inhibitor therapies represent a significant clinical need. Increased tumor neo-antigenic burden Ming Sound Tsao has been linked to PD1/PD-L1 therapeutic response Dr. Tsao is a Consultant Thoracic Pathologist, a in several conditions including metastatic melanoma, Senior Scientist and the M. Qasim Choksi Chair in non-small cell lung carcinoma and colorectal cancer. Lung Cancer Translational Research at the However, the challenges and high cost associated

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with neo-antigen discovery has shifted focus towards vary and encompass the positive diagnosis of the more efficient methods of response stratification. As tumor and its molecular taxonomy, its prognosis, the such, tumor mutational burden (TMB) determination choice of the best therapeutic option in from whole exome sequencing and comprehensive monotherapy, and guidance for treatment genomic profiling has emerged as a potential combinations. From a clinical perspective, the solution. Specifically, clinical feasibility of TMB diversity of genomic alterations and testing calculated from the FoundationOne comprehensive objectives underlines the need to define the best genomic profiling assay has been demonstrated in molecular testing algorithm based on optimal more than 500 patients across three disease types, benefit/cost ratio for a specific objective and in a including urothelial bladder carcinoma, non-small specific healthcare environment. The adopted cell lung cancer, and metastatic melanoma, with case molecular testing strategy also needs to take into reports in glioblastoma and colorectal cancer. We account the pre-analytical constraints such as tissue detail the method utilized to establish TMB and flows, the analytical turn-around times, and tests show that targeted sequencing of 1.25 Mb provides reimbursement. This presentation will discuss how an accurate measurement of exome-wide TMB. We these questions can impact the technological choice describe the landscape of TMB observed from in the clinical setting. We will discuss with examples >100,000 advanced clinical cancer specimens, taken from solid tumors the current molecular across > 400 cancer types and summarize the testing options, and examine how to capitalize on the clinical performance across multiple indications. excellent collaborative network that exists in Canada Finally, we discuss the development of an assay to to define an adaptive and sound robust molecular measure TMB from circulating tumor DNA and testing strategy. We will also discuss the importance retrospective analysis of clinical trial data using this and challenges to integrate transcriptomic and bTMB assay. These data demonstrate that TMB can proteins assessment in cancer precision medicine. be accurately assessed using a clinically available CGP assay and that this biomarker can stratify Alan Spatz patient response. Examining the landscape of TMB Dr. Alan Spatz is Director of the Division of across a diversity of tumor types provides new data Pathology of the McGill University Health Center to better understand the population that can OptiLab that integrates academic pathology labs potentially benefit from immunotherapy. from the McGill University network, Professor of Pathology and Oncology at McGill University, and Caitlin Connelly Director of the “X chromosome and cancer” basic Caitlin Connelly obtained her Ph.D. in Genome research lab at the Lady Davis Institute for Medical Sciences at the University of Washington (Seattle, Research. He is also the head of the Molecular WA). She is a Scientist in the cancer genomics Pathology research Center at the Jewish General group at Foundation Medicine, where she has carried Hospital of Montreal. out research using data from comprehensive Dr. Spatz received his medical education in genomic profiling of tumor specimens and cell-free Lyon, France, and did his residency in Pathology in DNA samples. Paris at the Pierre et Marie Curie University. He worked from 1994 to 2008 at the Gustave Roussy Cancer Institute in Villejuif, France. He was strongly Molecular Diagnostic Advancement in Oncology involved in translational and clinical research, for instance as a board member of the European Alan Spatz, McGill University, McGill University Organization for Research and Treatment of Cancer Health Center & Jewish General Hospital (EORTC) and as the chair of the EORTC Melanoma and Pathobiology groups. He was also President of Effective use of targeted cancer therapies typically the French division of the International Academy of depends upon the identification of actionable Pathology. He is currently co-Chair of the genomics alterations, and sometimes post- Melanoma committee of the Canadian Cancer Trials translational modifications. Genomic alterations can Group and serves as a board member of several include single-nucleotide sequence variants, international professional organizations, in editorial insertions/deletions, chromosomal copy number boards and strategic committees. variations, and somatic structural alterations. For a Dr. Spatz has created at McGill University a same molecular alteration, the testing objectives can highly successful molecular pathology program that

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integrates seamlessly clinical activities and research, completed research fellowships at the CCTG and has helped consolidate the role of research in (Formerly the NCIC Clinical Trials Group NCIC pathology training. He has made mandatory the CTG) and at the Institut Gustave Roussy, Villejuif, involvement of the pathology residents in research France. and has supervised more than 45 residents in In her current position, Dr. Dancey is molecular pathology and biomarkers-oriented responsible for the strategic development and research. He has been active in connecting research operational oversight of programs within CCTG and teams in different research centers and universities 3CTN. Her clinical focus is on melanoma and to create synergistic collaborations, especially in gastrointestinal malignancies. Key accomplishments melanoma which is his main expertise. He also acts included the development and implementation of the in different research consortiums, such as the Exactis CCTG strategic plan, establishment of the High NCE, which is a pan-Canadian research group on Impact Clinical Trial Program following successful precision medicine. One of his recent initiatives, international peer review, and the development of COSMET, is a consortium involving Quebec teams novel trials to evaluate investigational drugs in rare at McGill and Université de Montréal and partners tumour settings, to evaluate next- generation from China that has received funding from FRQS. sequencing technologies in cancer patient His research lab has two focuses: the molecular management. As Leader of the 3CTN, she is mechanisms associated with resistance to therapy, responsible that the network member trial staff and and the specific mechanisms of X chromosome institutions have resources to rapidly initiate and inactivation and its relation to cancer. His lab has conduct cancer clinical trials including those with deciphered the role of the PPP2R3B protein in complex biospecimen and imaging collections. melanoma progression and its main partners, and has Dr. Dancey has expertise in methodologies demonstrated the functional role of the gender- related to the development, implementation and related haploinsufficiency. His research is also analysis of phase I, II, and III studies of cancer oriented towards the role of the interaction between therapeutics and in the measurement of quality of CTCF and BORIS using X chromosome inactivation life in cancer trials. She has been a co-investigator, as a model of chromatin remodeling. principal investigator and study chair of institutional, He has authored more than 190 original industry, and Canadian cooperative group phase 1 scientific papers, reports, review articles, and books. and 2 trials. She was the co-applicant on one peer reviewed and three industry sponsored research grants. Panel for Discussion Dr. Dancey has presented at national and international oncology meetings and has been an Janet Dancey (Panel & Session Co-Chair) invited speaker at other cancer centres and CME Dr. Dancey is Director, Canadian Cancer Trials events. She is a member of the Editorial Board of Group (CCTG) and Scientific Director of the PDQ. She is/has been an ad hoc reviewer for peer Canadian Cancer Clinical Trials Network (3CTN) reviewed journals such as the Lancet, Journal of and Senior Investigator, Melanoma Disease Site Clinical Oncology, Journal of the National Cancer Committee for CCTG, and Professor, Department of Institute, Proceedings of the National Academy of Oncology, Queen’s University. Previously, she was Science (USA), Clinical Cancer Research, Cancer Program Leader for High Impact Clinical Trials, Research, Cancer Chemotherapy and Pharmacology, Ontario Institute for Cancer Research, Director, Cell Differentiation and Bone Marrow Clinical Translational Research and Chair, Cancer Transplantation. She has been a member of the Care Ontario Experimental Therapeutics Network. CCTG Investigational New Drugs Committee, From 1999-2008, she as senior investigator and rose CCTG Quality of Life Committee, CCTG Quality to Associate Chief in the Investigational Drug Assurance Committee, and CCTG GI Site Group, Branch of the Cancer Therapy Evaluation Program Colorectal Cancer Working Group. Dr. Dancey has of the National Cancer Institute, United States. She been the recipient of awards for excellence in post- completed medical school at the University of graduate teaching from the University of Toronto Ottawa in 1988. She received certifications in Department of Medicine (1994) and Division of internal medicine and medical oncology from the Medical Oncology (1997, 1998). Royal College of Physicians and Surgeons of Canada in 1992 and 1993 respectively. She has

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University of Toronto in the Department of Molecular Genetics, where he used peptide phage Raffi Tonikian, Merck Canada display libraries to identify specificity profiles for Raffi Tonikian is Associate Director Oncology signaling domains, which led to the mapping of Medical Affairs for Biomarkers, Melanoma and large-scale protein interaction networks in several Breast Cancer at Merck Canada Inc, where he model organisms. During that time, he also spent provides subject matter expertise and coordinates nearly two years at Genentech, Inc. as a Visiting Medical Affairs activities. In addition, Dr. Tonikian Scientist in the Department of Protein Engineering. is responsible for external collaborations and Dr. Tonikian performed his postdoctoral work at the partnerships in the areas of basic and translational Centre for Cellular and Biomolecular Research in oncology research. Toronto, where he developed and utilized phage- Prior to joining Merck Canada, Dr. Tonikian displayed libraries to isolate antibodies against was Medical Advisor in Neuroscience at Novartis cancer related antigens. In addition, he worked on Pharmaceuticals Canada, where he supported the development of antibody-DNA conjugates as Medical Affairs and clinical activities in the fields of biomarker detection reagents Multiple Sclerosis and Neuromuscular diseases. Dr. Tonikian was a Scientist in the Departments of Protein Engineering and Selected CSPS Oral Abstract Presentation Translational Medicine at Biogen in Cambridge, Massachusetts. His work focused on the screening of Combining Statins with Radio-immunotherapy antibody libraries for the discovery of antibody- as a Novel Therapeutic Strategy for Colorectal based therapeutics for autoimmune disorders. In Cancer addition, he studied the utilization of T-cell repertoire diversity assessed using next-generation Vessie Vassileva, Imperial College London sequencing as a potential biomarker for disease activity in autoimmunity. (See Poster Abstract # 13) Raffi received his doctorate degree from the .

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Thursday, May 24 SESSION 4B: Cannabinoids

Chair: Rachel Tyndale, CAMH

(e.g. pain) or ‘autoimpairing’ (e.g. obesity, fatty liver Session Chair: disease). We have developed a portfolio of novel Rachel Tyndale small molecules that target the allosteric binding site Rachel Tyndale PhD is head of Pharmacogenetics at on the cannabinoid CB1 receptor; these include both the Campbell Family Mental Health Research positive allosteric modulators (PAMs) which we are Institute, Centre for Addiction and Mental Health, testing in models of pain and negative allosteric the Canada Research Chair in Pharmacogenomics, modulators (NAMs) which we are testing models of and a Professor in the Departments of Pharmacology fatty liver disease, biopolar disorder and & Toxicology, and Psychiatry at the University of schizophrenia. CB1 PAMs have been shown to be Toronto. Dr. Tyndale focuses on sources of variation effective neuropathic pain models and demonstrate between individuals in drug response in the clinical no evidence of psychoactive side effects seen with area of addictions and mental health, with a focus on CB1 agonists. Furthermore they do not show smoking and opioids. Dr. Tyndale seeks to identify tolerance on repeated administration. and understand risk factors, and underlying There is a critical need for novel treatment mechanisms, in substance abuse and to implement approaches for psychiatric disorders. Perturbations approaches to personalize treatment. Her laboratory in the dopaminergic system playing a role in a program also has a major interest in understanding number of psychiatric disorders. Relating to the how interindividual variation in drug metabolizing dopamine system, the endocannabinoid systems enzymes within the brain alters drug and toxin serves as an important filter of afferent inputs, effects. Dr. Tyndale sits on numerous scientific helping shape how incoming information is advisory boards, editorial boards, was chair for conveyed onto dopamine neurons and to output NIH’s PharmacoGenomics Research Network targets. GluN1-knockdown (GluN1KD - F1: (PGRN.org), and is a lead writer for the 2018 C57Bl/6J x 129S1/SvlmJ) and DAT-knockout Surgeon General’s Report on Tobacco Cessation. (DATKO - C57Bl/6J) mice display hyperactivity, Dr. Tyndale has supervised over 100 scientists, post- impaired habituation and sensorimotor gating, along doctoral fellows and graduate students, published with increased stereotypy and vertical activity, in a over 350 papers and book chapters, given over 250 state of mania-like behaviour. Following acute invited presentations and received over 40 awards in treatment with the CB1 NAM, ABM300 (10mg/kg), clinical and basic pharmacology. amelioration of these dysregulated behaviours was observed. The data suggest that CB1NAMs represent a novel treatment for psychiatric symptoms Therapeutic Potential of CB1 Allosteric as a result of dopamine dysregulation. Furthermore, Modulators targeting the endocannanbioid system offers the opportunity to normalize deficits that arise from Catharine A. Mielnik1, Vincent M Lam1, Iain R. 2 1 1 differing underlying dysfunctions that manifest as Greig , Ali Salahpour , Amy J. Ramsey , Ruth A. 1 1 similar behavioural changes; both of which are Ross , University of Toronto, Faculty of Medicine, mediated by dopamine dysregulation. Department of Pharmacology & Toxicology; 2 University of Aberdeen, UK, institute of Medical Ruth A. Ross Sciences Ruth Ross obtained a PhD in Pharmacology from The University of Edinburgh in 1990. She has held Activation of the endocannabinoid system is research positions at Pfizer and Allergan Inc. In postulated to have opposing roles in various 2008 Dr Ross became Chair in Molecular disorders; the effect being either ‘autoprotective’

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Pharmacology at The University of Aberdeen in reward in both the NVHL and sham animals; both Scotland. In 2013, she relocated to The University of THC treated groups showed decreased responding Toronto to take up the position of Chair of the throughout the entire acquisition period, consistent Department of Pharmacology and Toxicology. Her with decreased motivation to work for a reward in research over the last 25 years has focussed on the adolescent cannabis smokers. In contrast, only the molecular pharmacology of the endocannabinoids THC-treated sham animals showed reduced food cup and phytocannabinoids. Her current research entries, while extinction or renewal of lever pressing involves characterisation of novel small molecules did not differ between groups. Conversely, the that offer new avenues for drug discovery by NVHL animals displayed impaired reinstatement of targeting the endocannabinoid system and related lever-pressing if given food pellets in the extinction orphan receptors for the treatment of pain, liver context. Lastly, THC-treated NVHL and sham disease and mental health disorders. Her research is animals displayed decreased binge-like sweet-fat also focussed on the molecular pharmacology and food consumption in a limited-access paradigm. In biological targets of cannabis constituents with the the autoshaping study, adolescent THC treatment goal of gaining a deeper understanding of both the significantly increased sign-tracking compared to potential deleterious and beneficial effects of vehicle treatment (consistent with increased cue- cannabis. reactivity in adolescent cannabis smokers). This study suggests the adolescent THC exposure may produce long-term changes in reward-related Growing up High: Long-Term Consequence of behaviors, independent of risk for schizophrenia. Adolescent Cannabis Use - Preclinical Studies The discordant findings between instrumental and Pavlovian conditioning may also provide important Jibran Khokhar, Assistant Professor, Department of clues regarding the neurobiological and behavioral Biomedical Sciences, Ontario Veterinary College, underpinnings of the potential “gateway drug” University of Guelph, Guelph, ON effects of adolescent cannabis use as it relates to the risk for future substance use. Adolescent cannabis use occurs commonly, affects neurodevelopment, and is a risk factor for Jibran Khokhar schizophrenia, as well as future substance use. Dr. Khokhar completed his undergraduate training at Schizophrenia, itself, is associated with high rates of Queen’s University, and his Ph.D. in the Department alcohol and drug use as well as motivational and of Pharmacology and Toxicology at the University reward-learning dysfunctions. Thus we were of Toronto, under the supervision of Dr. Rachel interested in whether Δ9-tetrahydrocannabinol Tyndale. During this time, Dr. Khokhar was (THC) exposure during adolescence would influence awarded a CIHR Tobacco Use in Special reward related behaviors in adulthood, especially in Populations Fellowship, as well as a publication the context of neurodevelopmental risk for award for "Best Publication in schizophrenia. Using a neurodevelopmental model Neuropsychopharmacology." He then completed a of schizophrenia, the neonatal ventral hippocampal post-doctoral fellowship in the Department of lesioned (NVHL) rat, we assessed the effects of Psychiatry at Dartmouth College with Dr. Alan adolescent THC (or vehicle) treatments (post-natal Green. In addition to numerous travel and poster day 28-42; 6 mg/kg i.p.) on: (a) free-access 2-bottle awards, Dr. Khokhar held a CIHR Post-doctoral choice alcohol (20% v/v) drinking; (b) context-based Fellowship as well as NIH K99/R00 Pathway to instrumental food reward acquisition, extinction, Independence Award from the National Institute on renewal and reinstatement; and (c) limited access Alcohol Abuse and Alcoholism. Dr. Khokhar was sweet-fat food binge-like eating (n=5/group). In a recently hired as an Assistant Professor in the subsequent study, we assessed the effects of Biomedical Sciences Department at the University adolescent THC (or vehicle) treatment on the of Guelph. Dr. Khokhar’s research aims to acquisition and extinction of Pavlovian autoshaping understand the mechanisms underlying co-occurring (sign-tracking) behavior (n=15-16/group). Neither schizophrenia and substance use disorders, using a NVHL-lesion status nor adolescent THC treatment variety of behavioural, pharmacological and altered free-access alcohol intake in adulthood. translational neuroimaging techniques. In addition, Adolescent THC treatment, however, significantly his research interests also include assessing the long- impaired the motivation to lever press for a food term effects of adolescent drug (e.g., cannabis) use,

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and how these effects might contribute to the risk for Council Integrative Epidemiology Unit at the serious mental illness and addiction. University of Bristol. He was an undergraduate at Website: https://ovc.uoguelph.ca/biomedical- the University of Oxford, before moving to the sciences/people/faculty/Jibran-Khokhar University of Southampton to complete an MSc in Health Psychology and a PhD. Following this, he returned to the University of Oxford, as a Adolescent Cannabis Use: Risk for Mental postdoctoral fellow in the Department of Public Health and Drug Dependence Health and Primary Care and later the Department of Clinical Pharmacology. In 2004-2005 he spent 6 Marcus Munafò, Professor of Biological months as a Visiting Professor at the University of Psychology, School of Experimental Psychology, Pennsylvania. In March 2005 took up a tenured University of Bristol position at the University of Bristol. He was promoted to Reader in Biological Psychology in Cannabis use is strongly associated with subsequent 2008, and Professor of Biological Psychology in adverse mental health outcomes and dependence on 2010. other substances, but determining whether or not this Professor Munafò’s research focuses on reflects a causal effect of cannabis use is complex. understanding pathways into, and the consequences Well-established problems of residual confounding of, health behaviours and mental health, with a and reverse causality mean that strong causal particular focus on tobacco and alcohol use. This inference is impossible in conventional work incudes: 1) observational and genetic epidemiology. Mendelian randomization is a form of epidemiology, and the use of a range of methods that instrumental variable analysis that uses genetic enable stronger causal inference from observational variants associated with exposures of interest (e.g. data, such as negative control and Mendelian cannabis use) to leverage stronger causal inference. randomization methods; 2) the laboratory study of This method has grown rapidly in popularity as an cognitive and neurobiological mechanistic pathways increasing number of relevant genetic variants have that underpin exposure-outcome relationships; and been identified via genome-wide association studies. 3) the development of novel individual- and Using this approach, we have shown that cannabis population-level interventions that target these use increases subsequent risk of schizophrenia, but mechanisms, including choice architecture also that genetic risk of schizophrenia increases the interventions. This work has informed ongoing likelihood of cannabis use initiation. This suggests policy debates, such as the introduction of that some of the observational association between standardised (“plain”) packaging for tobacco cannabis use and schizophrenia may in fact be due to products. He also has interests in the role of reverse causality (e.g. self-medication through the incentive structures in science, and the extent to use of cannabis). We have also shown that tobacco which these shape the robustness and reproducibility use, which is extremely common among regular of scientific research. cannabis users, is also likely to be a causal risk factor for schizophrenia (but, in this case, that schizophrenia risk does not lead to tobacco use). We Opioid Sparing Effects of Cannabinoids: Myth or have also shown that tobacco use leads to Reality? subsequent cannabis use, but not vice versa. Therefore, while adolescent cannabis use does Bernard Le Foll, Medical Head, CAMH; Professor appear to be a causal risk factor for schizophrenia, University of Toronto tobacco use also appears to play an important role. Cannabinoids, when co-administered with opioids, Marcus Munafò may enable reduced opioid doses without loss of Marcus Munafò is Professor of Biological analgesic efficacy (ie, an opioid-sparing effect). This Psychology in the School of Experimental presentation will focus on presenting the results of a Psychology at the University of Bristol, and Director systematic review to determine the opioid-sparing of the Tobacco and Alcohol Research Group potential of cannabinoids. Eligible studies included (http://www.bristol.ac.uk/expsych/research/brain/tar pre-clinical and clinical studies for which the g/). His group is part of the UK Centre for Tobacco outcome was either analgesia or opioid dose and Alcohol Studies, and the Medical Research requirements. Clinical studies included controlled

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studies and case series. We searched Scopus, Bernard Le Foll Cochrane Database of Systematic Reviews, Medline, Dr. Bernard Le Foll, MD PhD MCFP is a clinician- and Embase. Nineteen pre-clinical and nine clinical scientist specialized in drug addiction. He is the studies met the search criteria. Seventeen of the 19 Medical Head of the Concurrent Outpatient Medical pre-clinical studies provided evidence of synergistic & Psychosocial Addiction Support Service at the effects from opioid and cannabinoid co- Centre for Addiction and Mental Health (CAMH), administration. Our meta-analysis of pre-clinical providing care to several thousands of patients per studies indicated that the median effective dose year through a multi-disciplinary clinical team. He is (ED50) of morphine administered in combination the Head of the Translational Addiction Research with delta-9-tetrahydrocannabinol (delta-9-THC) is Laboratory within the Campbell Family Mental 3.6 times lower (95% confidence interval (CI) 1.95, Health Research Institute of CAMH and Head of the 6.76; n=6) than the ED50 of morphine alone. In Alcohol Research and Treatment Clinic within addition, the ED50 for codeine administered in CAMH. He is a Professor at University of Toronto combination with delta-9-THC was 9.5 times lower in the Departments of Family and Community (95% CI 1.6, 57.5, n=2) than the ED50 of codeine Medicine, Psychiatry, Pharmacology and Institute of alone. One case series (n=3) provided very-low- Medical Sciences and holds several graduate faculty quality evidence of a reduction in opioid appointments. Dr Le Foll has published >160 peer- requirements with cannabinoid co-administration. reviews manuscripts, H-index 46, >6,000 citations. Larger controlled clinical studies showed some He has performed research on the treatment of clinical benefits of cannabinoids; however, opioid cannabis use disorders, impact of cannabis of driving dose changes were rarely reported and mixed and the medical use of cannabis. He has received findings were observed for analgesia. In summary, numerous awards and his research is funded by pre-clinical studies provide robust evidence of the CIHR, NIH and other funding agencies. He has been opioid-sparing effect of cannabinoids, whereas one consultant/advisor for CAMH, CCSA, NIH and of the nine clinical studies identified provided very- Health Canada and has presented on cannabis issue low-quality evidence of such an effect. Prospective to the House of Commons and to the Senate. He has high-quality-controlled clinical trials are required to contributed to the CAMH cannabis policy statement determine the opioid-sparing effect of cannabinoids. and to the development of Lower Risk Cannabis Use Those findings will be discussed along more recent Guidelines. findings and put into perspective on how those systems may interact.

Panel Discussion: The Future of Medical Cannabis in Canada

Co-Chairs: Christine Allen, University of Toronto, and Aras Azadian, Avicanna

president of an investment corporation in the PANEL MEMBERS cannabis space and former COO of an oncology company. Aras has degree in economics from York Avicanna: Aras Azadian, President University in Toronto and MBA from EADA Business School in Barcelona. Aras is the chief executive officer and a co-founder of Avicanna, and brings with him extensive senior Beleave: Peter Chen, Vice President of Science management experience in the biotechnology and and Technology financial sectors including his involvement in several successful start-ups. In addition to his Dr. Peter Chen holds a PhD in food science from the international experience in corporate development University of Guelph and Agriculture and Agri-Food his diverse roles included his position as the Canada and is the recipient of the 2017 Governor

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General’s Academic Gold Medal for academic University of Toronto: Lakshmi P. Kotra, B. excellence. His research at the University of Pharm.(Hons), Ph.D. Waterloo – School of Pharmacy and the University of Guelph – Department of Food Science is funded Dr. Kotra is Professor, Leslie Dan Faculty of through NSERC and Beleave Kannabis Corp. As Pharmacy, University of Toronto; Senior Scientist, Vice-President of Science & Technology at Beleave, Toronto General Hospital Research Institute and his focus is on developing novel drug delivery Multi-Organ Transplant Program, and Director, systems for cannabinoids and to assess their Center for Molecular Design and Preformulations, pharmaceutical application potentials such as University Health Network, Toronto (Canada) bioavailability using a state-of-the-art simulated in Dr. Kotra is an academic entrepreneur with vitro gastrointestinal digestion system. expertise in drug discovery and development (http://kotralab.uhnres.utoronto.ca/). Kotra group CannTrust: Kaivan Talachian, Vice President, specializes in the areas of medicinal chemistry, Professional Services preclinical and clinical development of small molecule and natural product-based drugs. Dr. Kotra Kaivan Talachian holds a doctorate in pharmacy authored/co-authored over 120 peer-reviewed (Pharm. D) and is a practicing pharmacist in Canada articles and book chapters, and delivered over 110 with more than 20 years of diverse experience in scientific and plenary talks globally. Kotra research pharmaceutical, medical device and healthcare group has contributed to a number of research information technology. programs in the areas of infectious, metabolic and He has been involved in the medical cannabis neurodegenerative diseases. Dr. Kotra is a recipient research, education and innovation since 2013. He is of several awards including the Premier’s Research currently the vice president of healthcare services at Excellence Award from the Province of Ontario CannTrust, a publicly traded licensed producer of (Canada), Rx&D Health Research Foundation medical cannabis. He has directed the transformation Research Career award, GlaxoSmithKline/Canadian of this business from a startup to a billion-dollar Society for Pharmaceutical Sciences Young business. He is directing the development of Investigator Award. Dr. Kotra leads an international innovative cannabinoid dosage forms, clinical consortium with India for the development of novel education programs and cannabinoid based clinical chemical classes of drugs targeting malaria—a trials. consortium of public and private organizations in Prior to CannTrust, Kaivan was the vice Canada and India. Dr. Kotra is a co-founder of president of healthcare products at NexJ Systems, a WinSanTor Inc., San Diego, California, USA (drugs publicly traded Canadian company. In this role he targeting diabetic neuropathy, 2012-present), directed development and design of a patient-centric CIDAVA Innovations—an India-Canada joint software solution to activate and educate patients, venture (antimalarials, 2013-17), CannScience collaborate care and improve medication adherence. Innovations, Inc., Toronto, Canada (now Scientus This solution is being used by Prostate Cancer Pharma, Inc.; novel cannabinoid products for Canada. medical uses, 2014-17). He currently serves on the Kaivan has held senior positions at Baxter Board of Directors of WinSanTor Biosciences (San Pharmaceuticals and major pharmacy groups, such Diego, CA), Scientific Advisory Boards of Scientus as Shoppers Drug Mart, Loblaw pharmacy and Pharma Inc. (Toronto) where he maintains Chief Costco Pharmacy. He has trained many pharmacists Scientific Officer role, Montdorex Inc. (Montreal, and pharmacy technicians and has been a member of Canada), and College of Reviewers at the Canadian the peer review panel at Hospital Pharmacy Journal. Institutes of Health Research. Dr. Kotra lives in Toronto with his wife, Dasantila and their two daughters, Radha and Geetha.

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Thursday, May 24 SESSION 4C: Innovative Biomaterials for Drug Delivery

Co-Chairs: Todd Hoare, McMaster University, Marta Cerruti, McGill University

polyglyoxylates have great potential for drug Trigger-Amplifying Self-Immolative delivery applications. Nanoparticles for Drug Delivery Elizabeth Gillies Elizabeth Gillies, Department of Chemistry, Elizabeth Gillies is a Professor in the Department of Department of Chemical and Biochemical Chemistry and Department of Chemical and Engineering, The University of Western Ontario, Biochemical Engineering at the University of London, Canada Western Ontario. She received her PhD in Chemistry at the University of California, Berkeley with Jean Degradable polymers are of significant interest in Fréchet, then was a Marie Curie Postdoctoral Fellow nanomedicine, where they are frequently used to at the European Institute of Chemistry and Biology prepare nanoparticles that can encapsulate drugs and in Bordeaux with Ivan Huc. Her research group then release them as the polymers break down. focuses on the development of new biodegradable, Much progress has been made using polyesters such multifunctional, and stimuli-responsive polymers as as polylactide and polycaprolactone. However, the well as their applications in drug delivery and other ability to control drug release using these polymers biomedical areas. She has received a number of is limited as they may degrade more rapidly or more awards including a Canada Research Chair, NSERC slowly than desired. Many stimuli-responsive E. W. R Steacie Memorial Fellowship, and an Early polymers have been developed over the past couple Researcher Award. of decades, but these polymers typically require many stimuli-mediated events to achieve complete polymer degradation. To address these limitations, Polymer-Based Protein Delivery Systems we have been developing self-immolative polymers (SIPs), which undergo complete end-to-end S. Thayumanavan, Department of Chemistry, depolymerization following the cleavage of a single University of Massachusetts, Amherst, MA stimuli-responsive end-cap from the polymer Email: [email protected] terminus. This presentation will describe our group’s development of polyglyoxylate SIPs and their Using proteins as a therapeutic is attractive, as this applications in nanomedicine. We have prepared promises to directly address genetic deficiencies and polyglyoxylates with end-caps responsive to a wide therefore mitigates side-effects that plague many range of stimuli including light, heat, weak acids, small molecule drugs. Potential side-effects from hydrogen peroxide, and reducing agents, many of small molecule binders are understandable, as these which are accessible in vivo and are associated with molecules must be designed to target a specific disease states such as cancer and inflammation. protein in our complex biological system, Their degradation was studied in solution, as highlighted by the nearly 20,000 protein-encoding assemblies of block copolymers, in the form of genes. On the other hand, proteins can directly nanoparticles, and as coatings. In each case, the compensate for a specific deficiency and therefore triggered polymers underwent rapid the drug development is less heuristic. However, depolymerization whereas the untriggered controls realizing the full potential of protein-based remained quite stable. This provided triggered therapeutics has been difficult, mainly due to their in release of drug molecules. The toxicity of the vivo instability and immunogenicity. To overcome delivery system was also investigated in vivo. these issues, approaches to modify protein surfaces Overall, these studies have demonstrated that have been taken. These reports provide examples of

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innovative strategies that allow for enhanced Madurai, India. He received his Ph.D. from the circulation lifetimes and thus have impacted the University of Illinois at Urbana-Champaign in 1996. utility of proteins that function in the extracellular Following a postdoctoral stint at Caltech, he started environment. his independent career at Tulane University in 1999 The next significant challenge would involve and moved to UMass Amherst in 2003. His research development of systems for intracellular proteins, work involves the design and syntheses of new where trafficking the biomolecule across a cellular macromolecules, especially polymers, to obtain membrane is a hurdle. Two limiting approaches, novel responsive supramolecular nanoassemblies. involving electrostatic interactions or liposomal These responsive nanoassemblies are being pursued encapsulation, have been taken to address this need, for applications in the delivery of small molecules Non-specific fouling of the complex’ surfaces due to and biologics, in addition to imaging and diagnostics electrostatic interactions and low loading capacities applications. His work has resulted in more than in liposomes, along with the lack of triggerability, 200 peer-reviewed publications in high-impact have limited the reach of these approaches. We will journals. The innovation in his work has also present a novel covalent self-assembly approach, produced about 15 patents and patent applications. where the protein cargo itself acts as the template for Thai has received numerous national and the polymer to self-assemble around it, has the international recognitions for his creative potential to encapsulate proteins with high fidelity contributions. Thai is the scientific founder of a and present charge-neutral surface functionalities. start-up company Cyta Therapeutics, which is focused on translating a versatile polymeric nanogel platform to the clinic.

Controlled-Release Nano-Therapeutics: The Status of Translation

Subbu Venkatraman, School of Materials Science and Engineering, Nanyang Technological University; Singapore. E-mail: [email protected] Covalent polymer network formation using the protein as the template Although pharmaceutical products based on References controlled-release of the drug are commonplace  Dutta, K.; Hu, D.; Zhao, B.; Ribbe, A.; Zhuang, J.; now, such products typically employ macro- and Thayumanavan, S. "Templated Self-Assembly of a micro-sized carriers. Doxil® was the first Covalent Polymer Network for Intracellular Protein nanoliposome-based delivery system that won Delivery and Traceless Release" J. Am. Chem. Soc. approval in 1995, and this system is able to control 2017, 139, In press (DOI: 10.1021/jacs.7b01214). the release of doxorubicin for a few days.  Molla, M. R.; Marcinko, T.; Prasad, P.; Deming, D.; Subsequent research into nanocarriers has focused Garman, S.; Thayumanavan, S. “Unlocking a Caged largely on oncology with varying degrees of success. Lysosomal Protein from a Polymeric Nanogel with a pH Trigger” Biomacromolecules, 2014, 15, 4046-4053 It is fair to say that Nanomedicine administered (DOI: 10.1021/bm501091p).. systemically will have limited duration of action,  Ventura, J.; Eron, S. J.; González-Toro, D. C.; due to clearance mechanisms. Therefore, our focus Raghpathi, K. R.; Wang, F.; Hardy, J. A.; on controlled-release nanotherapeutics has been on Thayumanavan, S. “Reactive Self-Assembly of locally-administered concepts. Polymers and Proteins to Reversibly Silence a Killer We present two case studies of controlled- Protein” Biomacromolecules, 2015, 16, 3161-3171 release in the treatment of ocular disease. The first (DOI: 10.1021/acs.biomac.5b00779). involves the control of intra-ocular pressure, an indicator of glaucoma, over several days with a S. “Thai” Thayumanavan single sub-conjuctival injection. The system here is a S. “Thai” Thayumanavan is a Professor in the nanoliposome which incorporates the drug, Department of Chemistry at the University of latanoprost, in its lipid bilayer. If only diffusion Massachusetts Amherst. He received his B.Sc. and were to control the release, this system would M.Sc. degrees from The American College in exhaust its payload within a few hours (the bilayer is

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only about 5-10 nm thick). In contrast to Doxil, we hospitals and researchers, including the National show that this system is able to control the release of Heart Centre, Tan Tock Seng Hospital and the the drug over 45-60 days under sink conditions. We National Cancer Centre. Current interests include the attribute this control to partitioning effects, based on following: Nanomedicine, Localized drug/gene isothermal calorimetric studies of drug-lipid delivery, Biodegradable polymers, Injectable interactions2. implants and nanoparticles, Bio-inspired solutions to However, for the sustained delivery of gene medical problems. silencing molecules, which are hydrophilic in general, and of larger size, nanoliposomes are poor carrier candidates. For this we developed a Biomimetic Nanoparticles for Targeted Drug polyelectrolyte layer-by-layer (LbL) approach to Delivery and Detoxification sustain the release of siRNA, which forms one or more of the layers. We developed this system using Liangfang Zhang, Professor, Department of a hydroxyl apatite nanoparticle core, and optimized Nanoengineering and Moores Cancer Center, the polycationic layer using poly (L-arginine) 3. University of California San Diego With this system, we employed a sub-conjuctival injection to treat fibrosis in a glaucoma filtration The emerging nanotechnology in biomedicine has surgery model and showed that the fibrosis could be sparked new hope for the treatment and diagnosis of suppressed over 14 days with a single injection. various important human diseases. However, Controlled release from nanoparticles is not as development of functional nanomaterials and easy to achieve as with microparticles. Nevertheless, nanodevices can be encumbered by unanticipated we show that for lipophilic molecules, we can material properties and biological events, which can sustain in vitro delivery for over 30 days with negatively impact their effectiveness when selected liposomal compositions using partitioning; introduced into complex, physiologically relevant whereas for siRNA delivery, we have employed a systems. In this talk the preparation of nanoparticles layer-by-layer system that release the siRNA via enclosed in the plasma membrane of natural human slow defoliation. cells (e.g., RBCs, platelets, cancer cells, etc) is reported. The resulting cell membrane-coated Subbu Venkatraman nanoparticles are demonstrated to possess many Professor Subbu Venkatraman has a PhD in Polymer surface functions of natural cells via studies of Chemistry from Carnegie-Mellon University. He has interactions with plasma proteins, cells, tissues, and spent about 15 years in biomedical R&D in the microorganisms. Such multifaceted cell-mimicking USA, working with various applications of properties can be attributed to the preservation of polymeric biomaterials. He held a senior position in biomembrane on nanoparticle surfaces, which R&D at Alza Corporation (now Johnson & Johnson) facilitates the display of intricate biochemistry that is prior to joining NTU as Associate Professor in 2000. difficult to replicate using conventional Since then he has published extensively in the field functionalization approaches. As the platform is of biomaterials, with a total of 225 publications, H- entirely biocompatible and biodegradable, it can be index of 35 and a citation count of 5160 He also applied toward a myriad of biomedical applications, holds 88 granted patents from a total of 171 including active drug delivery and detoxification, applications. His work in biomaterials has led to 3 where the vast implications of cell surface properties successful spin-off companies, with one of them may benefit a variety of disease treatments. (Amaranth Medical) obtaining substantial series C funding. He has also received the 2014 President's Liangfang Zhang Technology Award together with Prof Freddy Boey Dr. Liangfang Zhang received his B.E. and M.S. and Adjunct A/P Tina Wong, for their innovative degrees in Chemical Engineering from Tsinghua application of nanostructures and novel drug University, and his Ph.D. in Chemical & delivery approach to combat blindness from Biomolecular Engineering from the University of glaucoma. He is also the co-founder of Peregrine Illinois at Urbana-Champaign in 2006 under the Ophthlamic Pte Ltd and Amaranth Medical Pte Ltd. supervision of Prof. Steve Granick. He was a His research group is interested in designing postdoctoral associate in the laboratory of Prof. and modifying materials for biomedical applications. Robert Langer at MIT during 2006-2008. He joined In this work, they are closely associated with local the Department of Nanoengineering at UC San

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Diego as an Assistant Professor in July 2008 and Department of State ASPIRE Award (2017), and was promoted to an Associate Professor with tenure Kabiller Young Investigator Award (2017). in March 2012 and to Professor in July 2014. Dr. http://nano.ucsd.edu/~l7zhang/ Zhang’s research interests focus on biomimetic nanomedicine, with a particular interest in creating and evaluating nanostructured biomaterials for drug delivery, detoxification and vaccination for Selected oral abstract presentation: treatment of infectious diseases and cancer. He has published 165 peer-reviewed articles and holds 55 Hyperthermia-mediated Drug Delivery Increases issued/pending patents. He received the ACS Victor Cisplatin Sensitivity and Accumulation Resulting K. LaMer Award (2009), UCSD Jacobs School of in improved Efficacy in Triple Negative Breast Engineering Best Teacher Award (2011), ACS Cancer Unilever Award (2012), MIT Technology Review’s TR35 Innovator Award (2013), AIChE Allan P. Michael Dunne, University of Toronto Colburn Award (2014), AIMBE Fellow (2015), (See Poster Abstract # 94) Popular Science’s Brilliant 10 Award (2016), U.S.

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Friday, May 25 PLENARY SESSION 4 Richard Weinshilboum, Mayo Clinic

Chair: Micheline Piquette-Miller, University of Toronto

also a Pharmacology Research Associate at the NIH Pharmacogenomics: Clinical Implementation and in the laboratory of Nobel Laureate Dr. Julius Future Challenges Axelrod. He is presently Professor of Pharmacology and Medicine and Dasburg Professor of Cancer Richard Weinshilboum, Professor of Pharmacology Genomics Research at Mayo Clinic. He also co- and Medicine and Dasburg Professor of Cancer directs the Pharmacogenomics Program of the Mayo Genomics Research, Mayo Clinic Center for Individualized Medicine. Dr. Weinshilboum’s research has focused on Pharmacogenomics, the science of the role of pharmacogenetics, with over 425 manuscripts on inheritance in variation in drug response phenotypes, that topic. His major area of research has been the is almost certainly the aspect of clinical genomics pharmacogenetics of drug metabolism, with a focus that will eventually touch every patient everywhere. on methylation and sulfation. He has also applied Pharmacogenomics continues to advance as genome-wide “omics” to study drug response— discovery science and—at the same time—it is being especially the drug therapy of depression and breast translated and implemented in the Clinic. This cancer. Dr. Weinshilboum has been the recipient of presentation will outline challenges associated with many awards including an Established Pharmacogenomic translation and clinical Investigatorship of the American Heart Association, implementation. It will also outline some of the a Burroughs Wellcome Scholar Award in Clinical trends in pharmacogenomic discovery science, Pharmacology, the Oscar B. Hunter Award of the including the merging of multiple “omics” data American Society for Clinical Pharmacology and types to become “Pharmac-omics”. Therapeutics, the ASPET Harry Gold Award and the Edvard Poulsson Award from the Norwegian Richard Weinshilboum Pharmacology Society. He has also served on the Dr. Weinshilboum received B.A. and M.D. degrees Advisory Councils for two US NIH Institutes, the from the University of Kansas, followed by NIGMS and NHGRI. residency training in Internal Medicine at the Massachusetts General Hospital in Boston. He was

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. Friday, May 25 SESSION 5A: Pharmacogenomic Implementation

Chair: Micheline Piquette-Miller, University of Toronto

objectives of PRIME (Pharmacists as Personalized Session Chair: Medicine Experts in Primary Care) were: 1. to Micheline Piquette-Miller develop, implement and evaluate a pharmacogenomic specialization training program Micheline Piquette-Miller is a Professor at the Leslie directed to pharmacists, and 2. to assess the use of Dan Faculty of Pharmacy at the University of pharmacogenomic testing initiated by pharmacists in Toronto and an Associate Editor of Clinical primary care settings. Pharmacology & Therapeutics. Dr. Piquette-Miller Methods: The pharmacist’s training program completed a BSc. in Pharmacy and PhD in was comprised of online lectures, a two-day training Pharmacokinetics at the University of Alberta and a workshop, and completion of patient case Postdoctoral Fellowship at the University of pharmacotherapy work-ups. Pharmacists then California in San Francisco. Her research primarily recruited patients in their practice to receive the focuses on understanding the regulation of drug pharmacogenomics service. Eligible patients were transport proteins and how this impacts drug aged > 18 years, were starting or switching to a new disposition. She has published over 100 research antidepressant or antipsychotic medication, articles and has been the recipient of numerous demonstrated poor response or experienced prestigious national and international research significant and repeated side effects to these agents. awards including ASCPT’s Leon Goldberg Young Patients were followed up for 2 months post-testing. Investigator Award, RX&D/CIHR Research Career The study was conducted in collaboration with the Award; Pfiasky Young Investigator Award, CAMH IMPACT study. University of Alberta’s Horizon Award, AFPC’s Results: Twenty-two pharmacists successfully Pfizer Research Career Award, FDA’s ORISE completed the training program, demonstrating Fellowship Award and Canadian Society of improved knowledge and confidence in applying Pharmaceutical Sciences (CSPS) Fellow Award. She pharmacogenomics in practice. A total of 187 is currently Chair of ASCPT’s International patients were invited to participate by 15 Transporter Community and has previously served pharmacists (with a wide range in the number of on the executive councils of ASCPT and CSPS, and patients included per pharmacist: 0 to 42 patients). is a past-president of the Canadian Society of Of these, 127 patients completed at least one study Pharmacology & Therapeutics (CSPT). visit and 65 patients completed all visits. Most patients were female (60%), mean age 47±13 years (range 18-75 years). Many patients were new to the PRIME: Implementing Pharmacogenomic pharmacist and practice site (70%), although Testing into Pharmacy Practice - Focus on pharmacists reported established relationships with Mental Health Pharmacotherapy the prescribers for 91% of patients. Reasons for recommending pharmacogenomics testing were: Natalie Crown, Leslie Dan Faculty of Pharmacy, poor response to an antidepressant (67%) or University of Toronto antipsychotic (6%), switching (32%) or starting (17%) a new antidepressant, and/or significant and Pharmacists are ideally positioned to lead the repeated side effects to an antidepressant (24%) or integration of pharmacogenomics into practice by antipsychotic (4%). Of the medication partnering with patients and their prescribers to recommendations made by pharmacists at the post- optimize medication therapy outcomes. The testing results visit, most were for a medication

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change (62%), a dose increase (10%) or a dose Clinical Pharmacogenomics Program in Pediatric decrease (8%). By the end of the study 46% of those Oncology: 257 Patients and Counting attending the final visit (n=29 of 65 patients, or 24% of all patients) had Clinical Global Impression (CGI) Bruce Carleton, PharmD, FISPE, Professor and ratings indicating marked or moderate improvement Chair, Division of Translational Therapeutics, with side effects either not present or not Department of Pediatrics, Faculty of Medicine, significantly interfering with functioning. Positive University of British Columbia; Senior Clinician outcomes were also suggested with other included Scientist, BC Children’s Hospital Research Institute; clinical measures. Director, Pharmaceutical Outcomes Programme, BC Conclusion: Most pharmacists in PRIME were Children’s Hospital, Vancouver, BC able to provide pharmacogenomics services in their primary care practice, working with patients and Adverse Drug Reactions (ADRs) cause significant prescribers to improve medication outcomes. The morbidity and mortality. We built a national reasons for testing were primarily related to network in Canada (The Canadian problems associated with antidepressant therapy, Pharmacogenomics Network for Drug Safety or with mostly medication change recommendations, CPNDS) to rigorously characterize drug outcomes in and indications of positive clinical outcomes. children and in particular to find genomic solutions to the lack of predictability of many severe ADRs. Natalie Crown Drug biotransformation and other genes are analyzed Natalie Crown is a Clinician Educator at Women’s to determine their role in the development of specific College Hospital and Assistant Professor with the ADRs and to identify predictive, clinically-relevant Leslie Dan Faculty of Pharmacy at the University of (odds ratios ≥3) genomic markers. Identified Toronto. She completed her Bachelor of Science in biomarkers are replicated and then validated with Pharmacy at Dalhousie University, a pharmacy functional and pharmacokinetic studies. The practice residency at Capital District Health identification of highly-predictive genomic markers Authority in Halifax NS, and her Doctor of is essential for developing diagnostic tests to predict Pharmacy degree at the University of Toronto. which patients are at higher risk of developing She is a co-investigator in the research study ADRs so that patients, families and clinicians can “Pharmacists as Personalized Medicine Experts in make more informed decisions about the likelihood Primary Care (PRIME)”. For PRIME, she led the of therapeutic success and harm. We have now development a pharmacogenomics (PGx) implemented pharmacogenomic testing in British specialization training program directed to Columbia for children undergoing cancer pharmacists that could be adapted for other health chemotherapy. All patients are tested. This session professions. Dr. Crown was one of the first will highlight examples of the impact of pharmacists in Canada to use pharmacogenetics in pharmacogenomic testing on clinical decision- practice. She worked as part of a team with the making, some of the key challenges in Division of Clinical Pharmacology at Western implementation, and next steps as CPNDS rolls out University and London Health Sciences Centre to its pharmacogenomic implementation program in develop a personalized medicine warfarin clinic– the pediatric oncology across Canada. first of its kind in Canada. At Women’s College Hospital she developed and serves as the Director of Bruce C. Carleton a Pharmacy Residency Program in ambulatory care, Dr. Carleton’s lifelong goal is to make medication and maintains a practice in ambulatory care clinics. use more effective and safer for all patients, particularly children. His research focus is on the impact of drug therapy on human health and quality of life. He is particularly interested in developing better ways to evaluate the effectiveness of drugs, medication-use models designed to improve patient health, as well as practical surveillance systems to improve the safe use of medication. A key element of Dr. Carleton's research is the communication of results to clinicians, patients, healthcare administrators, and government officials

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– those who also hold responsibilities to improve Pharmacists will play an integral role in supporting patient care and our systems of healthcare delivery. safe and responsible utilization of this technology as In addition to his appointment as Professor of well as helping maximize its benefits to patients and Paediatrics and Chair of the Division of the healthcare system. Translational Therapeutics, Department of Pediatric Medicine at UBC, Dr. Carleton is a Senior Clinician Christopher Trevors Scientist at BC Children’s Hospital Research Christopher Trevors, MS, CGC graduated with a Institute. He directs the Pharmaceutical Outcomes B.Sc. (Honours) in Biology from Queen’s Programme at BC Children’s Hospital and he has University and a master’s degree in Human Genetics served in this capacity since 1994. He holds (Genetic Counseling) from Sarah Lawrence College appointments at UBC in the Centre for Health in Bronxville, New York. He worked at the Services and Policy Research, the School of Westchester Medical Center in Hawthorne, New Population & Public Health and the Faculty of York before starting at The Hospital for Sick Pharmaceutical Sciences and the School of Health Children (SickKids) in Toronto as a genetic Information Science, University of Victoria. Dr. counsellor. During his nine years at SickKids he was Carleton’s public service is expansive. It includes involved in clinical care before taking on a role as a serving as a charter member on the national clinical educator and evaluator in the areas of Canadian Expert Drug Advisory Committee. Dr. genetics, ethics and molecular/genomic Carleton was recently asked to serve the US technologies. Christopher worked as Canadian Government as a Special Government Employee to General Manager of Centogene AG, a German advise the Advisory Committee for Pharmaceuticals molecular diagnostics company for 3 years before and Clinical Pharmacology of the FDA. transitioning to help build a genetic diagnostics division at LifeLabs in Toronto as Director of Genetics and Genomics. Christopher is currently the Clinical Utilization of Pharmacogenomic Testing National Director of Genetic Health Solutions at – The Evolving Canadian Environment Dynacare where he is part of the business development team working to promote the Christopher Trevors, MS, CGC National Director, utilization of genetic technologies across all business Genetic Health Solutions, Dynacare segments. He is a Lecturer in the University of Toronto Genetic Counselling MSc program, the Pharmacogenomic testing has been used in medical Medical Laboratory Technology Program at The research and limited segments of clinical care for Michener Institute and the George Brown Nursing decades, however, uptake more broadly has been Program. slow. This talk will review briefly, the historic and current utilization of pharmacogenomics in Canada as well as future trends. Pharmacogenomic uptake, Pharmacogenetics in the Benefits Arena – Baby like many other beneficial genetic technologies, has Steps; Giant Opportunities been limited by structural limitations in the healthcare system, medical culture and cost. Despite Wayne Murphy, Prudent Benefits Administration all of the barriers there is a trend towards widespread Services Inc. utilization of pharmacogenomics within both the public and private healthcare environments in As we enter the age of Personalized Medicine, Canada. This increase is supported by a number of Pharmacogenetics is poised to provide consumers, factors - improved computing power, decreased prescribers and payers of drug benefits with a far costs of laboratory analysis, positive medical, safer, more customized and cost-effective approach scientific and health economic publications, the to prescription for a wide range of drugs. Given the rising costs of therapeutics, increasing absenteeism current landscape where there are more than 200,000 of employees as well as a broader awareness of documented adverse drug reactions each year in health technologies. This demand is coming from Canada, some of those involving death AND where consumers, clinicians, employers and insurance approximately 65% of mental health drugs companies. Canada can and is playing a significant prescribed are abandoned due to such causes as “side leadership role in improving our understanding of effects”; is it possible that pharmacogenetics could pharmacogenomics and personalized medicine. be a revolutionary advancement that will change the

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world of pharmacology? This session will involve actuarial and consulting services to plan sponsors the sharing of an example of early adoption of across Canada. Murphy received his Certified pharmacogenetic testing in the Benefits arena. The Employee Benefits Specialist (CEBS) designation speaker will tell his story of how his firm has used from Dalhousie University in 2004 and has been pharmacogenetic testing and anecdotally, what involved with the International Society of Certified the impact and outcome looked like. The session Employee Benefits Specialists (ISCEBS) as a will be an informal sharing as the case example speaker and moderator. He also holds Fellowship represents baby steps in the areas of Disability status with the ISCEBS. In 2009, he was elected Management and a unique Employer benefits President of the Toronto Chapter, ISCEBS and, in program. The speaker will also undertake to share 2014, was elected, National President of the some of his impressions and conjecture around the ISCEBS. Most recently he was appointed Chair of barriers to utilization in the benefits arena. the CEBS Committee for 2018 and will lead a Committee which will oversee the implementation Wayne Murphy of polices, plans, and procedures for the growth and Wayne Murphy is the Senior Manager, Corporate development of the CEBS program with the Services and Chief Privacy Officer for Prudent International Foundation of Employee Benefit Plans Benefits Administration Services Inc. (The PBAS (IF) which cosponsors the CEBS program with the Group). The firm, founded in 1987, with seven Wharton School of the University of Pennsylvania offices across Canada, provides administration, and Dalhousie University.

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Friday, May 25 SESSION 5B: Drug Therapy in Children

Chair: Michael Rieder, Western University

Hospital Research Institute, the Research Institute of Nephrotoxic Acute Kidney Injury in Hospitalized the Hospital for Sick Children, and the National Children and Description of a National Cisplatin Institutes of Health. Pediatric Cohort Dr. Zappitelli was clinically trained in Pediatric Nephrology and obtained a Master’s degree in Mike Zappitelli, The Hospital for Sick Children, Epidemiology & Biostatistics at McGill University. Toronto He completed a 2 year clinical and research fellowship in Pediatric Acute Care Nephrology at [Abstract not available] Baylor College of Medicine, Texas from 2005-2007. He was on staff as a Nephrologist and Clinician Mike Zappitelli Scientist and as Director of the Dialysis & Apheresis Dr. Zappitelli performs research on acute kidney program at the Montreal Children’s Hospital until injury (AKI) in children as well as measurement of December 2017. In January 2018 Dr. Zappitelli pediatric blood pressure and kidney function. AKI transitioned to The Hospital For Sick Children/ mostly occurs in hospitalized patients. Research Research Institute. He is currently a Staff Paediatric from Dr. Zappitelli’s lab and others has shown that Nephrologist, Senior Scientist, and Associate AKI in children is associated with hospital morbidity Professor within the Division of Nephrology, Child and mortality. Currently, the Zappitelli Lab is Health Evaluative Science Research Program and performing multiple studies in different patient Department of Paediatrics at the University of populations (including cardiac surgery, critical Toronto. Dr. Zappitelli is also an Adjunct Professor illness and cancer treatment) to determine whether at the Faculty of Medicine of McGill University. AKI causes long-term kidney damage and high blood pressure. This work is important, since chronic kidney damage (or chronic kidney disease) Novel Approaches to Improving are important cardiovascular risk factors. The Pharmacotherapy in Epilepsy: Machine Learning Zappitelli Lab is also trying to improve how AKI is and Human Organoids diagnosed in hospitalized children, by studying new urine and blood biomarkers of AKI, specifically for Peter L. Carlen MD, FRCPC; Krembil Research early AKI diagnosis. Part of studying long-term Institute; Toronto Western Hospital, University kidney outcomes of AKI, includes trying to Health Network; Departments of Medicine determine the best way to measure kidney function (Neurology), Physiology, and IBBME, University of and express blood pressure in children. Thus, the Toronto second major aspect of the Zappitelli Lab’s goal is to explore different ways of measuring and expressing With the tremendous advances in computer kidney function and blood pressure in children and technology and cell biology, personalized youth, and determining how these methods are pharmacotherapy is becoming a reality. This talk associated with evidence of other organ damage will outline approaches now possible for resolving (e.g., the heart). Dr. Zappitelli currently uses several the difficult quandary that clinicians often face when methodologies for performing his research, mostly treating patients with epilepsy: which drug or which including observational cohort studies. The treatment (such as dietary therapy) is most likely to Zappitelli Lab’s funding sources have included or succeed in any individual patient. There are over 20 include Canadian Institutes of Health Research, anticonvulsants available from which to choose. To Fonds de Rrecherche du Quebec-Sante, Kidney go through this list attempting to find the ideal drug Foundation of Canada, the Montreal Children’s can take years of testing and frustration till a proper

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drug or drug combination is found. Furthermore, available clinically. This will give us an individual approximately 30% of patients with epilepsy are patient’s “brain in a dish” to devise optimal drug resistant. treatment strategies, possibly avoiding years of Machine Learning: fruitless clinical testing. Recent advances in computer speed and storage and in machine learning paradigms, permit the mining of Peter L. Carlen large databases to define an individual patient’s Peter L. Carlen MD, FRCPC, obtained his MD from characteristics, which can guide the clinician the University of Toronto and his internship and towards an optimized treatment plan. This plan will Internal Medicine training at McGill University, be focussed on that patient’s specific characteristics completing his Neurology training at the University and not on a “guideline” for the “average patient”, of Toronto. He also did postgraduate training in which doesn’t really exist. Colic et al. (2017) used cellular electrophysiology for 3 years at the machine learning algorithms which were trained and Neurobiology Unit of the Hebrew University of evaluated using features obtained from intracranial Jerusalem, Israel. He is a Professor in Medicine EEG (iEEG) recordings of the epileptiform (Neurology), Physiology, and the Institute of discharges observed in a Mecp2-deficient mouse Biomaterials and Biomedical Engineering at the model of the Rett Syndrome. Previous work has University of Toronto. He was formerly the Head of linked the presence of cross-frequency coupling Neurology at the Addiction Research Foundation. In 1989, he was appointed Director of the Playfair Index (ICFC) of the delta (2–5 Hz) rhythm with the fast ripple (400–600 Hz) rhythm in epileptiform Neuroscience Unit and Neuroscience Research at the University Health Network for a 10 year term, where discharges. Using the ICFC to label post-treatment outcomes they used machine learning classifiers for he is now a Senior Scientist and Head of the providing likelihood scores of successful treatment Division of Fundamental Neurobiology. He has over outcomes, which yielded predictions of successful 300 peer-reviewed biomedical publications and 6 drug treatment outcomes. Similarly in humans, one patents. His main research interests are mechanisms can derive a computer-based multivariate and control of neural synchrony and entrainment in classification from a dataset of 100’s of patients with epilepsy, mechanisms of sudden unexplained death epilepsy including EEG, demographics, seizure in epilepsy (SUDEP), hypoglycemic seizures, gap type(s), genotype, and anticonvulsant drug junctional communication, brain state classification, responses, to predict the optimal pharmacotherapy and the cerebral pathophysiology of the fetal alcohol for an individual epileptic patient. syndrome. He is also an active neurological clinician at the University Health Network (Toronto Western Human Cerebral Induced Pluripotential Stem Hospital) with a practice focused mainly on patients Cells and Organoids: with epilepsy. Based on recent exciting advances in stem cell research, it is now possible to create stem cells from adult humans and induce these pluripotential stem Vaccinating Children Against Pain and Fear cells (iPSCs) to form cerebral organoids, which have the detailed organization of the cerebral cortex. We Anna Taddio, University of Toronto have examined human cerebral organoids showing that we can measure cerebral activity both extra- and Despite their effectiveness for preventing disease, intracellularly, which is greatly increased with a vaccinations are associated with a negative convulsant. Drug resistant patients with epilepsy experience for many children due to the pain and will be phenotyped (history including fear associated with their administration. anticonvulsants taken, neurological exam, EEGs, Importantly, these negative experiences can MRI, blood tests) and genotyped in the epilepsy contribute to vaccine hesitancy and reduced clinic. Fibroblasts, obtained from these patients will compliance with future vaccinations, undermining be treated to become iPSCs and cerebral organoids. vaccination. The objectives of this presentation are These tissues will be kept on multi-well plates for to describe: 1) the importance of pain and fear multiple pharmacodynamic and pathophysiological mitigation during vaccination in children; and 2) testing. The patient’s responses to different new evidence regarding effective strategies for pharmacotherapies will be assessed and correlated mitigating pain and fear. The presentation will also with the extensive clinical and genetic profiling include discussion about efforts underway to

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incorporate pain and fear mitigation strategies into based practice and implementation research. Dr. routine vaccinations in different practice settings. Taddio currently leads a national inter-disciplinary team, Help ELiminate Pain in Kids and Adults Anna Taddio (HELPinKids&Adults), investigating and promoting Anna Taddio is a Professor of Pharmacy at the evidence-based pain management during University of Toronto, and Senior Associate vaccination. She has authored over 200 scientific Scientist at SickKids. Her program of research papers and book chapters, and is the recipient of examines: (1) the short-term and long-term effects of numerous awards recognizing her scholarly and pain in children; (2) the effectiveness and safety of advocacy achievements in pediatric pain. pain management interventions; and (3) evidence

CSPT Senior Investigator Award Anne-Noël Samaha Dr Samaha is a behavioural neuroscientist interested Addiction to Cocaine: How you Take the Drug is in the neurobiology of drug addiction, and in the More Important than how Much long-term effects of antipsychotic treatment. She completed her PhD at the University of Michigan, Anne-Noël Samaha, PhD, Université de Montréal with her dissertation receiving the James McKeen Cattell award from the New York Academy of A fundamental question in addiction research Sciences. Dr Samaha completed her post-doctoral concerns how recreational patterns of drug use training at the Center for Addiction and Mental change the brain to promote a transition to the Health, Toronto. In 2008, she joined the faculty at pathological patterns of drug use that define the University of Montréal. addiction. This is studied in animals using drug self- Using animal models, Dr Samaha is pursuing administration procedures. Currently, the most research on two fronts. First, she is investigating the widely used animal model of addiction involves behavioural and neural plasticity induced by chronic letting animals self-administer a drug continuously, exposure to antipsychotic medications. Second, she for several hours a day. I will argue that continuous is investigating the question of how the temporal intake of large amounts of drug is actually not very dynamics of psychostimulant drug use (continuous good for studying the transition to addiction. I will or intermittent intake, fast or slow drug onset) also present data from an alternative animal model, determine outcome. where drug intake is intermittent, rather than Dr. Samaha has been an FRQS research scholar continuous. This recent work is providing new ways since 2009. Her research is also funded by CIHR, of thinking about what is necessary and sufficient to the Canada Foundation for Innovation, and NSERC develop symptoms of addiction.

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Poster Session 1

CSPS and CC-CRS

Wednesday, May 23

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Poster Session 1

Wednesday, May 23

medium flow with a flowrate of 5 ml/min for 2.5 Biomedical Sciences mins was studied. Results: Fluorescent microscopic images of immunostained cells before and after cell 1. Wrinkled Microparticles as new detachment using hydrodynamic shearing illustrate Microcarriers for Cell Culture Applications that the cells detach or change their arrangements in Vaccine Production due to the flow. Our results indicate that the detachment efficiency depends on the flowrate as Marziye Mirbagheri1,2, Cynthia B. Elias4, Stephen D. well as the wrinkling wavelength. Waldman1,2, Dae Kun Hwang1,2 Conclusion: It has been shown previously that 1Department of Chemical Engineering, Faculty of wrinkling patterns can improve cell attachment, even Engineering & Architectural Science, Ryerson on protein-repellent poly(ethylene glycol) diacrylate University, Toronto, Ontario; 2Keenan Research surfaces. Here, we demonstrated that the adherent Center, Li Ki Shing Knowledge Institute, St. cells on wrinkled substrates can simply be removed Michael's Hospital, Toronto, Ontario; 4 Bulk using hydrodynamic shearing. Therefore, wrinkled Manufacturing, Sanofi Pasteur, Toronto, Ontario, microcarriers can be promising alternatives for cell Canada culture in vaccine production.

Purpose: In vaccine production, cell culture is mainly performed using smooth spherical 2. S-Enantiomer of 19-Hydroxyeicosate- microcarriers, onto which the cells adhere and traenoic Acid Preferentially Protects Against proliferate. However, this process is costly and Angiotensin II-Induced Cardiac complicated, because the microcarrier surfaces Hypertrophy should be chemically modified to improve cell attachment, while the adherent cells can only be Sherif M. Shoieb and Ayman O.S. El-Kadi. detached enzymatically. This study aims to Faculty of Pharmacy and Pharmaceutical Sciences, investigate the feasibility and performance of University of Alberta, Edmonton, AB, Canada wrinkled microparticles as alternative microcarriers. Recently, we have shown that the wrinkling patterns Purpose: We have recently demonstrated that the improve cell attachment, thus can eliminate the need racemic mixture of 19-hydroxyeicosatetraenoic acid for chemical surface modification. Here, we (19-HETE) protects against angiotensin II (Ang II)- demonstrate that the adherent cells on the wrinkled induced cardiac hypertrophy. Therefore, the purpose surfaces can be removed by hydrodynamic shearing of this study is to investigate whether R- or S- in a microfluidic channel. Therefore, the cell enantiomer of 19-HETE confers cardioprotection attachment and detachment on wrinkled against Ang II-induced cellular hypertrophy in RL- microcarriers can be undertaken without additional 14 cells. treatments, leading to reduced cell culture costs and Methods: Human ventricular cardiomyocytes RL-14 simplified cell recovery processes. cells were treated with vehicle or 10 μM Ang II in Method: The wrinkled surfaces with various the absence and presence of 20 μM 19(R)-HETE or wavelengths were fabricated. The primary bovine 19(S)-HETE for 24 h. Thereafter, the level of mid- ligament fibroblast cells were cultured onto chain HETEs was determined using liquid sterilized substrates using culture medium DMEM chromatography–mass spectrometry (LC/MS). Gene containing 10% FBS and antibiotics. After 72 hours, expression was measured using real-time PCR and the substrates were transformed into sterilized Western blot analysis was performed to assess microfluidic channels for cell detachment using protein level of different enzymes. hydrodynamic shearing. Cell response to a DMEM Results: The results showed that both 19(R)-HETE

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and 19(S)-HETE significantly decreased the Methods: Wild-type mice (n=18) were fed mash of metabolite formation rate of mid-chain HETEs powdered rat meal and water for 4.5 weeks. The namely 8-, 9-, 12- and 15-HETE compared to control group received 5 g plain mash each day. The control group while the level of 5-HETE was experimental group received 5 g mash with 2% w/w selectively decreased by S-enantiomer. Moreover, wild blueberry. During the period of feeding, the both 19(R)-HETE and 19(S)-HETE significantly mice completed rota-rod testing at 5, 10, and 15 rpm. inhibited the catalytic activity of CYP1B1 and Following completion of the feeding, all mice decreased the protein expression level of 5- and 12- completed a novel object recognition test. lipoxxygenase (LOX) as well as cyclooxygenase-2 Results: Both groups displayed significant weight (COX-2). Notably, the decrease in the protein gain at the end of the study, indicating the mash was expression level of 15-LOX was only mediated by palatable long term. Although there were no 19(S)-HETE. Moreover, both enantiomers protected significant differences between the control and against Ang-II induced cellular hypertrophy as experimental group data for rota-rod or novel object evidenced by a significant decrease in mRNA recognition, a trend in differences can be seen. In expression of β/α-myosin heavy chain ratio, ANP, both tests, the experimental group outperformed the IL-6 and IL-8. control group. Conclusion: Our data demonstrated that S- Conclusion: A blueberry-enriched mash is palatable enantiomer of 19-HETE preferentially protected to mice and could be used in a long-term study against Ang II-induced cardiac hypertrophy via evaluating the neuroprotective effects of blueberries decreasing the level of mid-chain HETEs, inhibiting in a mouse model of PD. There is also potential for catalytic activity of CYP1B1, decreasing protein further research evaluating if blueberries provide a expression level of LOX and COX-2 enzymes and motor or cognitive benefit in normal health. decreasing mRNA expression level of Acknowledgement: Rachel Ward is the recipient of proinflammatory markers IL-6 and IL-8. Support: a 2018 GSK/CSPS National Undergraduate Student This work was supported by a grant from CIHR to Research Program Award. A.O.S.E. S.M.S. is the recipient of Mike Wolowyk Graduate Scholarship. 4. Alpha-2C Adrenergic Receptor Expression in Rat Caudal Arteries 3. Potential Neuroprotective Effects of Wild Blueberries: A Pilot Study Kayla Kitselman1, Noriko Daneshtalab2, Reza Tabrizchi3 Rachel Ward1, Erin Kelly1, Poorva Vyas1,2, Andre 1Department of Biochemistry, Memorial University Igamberdiev2, and John T. Weber1 of Newfoundland; 2School of Pharmacy, Memorial School of Pharmacy1 and Department of Biology2, University of Newfoundland; 3Department of School of Pharmacy, Memorial University of Biomedical Sciences, Memorial University of Newfoundland, St. John's, NL. Newfoundland

Purpose: Parkinson’s disease (PD) is a Purpose: The rat caudal artery has been shown to be neurodegenerative disorder characterized by thermoregulatory and innervated by the sympathetic progressive loss of dopaminergic ne urons in the nervous system; in response to cold environments substantia nigra. Glutamate excitotoxicity and the artery would remain dilated to increase blood production of alpha-synuclein are two mechanisms flow. Alpha 2-adernergic receptors are G-protein implicated in the disease. Glutamate and alpha- coupled receptors that are primarily neuronal in synuclein also activate microglia, which release origin. They are shown to change its location in the reactive oxygen species (ROS), leading to death of cell in response to changes in temperature. The aim neurons. Blueberries are high in polyphenols which of our study was to determine whether alpha-2C act as antioxidants. Antioxidants may exert adrenergic receptor regulates vascular tone and thus neuroprotective effects by helping to clear ROS. The be involved in thermoregulation in the rat caudal current study is a pilot experiment aimed at testing arteries. the effects of a blueberry fruit-enriched diet in wild- Methods: Sprague Dawley rats (SDR) were type mice, before testing the effects of a berry- sacrificed and their caudal arteries were collected enriched diet in mouse models of PD. and incubated ex vivo in Krebs buffer at 24oC or

86s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

37oC for one hour. The samples were then fixed and aims to further investigate the role of VDR in the blocked in paraffin. 6 µm sections of the samples regulation of RFC at the BBB, using a FRα were cut then placed on positively charge glass knockout mouse model. slides for immunofluorescence experiments to stain Methods: qPCR and immunoblotting were used to for alpha 2C receptors. Upon staining, confocal assess relative expression of folate transporters in imaging was performed using Fluoview 1000. The FRα knockout and wild type mice. To examine the images were then semi-quantified using ImageJ with effect of VDR activation on RFC, mice were treated FIJI plugin and the mean grey value of the area intraperitoneally with the VDR ligand, calcitriol outside of the vascular smooth muscle of the images (1,25(OH) 2D3; 2.5 g/kg), or vehicle (corn oil) was used for semi-quantification. every other day for 8 days. On day nine, animals Results: Qualitative analysis showed increased were sacrificed and tissues (kidney, liver, and expression of alpha-2C adrenergic receptors in 24oC isolated brain capillaries representative of the BBB) samples compared to 37oC samples. Semi- were collected for quantification of RFC expression. quantification and statistical analysis of the images Results: Treatment with calcitriol induced RFC showed a significant difference (p<0.05) in the mRNA expression in the brain capillaries (1.5-fold), alpha-2C adrenergic receptor expression between the kidney (1.3-fold), and liver (2-fold) of wild type and two sample groups (n=4/group). FRα knockout animals compared to vehicle. Conclusion: The increase in alpha-2C adrenergic Conclusion: Induction of RFC expression in brain receptor expression at colder temperatures supports capillaries of FRα knockout mice through VDR the idea that alpha-2C adrenergic receptors maybe activation supports our previous in vitro findings and involved in the thermoregulatory mechanism of rat suggests a potential role for RFC in enhancing folate caudal arteries. brain permeability. This work will elucidate whether folate transport by RFC can compensate for the loss of FRα function, thereby potentially constituting a 5. Upregulation of Reduced Folate Carrier novel treatment strategy for neurometabolic (RFC) by Vitamin D Enhances Folate disorders caused by cerebral folate deficiency. Uptake at the Blood-Brain Barrier (BBB) (Supported by NSERC)

Camille Alam1, Constantine Georgiou1, Richard H. Finnell2, I. David Goldman3, Reina Bendayan1 6. Examining the Cholesterol Synthetic 1Department of Pharmaceutical Sciences, Leslie Dan Pathway in the Search for New Druggable Faculty of Pharmacy, University of Toronto, Targets for Glioblastoma Toronto, Ontario, Canada; 2Departments of Molecular and Cellular Biology and Medicine, Wendy Siu, Andy Yang, Lilia Magomedova, Baylor College of Medicine, Houston, Texas, USA; Graham Macleod, Nishani Rajakulendran, Stephane 3Department of Molecular Pharmacology, Albert Angers and Carolyn L. Cummins. Einstein College of Medicine, Bronx, New York, Faculty of Pharmacy, University of Toronto, USA Toronto, Ontario, Canada

Purpose: Folates are essential for brain development Background: Glioblastoma (GBM) is the most and function. Folate transport is mediated by three aggressive form of primary brain cancer with fewer major transport pathways, i.e., RFC, proton-coupled than 5% of patients surviving beyond five years. folate transporter (PCFT) and folate receptor alpha Genome-wide CRISPR screens revealed enzymes in (FRα), known to be regulated by ligand-activated the cholesterol biosynthetic pathway: squalene nuclear receptors. Cerebral folate delivery occurs synthase (FDFT1), squalene epoxidase (SQLE), and predominantly at the choroid plexus through lanosterol synthase (LSS), are essential for survival concerted actions of FRα and PCFT, but mutations of GBM cells but not for other oncogenic cells. We in these transport systems can lead to early hypothesized that inhibiting/disrupting the childhood neurodegeneration. Our laboratory has cholesterol biosynthetic pathway may be a unique demonstrated in vitro that functional expression of avenue for targeting GBM. RFC at the BBB and its upregulation by the vitamin Methods: Two patient-derived primary GBM stem D nuclear receptor (VDR) could provide an cell lines (GBM510 and GBM514) and one normal alternative route for brain folate delivery. This study neural stem cell line were propagated in culture.

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Cholesterol and its intermediates were extracted Cellular targets in the brain include microglia and using MTBE and analyzed by LC/MS/MS. To astrocytes which in response to infection release validate the genome-wide results, we knocked out inflammatory markers and viral proteins (i.e., gp120, the enzymes using CRISPR and then performed Tat). PPARs are ligand-activated transcription rescue experiments with exogenous cholesterol or its factors that play a role in glucose/lipid metabolism. intermediates measuring cell viability with Alamar Compelling evidence suggests that the PPARγ Blue. Small molecule inhibitors RO48-8071 (LSS), isoform exerts anti-inflammatory properties in terbinafine (SQLE), and zaragozic acid A (FDFT1) neurological disorders. The goal of this study was to were also tested. examine the role of PPARγ in the context of HIV- Results: The levels of cholesterol and intermediates associated brain inflammation in vivo, in acute and were similar in all three cell lines. Cholesterol, chronic rodent models. lanosterol and desmosterol, downstream of LSS, Methods: In the acute model, rats were administered were able to rescue LSS knockout GBM cells but an intracerebral ventricular (ICV) injection of the squalene, the upstream precursor, had no effect. HIV-1 viral protein, gp120ADA and received PPARγ Zaragozic acid (100μM) had no effect on the growth agonist (rosiglitazone). Inflammatory markers were of any of the cells. Compared to vehicle, terbinafine measured using qPCR (24h post ICV). Activation of hydrochloride (>25μM) and RO48-8071 (10μM) transcription factor (NF-kB) was quantified by inhibited the growth of both the GBM and control immunoblotting (5h post ICV). In the chronic cell lines. Compared to vehicle, RO 48-8071 at model, mice were administered an intracranial 100nM was able to selectively inhibit the growth the injection of ecotropic HIV-1 (EcoHIV) which is a GBM cell lines without impacting the control cells. chimeric strain of HIV where gp120 is replaced with Conclusions: The cholesterol biosynthetic pathway leukemia virus gp80, rendering the virus capable of is active in GBM cells but the level of cholesterol infecting mice. In this model, we quantified viral produced is not different between GBM and normal genes and inflammatory cytokines/chemokines 5d neural stem cells. The LSS gene identified from the and 21d post infection and treated mice with CRISPR screen could selectively inhibit the growth rosiglitazone or pioglitazone. GBM cells but not the normal neural stem cells Results: Rosiglitazone reversed the HIV-1 gp120 indicating that lanosterol synthase may be a induced inflammatory response and inhibited NF-kB druggable target. activation. EcoHIV infection significantly induced Acknowledgement: Wendy Siu is the recipient of a several inflammatory cytokines/chemokines 5d and 2018 GSK/CSPS National Undergraduate Student 21d post infection. Detection of viral genes Research Program Award. demonstrated productive infection. Treatment with rosiglitazone or pioglitazone for 5d reduced inflammatory responses. 7. Role of Peroxisome Proliferator-activated Conclusions: To date, we have successfully Receptor-γ (PPARγ) in Regulating implemented a robust model of HIV-1 Inflammatory Signalling in Acute and neuropathogenesis i.e., the EcoHIV mouse model Chronic Rodent Models of HIV-1 Associated which recapitulates many clinical features of the Brain Inflammation disease. This model is a non-hazardous approach for investigating treatment strategies. Herein, we have 1 1 Amila Omeragic , Nareg Kara-Yacoubian , Jennifer also demonstrated that targeting PPARγ may provide 2 2 Kelschenbach , David J. Volsky and Reina a novel molecular target for preventing/treating 1 Bendayan HIV-associated brain inflammation. 1 Department of Pharmaceutical Sciences, University 2 of Toronto, Toronto, Ontario, Canada; Department of Medicine – Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York City, USA

Purpose: Despite the use of antiretroviral therapy for the treatment of HIV-1 infection, cognitive impairments remain prevalent due to persistent viral replication and associated brain inflammation.

88s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

8. Vascular Endothelial Growth Factor a significant reduction in all parameters. Diagnostic Test for POEMS Syndrome Conclusions: Extreme elevation of VEGF levels is diagnostic for POEMS syndrome, and should be Manuela G. Neumana, Steven K. Bakerb, Graeme followed to assess response to therapy. A.M. Fraserc, John Nearyd, Susan E. Goodwine, Ann Bengerf 9. Investigating the Role of the IKK Protein aIn Vitro Drug Safety and Biotechnology, Kinase in Vascular Remodeling Events Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON; bDepartment of Francis Lefebvre and Marc J. Servant. Medicine, Physical Medicine & Faculty of Pharmacy, Université de Montréal, Neurology, Neuromuscular Disease Clinic, Montréal, Québec, Canada McMaster University, HSC, Hamilton, ON; cDepartment of Hematology, Juravinski Cancer Purpose: The IKK protein kinase is an important Centre and Department of Oncology, McMaster regulator of the chronic inflammatory response and University, Hamilton, ON; d Department of is increasingly shown to be central in vascular Medicine, McMaster University, Hamilton, ON; e inflammation. As blood vessels respond to injuries, Clinical Neurological Sciences, Juravinski Hospital, they undergo a process called “remodeling” which Hamilton, ON; f Department of Hematology, allows them to heal and maintain their function. Juravinski Cancer Centre, Hamilton, ON. However, in conditions involving chronic vascular inflammation, a dysregulation in vascular Background and Aims: POEMS syndrome is remodeling (VR) processes is observed, leading to characterized by poly-neuropathy, osteo-sclerotic clinical outcomes such as atherosclerosis and arterial myeloma, organomegaly, endocrinopathy, aneurysm. The aim of this study was to better monoclonal plasma cell disorder, and skin changes. understand the role of IKK in modulating VR We aim: (1) to demonstrate the utility of quantitative phenomena, specifically by generating IKK- measurement of serum levels of VEGF in the deficient primary human aortic smooth muscle cells diagnosis of POEMS and the monitoring of (HASMCs) to be used as an in vitro research tool to therapeutic interventions; (2) to demonstrate that characterize differential VR gene expression. overproduction of pro-inflammatory cytokines is a Methods: LentiX 293T packaging cells were used to characteristic of POEMS. produce third generation lentiviral particles encoding Methods: We studied 14 POEMS patients clinically the Cas9 endonuclease and different guide RNA presenting POEMS. We compare the serum levels of sequences designed to target the human IKBKB gene cytokines and chemokines between the POEMS at six different loci. Transduction of the primary patients with 80 patients with viral hepatitis C HASMCs was followed by antibiotic selection (HCV), 12 healthy controls, and 80 individuals with giving rise to seven stable populations: populations alcoholic liver disease (ALD). We quantified #1 through #6 in which the IKBKB gene is targeted (ELISA pg/mL) the levels of VEGF, Interferon and a non-target control population. These cells were gamma (IFN-γ), Tumor Necrosis Factor alpha (TNF- then exposed to the proinflammatory cytokine TNF- α), Regulated-upon-Activation Normal-T-cell-  for different periods of time. Isolated protein and Expressed and presumably-Secreted (RANTES), and RNA were used in Western blot and RT-qPCR Nuclear Factor kappa-B (NFκB). analyses respectively to assess the activation of Results: In POEMS patients, VEGF levels were 20 IKK-dependent proinflammatory cellular x elevated versus control, 16 x ALD, 14 x vs HCV. responses. TNFα levels were 8x higher versus control, but Results: The steady-state expression of IKK was significantlylower when compared with HCV or dramatically reduced in populations #1 and #2. This ALD patients. VEGF levels in POEMS patients was associated with a defect in TNF- cellular decreased with therapeutic intervention. Interferon signaling events, more specifically with a decrease gamma (IFN-γ), RANTES levels were x10 vs, in both IB phosphorylation and interleukin 6 control, but not differed significantly from ALD and induction. HCV. NFκB levels were not significantly different Conclusion: Stable populations of IKK-deficient from HCV and ALD. The follow up of individual HASMCs were successfully generated using cytokine kinetics during the 4 years showed

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CRISPR-Cas9 technology, giving rise to populations ascites concentrations of CXCL2/MIP-2 (mouse of cells which proved resistant to TNF--induced analogue of human IL-8) and IL-10 were associated proinflammatory cellular responses. Further with tumor progression. experiments will explore the effect of vasoactive Conclusion: The BRCA1 deficient OVCAR8luc proinflammatory inducers on these cells with respect model possesses characteristics that are associated to genes involved in VR. with clinical features of ovarian cancer. The Acknowledgement: Francis Lefebvre is the correlation of bioluminescent signal with tumor recipient of a 2018 GSK/CSPS National burden allows for real-time monitoring of disease Undergraduate Student Research Program Award. progression and treatment response. The current model may provide a clinically relevant platform for the preclinical assessment of novel therapeutic 10. Quantitative and Qualitative Analysis of a options for serous ovarian cancer. Bioluminescent BRCA Deficient Model of Serous Ovarian Cancer 11. Injectable, Covalently In Situ-Gelling Block Yen Ting Shen, Lucy Wang, James C. Evans, Copolymers for the Improved Loading and Christine Allen, Micheline Piquette-Miller Prolonged Release of Hydrophilic Drugs Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON Michael J. Majcher, Lukas P. Sadowski, Francis M. Yavitt, Rachelle Kleinberger, Harald Stover, Todd Purpose: Currently there is a lack of in vivo Hoare*. xenograft models of BRCA deficient ovarian cancer. Departments of Chemical Engineering and The purpose of this study is to develop a Chemistry, McMaster University, Hamilton, ON bioluminescent model of BRCA deficient serous ovarian cancer for real-time assessment of disease Purpose: Poly(N-isopropylacrylamide) (PNIPAM)- progression and treatment response. based “smart” hydrogels [1] exhibit a volume phase Methods: Firefly luciferase was transfected in transition at ~32°C, leading to improved entrapment BRCA1 deficient OVCAR8 cells. Five or ten of hydrophobic drugs but rapid burst-like convective million OVCAR8luc cells were injected release of hydrophilic drugs [2]. The lower pore size intraperitoneally in 7 weeks old, female NOD/SCID of PNIPAM hydrogels in their collapsed state offers mice. Bioluminescence imaging was performed an opportunity to significantly prolong the release of weekly to monitor tumor development. Levels of IL- hydrophilic drugs if the initial convective burst 6, IL-8 and IL-10, which are associated with release is minimized. In response, we synthesized in enhanced tumorigenesis and metastasis, were situ-gelling block copolymers based on PNIPAM measured in serum and ascites using ELISA assay. and poly(N-(2-hydroxyethyl)acrylamide) (PHEA), a Results: Death or ethical endpoints were reached in highly hydrophilic polymer that can self-associate all mice at 58±4 days post-inoculation. As into domains, the presence of which is hypothesized determined by bioluminescence signaling, to improve uptake and to slow release kinetics. significant differences in tumor growth rate and Methods: Reverse addition-fragmentation chain- tumor burden were not seen in animals inoculated transfer (RAFT) polymerization was used to with either 5 or 10 million cells. The model was copolymerize PNIPAM with tert-butyl acrylate characterized by ascites formation, distended (tBA) to form P(NIPAM-co-tBA) (Mw ~16 kDa) abdomen and a high degree of tumor burden. followed by chain extension with HEA to form Following post-mortem examination, disseminated P(NIPAM-co-tBA)-b-PHEA. The molecular weight disease was found in the liver, intestine, gall bladder of the PHEA block length was systematically varied and peritoneal wall. Regression analysis (2.5 kDa, 5 kDa, 10 kDa, and 20 kDa). The tBA demonstrated significant correlations between groups were then hydrolyzed and converted to bioluminescence signal and tumor weight or tumor hydrazide groups via carbodiimide-mediated volume (R2 = 0.65 and 0.61, respectively). conjugation of adipic acid dihydrazide. These block Immunoblots of OVCAR8 cells and collected copolymers were co-extruded via double barrel tumors confirmed that a low protein expression of syringes with fluorescein-ovalbumin and aldehyde- BRCA1 was maintained in the xenografts. A 3-fold functionalized PNIPAM to form protein-loaded increase in serum IL-6 and a 2-fold increase in hydrogels.

90s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

Results: Polymers with HEA block lengths of 5 plus anti-CTLA-4 (300 µg) at days -3, -1, and every kDa and 2.5 kDa at concentrations of 15 and 20 wt% subsequent week after until endpoint. formed gels within 5 minutes of mixing the Results: Neither dose resulted in an increase in functionalized precursors, while longer HEA block serum ALT in wild type animals, but a dose of 500 lengths did not form gels. Relative to PNIPAM-only mg/kg produced a delayed onset increase in ALT in hydrogels, PNIPAM-b-PHEA hydrogels showed the PD-1-/- females and a more acute increase in PD- significantly different release kinetics for 1-/-males. There was also an inflammatory fluorescein-ovalbumin as a function of PHEA block mononuclear infiltrate in the livers of female PD-1-/- length. mice. Conclusion: Using block copolymers with Conclusion: The increase in ALT and inflammatory amphoteric properties as building blocks for hepatic infiltrate indicates the presence of liver injectable hydrogels can address key challenges with injury in the PD-1 deficient mice. These results the use of smart thermoresponsive hydrogels for support the hypothesis that green tea extract can drug delivery. cause immune-mediated liver injury in humans and References: [1]N. A. Peppas, Curr. Opin. Col. provides a method for mechanistic studies. Future Interf. Sci., Vol. 2, No. 5, pp. 531–537, 1997. work will delineate if EGCG is responsible for [2]D. Schmaljohann, Adv. Drug Deliv. Rev., Vol. 58, causing the liver toxicity. No. 15, pp. 1655–1670, 2006.

13. Combining Statins with Radioimmuno- 12. Using PD-1 Knockout Mice to Test the therapy as a Novel Therapeutic Strategy for Potential of Green Tea Extract and (-)- Colorectal Cancer epigallocatechin-3-gallate (EGCG) to Cause Idiosyncratic Drug-induced Liver Injury Tiffany Tong2, Mathew Robson2, Matthias Glaser3, Erik Årstad3, Tammy Kalber4, Mark Lythgoe4, Tiffany Cho, Susie Wang, Karen Yeung, and Jack Stephen Pereira5, R. Barbara Pedley2, Vessela Uetrecht Vassileva1,2 Faculty of Pharmacy and Department of 1Imperial Centre for Translational and Experimental Pharmaceutical Sciences, University of Toronto, Medicine, Department of Surgery and Cancer, Toronto, Ontario, Canada Imperial College London; 2Department of Oncology, University College London Cancer Institute; Purpose: Idiosyncratic drug-induced liver injury 3Department of Chemistry and Institute of Nuclear (IDILI) can lead to liver failure or even death. The Medicine, Division of Medicine, University College dominant immune response to drugs that can cause London; 4Centre for Advanced Biomedical Imaging, IDILI appears to be immune tolerance, and we have University College London; 5Institute for Liver and developed the first validated animal model by using Digestive Health, Royal Free Hospital, University a PD-1 deficient mouse model with anti-CTLA-4 to College London block immune checkpoints. Herbal products have become a significant cause of IDILI. Green tea Purpose: Advanced colorectal cancer (CRC) extract, which is used for weight loss, has been remains the fourth leading cause of cancer-related associated with several cases of liver failure leading deaths worldwide. Therefore, there is an urgent need to liver transplantation or death. It is suggested that for the development of more-successful therapies. hepatotoxicity is most likely due to (-)- Radioimmunotherapy can selectively target tumour- epigallocatechin-3-gallate (EGCG), the major associated antigens and deliver prolonged low-dose catechin in green tea formulations. We hypothesize ionizing radiation. It is well tolerated and has shown that the IDILI caused by green tea extract is encouraging therapeutic activity in CRC; however, immune-mediated and will be unmasked in PD-1 outcomes are far from optimal. Recently, HMG-CoA deficient mice. reductase inhibitors (statins) have been implicated as Methods: Male and female C57BL/6J mice radiosensitizers, representing a potential effective (n=3/group) were treated with green tea extract combination with radioimmunotherapy. mixed thoroughly in their food at a dose of 250 Methods: We investigated whether simvastatin can mg/kg or 500 mg/kg for 5 weeks. PD-1 deficient radiosensitize CRC cells, and if it can be effectively mice received the same dose of green tea extract combined with radioimmnotherapy in vivo, using a

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radiolabeled anti-CEA antibody. We evaluated cell sex hormones could provide beneficial effects in viability in response to simvastatin and irradiation in post-menopausal women who are at a greater risk of four human CRC cell lines (SW48, SW1222, LoVo, dementia and might provide cognitive benefits. LS174T). We then evaluated the therapeutic effect Acknowledgement: Stephanie De Jong is the of simvastatin and radioimmunotherapy in vivo in recipient of a 2018 GSK/CSPS National the human SW1222 CRC xenograft model. Efficacy Undergraduate Student Research Program Award. was evaluated based on tumour growth delay and survival. Results: Irradiation or simvastatin significantly reduced cell survival in a dose-dependent manner, Clinical Sciences & Pharmacy and a further significant reduction in survival was observed with the combination in all cell lines. The Practice combination of simvastatin with radioimmunotherapy significantly and synergistically reduced in vivo tumour growth and 15. Aspirin and Other Non-Steroidal Anti- prolonged survival of mice. Inflammatory Drugs Interactions: A Conclusion: Our results demonstrate significantly Systematic Review enhanced therapeutic efficacy with the combination of simvastatin and radioimmunotherapy in CRC, Zuhair Alqahtani and Fakhreddin Jamali. which could potentially translate into well-tolerated Faculty of Pharmacy and Pharmaceutical Science, successful clinical outcomes. University of Alberta, Edmonton, Alberta, Canada.

14. Effect of Female Sex Hormones and Their Purpose: Some clinical trials and epidemiological Derivatives on Amyloid Beta Aggregation studies suggest reduced cardiovascular (CV) risk for non-Aspirin non-steroidal anti-Inflammatory drugs Stephanie De Jong and Praveen P. Nekkar Rao (NANSAIDs) if used along with low-dose of Aspirin School of Pharmacy, University of Waterloo, Health which is believed to be through its anti-platelet Sciences Campus, Kitchener, ON action. In the meantime, in vitro and ex vivo studies suggest that NANSAIDs may mask the CV benefits Purpose: Alzheimer’s disease (AD) is the most of Aspirin. We, therefore, carried out a prevalent form of dementia, accounting for over comprehensive systematic search to assess the CV 60% of all cognitive dysfunction in the elderly. risks of concomitant use of NANSAIDs and Aspirin. There are three hallmark features that have been Methods: We searched MEDLINE, EMBASE, identified in Alzheimer’s patients (i) deficiency in CINAHL, Web of Science, and the Cochrane cholinergic neurons (ii) accumulation of insoluble Library databases up to August 2017 using the amyloid beta (Aβ) plaques and (iii) the formation of following keywords: acetylsalicylic acid, Aspirin, neurofibrillary tangles. The Aβ cascade is an NSAIDs, nonselective NSAIDs, cyclooxygenase-2, attractive target in developing potential therapy NSAID/aspirin interaction, adverse effects and options to treat AD. We investigated the effect of platelet effects. Clinical Trials Registry platforms natural and synthetic female sex hormones in and bibliographies of included studies were searched preventing the formation of neurotoxic Aβ for relevant additional studies. Titles and abstracts of aggregates. included studies were retrieved and screened Methods: The anti-Aβ activity of sex hormones was independently by two reviewers to identify evaluated by fluorescence spectroscopy and the potentially relevant studies. The risk estimates of binding interactions were investigated by molecular CV risk (OR, RR or HR; 95% CI) were extracted docking studies. and the quality of included epidemiological studies Results: The Aβ40 aggregation kinetics assays were assessed. results demonstrate that naturally occurring Results: In total, 32 eligible studies (20 estrogens or their semi-synthetic derivatives exhibit biochemistry studies and 12 observational trials) on anti-Aβ activity whereas progesterone and its the interactions of Aspirin and NANSAIDs were synthetic derivatives were generally inactive. found. in vitro studies suggest that the anti-platelet Conclusion: These studies show that use of female effect of Aspirin is diminished when combined with

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some NANSAIDs like ibuprofen, naproxen and Research Ethics Board. refecoxib. Nevertheless, with a few exceptions, Results: The survey was distributed to 1,884 studies suggest that the risk of myocardial infarction physiotherapists registered with the Alberta and death is comparable between patients who used Physiotherapists Association with 362 responses. Aspirin alone or with ibuprofen, naproxen, 41% of the responders had over 20 years of clinical diclofenac, meloxicam, celecoxib or rofecoxib; i.e., experience, 52% worked in general practice. The NANSAIDs do not reduce the cardioprotective responders practiced in either Edmonton or Calgary effect of Aspirin. (57%), with the most common specialty reported Conclusion: There does not seem to be an increased being orthopaedics (14%). Physiotherapists reported risk of myocardial infarction or death among being unfamiliar with statins (67%), psychiatric patients who use long term Aspirin and NANSAIDs medications (63%), antihyperglycemic agents concomitantly compared with Aspirin alone. The (55%), and medications affecting the stomach (e.g. possibility of a transient short-term therapeutically PPIs; 67%). A four module accredited online relevant interaction between these drugs remains to program was subsequently outlined with topics be studied. including: (1) drug induced tendinopathy; (2) drug Funding: University of Alberta Self-Directed Grant induced myalgias arthralgias, and rhabdomyolysis; and Studentship from King Saud University. (3) physical function and drugs in the elderly; and (4) antidepressants and post-stroke motor recovery. Conclusion: This project demonstrated that 16. Needs Assessment and Online Program for physiotherapists identified a number of medication- Physiotherapists in Alberta Regarding related learning needs for professional practice, and Physical Function and Drugs learning needs can be addressed in health professional continuing education through 1 2 Jonathon Thomson , Allyson Jones , and Cheryl interprofessional collaboration. 1 Sadowski Acknowledgement: Jonathon Thomson is the 1 Faculty of Pharmacy and Pharmaceutical Sciences, recipient of a 2018 GSK/CSPS National 2 University of Alberta; Faculty of Rehabilitation Undergraduate Student Research Program Award. Medicine, University of Alberta, Edmonton, Alberta, Canada 17. Nocturnal Hypoglycemia Associated with Purpose: To identify learning needs of practicing Bedtime Insulin Mixture Administration in physiotherapists in Alberta regarding medications, Hospitalized Patients and to translate these identified needs into learning activities. Kelsey Mann1, John Manderville2 and Heather Methods: An online survey was compiled from Neville2. existing literature regarding self-identified learning 1College of Pharmacy, Dalhousie University, needs of health professionals, and a scoping review Halifax, Nova Scotia; 2Pharmacy Department, Nova that was previously conducted by this research team. Scotia Health Authority, Halifax, Nova Scotia, Demographic questions regarding physiotherapists Canada. in Alberta was obtained from the 2015 Alberta Physiotherapists Association Annual Report. The Purpose: Administration of regular or rapid-acting survey was administered through the University of insulin without concomitant carbohydrate ingestion Alberta IT department with one original email and 2 increases hypoglycemia risk. Bedtime administration reminders at two-week intervals. The survey of insulin mixtures, which contain regular or rapid- feedback, scoping review, and Health Canada Drug acting insulin, has been observed in our hospitals. and Health Products Safety Review were used to Our aim was to compare nocturnal hypoglycemia outline the content for continuing education rates following insulin mixture administration at modules. The online modules were outlined and bedtime compared to suppertime in hospitalized guided by the online learning format used by the patients. Faculty of Rehabilitation Medicine, University of Methods: Insulin mixture orders were extracted Alberta. The modules were presented for peer from the pharmacy information system of the Queen review to Rehabilitation Medicine. The study was Elizabeth II Health Sciences Centre between January approved by the University of Alberta Health 1, 2016 and December 31, 2017. Retrospective chart

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review was conducted on inpatient visits. Visits Drug Delivery and were excluded if length of stay was less than 48 hours, if the patient received less than two Pharmaceutical Technology administrations of an insulin mixture, or if blood glucose readings between 2200h and 0900h were not documented. Insulin mixture administration was categorized as supper if prior to or at 1800h and 18. Cytotoxicity Profiles of Lanthanide bedtime if after 1800h. Nocturnal hypoglycemia was Compounds within Human Kidney (HEK- defined as point-of-care blood glucose reading of 293), Liver (HEPG2), and Osteoblast (HOb) less than 4mmol/L between 2200h and 0900h. Rates Cells in addition to Murine Pre-osteoclast were calculated as instances of nocturnal (RAW 264.7) Cells hypoglycemia, divided by total administrations per a a a visit. Descriptive analyses and a Mann-Whitney test Grace Cuddihy , Yunyun Di , Jacqueline Cawthray , Ellen Wasana, Chris Orvigb, Thomas. I. Kostelnikb, were performed. c a Results: A total of 123 patient visits were included, David Cooper , Kishor M. Wasan aCollege of Pharmacy and Nutrition, University of mean age 73.4 (9.9) and 56.1% male. For those in b the supper administration group (n=102), the mean Saskatchewan, Saskatoon, SK; Medicinal Inorganic nocturnal hypoglycemia rate was 4.26% compared Chemistry Group, Department of Chemistry, University of British Columbia, Vancouver, BC; to 15.24% (p=0.143) in the bedtime administration c group (n=21). Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, Supper Bedtime Saskatoon, SK, Canada.

Number of patient 102 21 Purpose: Our team has developed a promising visits lanthanide compound (LaXT) that has the potential Number of insulin 867 142 to treat bone density disorders such as osteoporosis. administrations Recently published animal studies found that La3+ Mean insulin 8.50 6.76 preferentially accumulates in tissues and particularly administrations (7.80) (5.66) in bone. The purpose of this study is to develop a per visit (SD) cytotoxicity profile for the lanthanum compounds in Mean nocturnal 0.0426 0.1524 human kidney and liver cells as well as bone-related hypoglycemia rate (0.1096 (0.269 human osteoblast cells after a preliminary per visit (SD) ) 0) investigation into the IC50 of the compound in a prostate cancer cell line (C4-2). Conclusion: To our knowledge, this is the first Method: For all cell lines, 5000 suspended cells in study to examine the safety of insulin mixture 100 µL of complete culture medium, were seeded in administration at bedtime. When compared to 96-well plates and allowed to attach overnight. suppertime administration, bedtime administration Subsequently, cells were treated with varying of insulin mixtures was associated with a higher rate concentrations of each lanthanum compound for 48 of nocturnal hypoglycemia, however, this difference or 72 hours then cell viability was determined using was not statistically significant. CellTiter 96® AQueous One Solution Cell Acknowledgement: Kelsey Mann is the recipient of Proliferation Assay (MTS). Data were plotted in a 2018 GSK/CSPS National Undergraduate Student GraphPad Prism5 and analyzed using two-way Research Program Award. ANOVA with Bonferroni post hoc tests. Results: Preliminary investigation into the cytotoxicity of LaXT in C4-2 cells demonstrated that the concentration when 50% of cell death occurred was 355.3 µM. Limited toxicity was observed in HEK-293 human kidney cells, HepG2 human liver cells (Figure 1), and RAW264.7 murine pre- osteoclast macrophage cells treated with <300 µM of

LaXT or LaCl3 (docetaxel 25nM and 1% (v/v) Triton X-100 were positive controls used to achieve

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an average of approximately 60% and 99% cell 187.7±1.4 nm, with a polydispersity of 0.179±0.029. death respectively). In HOb bone-related human For both drying methods, there was no size change osteoblast cells, no significant reduction in cell observed. The particle sizes were uniform and no viability occurred until concentrations of LaXT or agglomeration was observed under TEM. The spray- LaCl3 ≥1000 µM). drying process caused spherical agglomerates visible Conclusion: The present study shows that the LaXT by SEM. The saturation solubility of esculetin compound has only limited in vitro toxicity at very increased 1.2-1.5 folds in nanocrystals compared high concentrations in the human kidney and liver with the raw material. The nanosuspension and dried cells with similar toxicity profiles in bone-related nanocrystals were stable during 90 days at 4°C. human osteoblast and murine pre-osteoclast cell Conclusion: This study revealed that an esculetin- lines. PovacoatTM nanocrystal was successfully produced Acknowledgements: Funding provided by a using a small-scale approach. Nanocrystals have the Saskatchewan Health Research Foundation (SHRF) potential to enhance the bioavailability of esculetin. Establishment Grant to KMW, EKW, JC, CO and DC. Grace Cuddihy is the recipient of a 2018 GSK/CSPS National Undergraduate Student 20. Core-Shell Spray Dried Dry Powder Research Program Award. Vaccines for Controlled Enteric Delivery

Daniel A. LeClair1, Emily D. Cranston1, Brian D. 19. Preparation and Solidification of Esculetin Lichty2, Zhou Xing2, Michael R. Thompson1 Nanocrystal: Towards an Innovative 1Department of Chemical Engineering, 2McMaster Approach for Hyperuricemia Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster Jieyu Zuo1, Nadia Bou-Chacra2, Raimar Löbenberg1. University 1Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada; 2Faculty Purpose: Current global vaccination programs are of Pharmaceutical Science, University of Sao Paulo, challenged by costs associated with vaccine cold Sao Paulo, Brazil chain storage and administration. A solid oral dosage form for vaccines would alleviate these costs but is Purpose: In a previous study, esculetin illustrated difficult to produce due to general vaccine instability the possibility to treat hyperuricemia. As a poorly and the complication of bypassing the gastric barrier. aqueous soluble substance, its therapeutic efficacy We have developed a novel consecutive spray maybe limited. Nanocrystals are a dosage form to drying method for this purpose, demonstrated with improve bioavailability by enhancing the saturation dry powder encapsulated recombinant replication solubility. The study aimed to prepare esculetin deficient human type-5 adenovirus (AdHu5) and nanocrystals using a small-scale wet bead milling vesicular stomatitis virus (VSV) by employing an approach. The solidification methods, morphology, anionic copolymer as the enteric coating. saturation solubility and stability of esculetin Methods: A two step spray-drying procedure was nanocrystals were also investigated. developed using a BÜCHI B290 spray dryer. Step 1 Method: The esculetin suspension (3.0% w/w featured the viral vector encapsulated with a esculetin and 3.0% w/w PovacoatTM) were milled at stabilizing sugar matrix for purposes of thermal 800 rpm for 3 days at room temperature. The particle stability. Step 2 involves the microparticles to be size was measured using a Zetasizer ZS 90. The suspended in ethanol with Eudragit® L100 polymer suspension was dried by spraying-dry and freeze- (Evonik Industries) and spray dried again. Particle drying methods. The transmission electron properties and coating efficiency were assessed with microscopy (TEM) and scanning electron and without the active biological ingredient. In vitro microscopy (SEM) were employed to observe the viral activity was determined by GFP assay. morphology of the dried powders. The saturation Results: Up to 25% of the starting material was fully solubility was evaluated at pH 1.2, 4.5 and 6.8 encapsulated within the enteric coating and buffers using a shake-flask method. The fresh encapsulation efficiency was largely dependent on suspension and dried powders were stored in capped spray gas flow rate and solids concentration in the glass flasks at 4°C for a stability test. feed. Coated particles retained in vitro AdHu5 and Results: The milled suspension had a particle size of VSV activity after testing in gastric-like acidic

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conditions while uncoated controls resulted in nanocomposite hydrogel system components complete activity loss. showed promising cytocompatibility. Conclusion: The overall encapsulation efficiency Conclusion: Remote magnetic triggering of the was low (25%) but could be improved by adjusting developed Tg switchable nanocomposite injectable the spray drying process parameters. Most hydrogel by the application of a pulsed AMF can importantly, retained viral activity was demonstrated provide a minimally-invasive approach for localized for these coated vaccine powders after incubation in repetitive on-demand drug delivery over prolonged acidic conditions that simulated the gastric barrier. periods of time, with good resolution between the on- and off-states.

21. Repetitive On-demand Drug Delivery by External Triggering of Injectable Magnetic 22. Dynamic PEGylation Reduces the Viscosity Hydrogels Incorporated with Glass of Concentrated Protein Solutions Transition (Tg) Switchable Nanoparticles Hoda Soleymani Abyaneh1, Yuhui Gong2, Andreas Scott Campbell, Somiraa Said, Angus Lam, Nahieli Niederquell3, Martin Kuentz3, Jean-Christophe Preciado, Niels Smeets, and Todd Hoare* Leroux2, and Marc A. Gauthier1. Department of Chemical Engineering, McMaster 1Institut National de la Recherche Scientifique University, Hamilton, Ontario, Canada (INRS), EMT Research Center, Varennes, Canada. 2Swiss Federal Institute of Technology Zurich Purpose: Chronic local pain management, treatment (ETHZ), Department of Chemistry and Applied of infections, insulin delivery, and chemotherapy Biosciences, Institute of Pharmaceutical Sciences, would benefit from repeated, pulsatile, localized, Zurich, Switzerland. 3University of Applied and remotely-triggered drug delivery. By co- Sciences Northwestern Switzerland, School of Life encapsulating superparamagnetic iron oxide Sciences, Institute of Pharma Technology, Muttenz, nanoparticles (SPIONs) that can induce localized Switzerland. heating upon application of an alternating magnetic field (AMF) together with glass transition Purpose: Proteins in solution tend to self-assemble temperature (Tg) switchable nanoparticles inside an and oligomerize at high concentration, resulting in injectable in situ gelling hydrogel, a minimally- important increases in viscosity beyond what is invasive strategy to achieve repetitive localized on- acceptable for injection. This project investigates the demand drug release is demonstrated. means to reduce the viscosity of concentrated Method: We synthesized hydrophilic SPIONs by protein solutions using a newly discovered class of co-precipitating iron (III) and iron (II) chloride additives to address manufacturing and formulation followed by coating with polyethylene glycol. Drug- challenges posed by high viscosity. loaded Tg switchable nanoparticles (Tg ~39°C) were Methods: We recently developed new chemistry, synthesized through the miniemulsion using phenylglyoxals (PGO), to reversibly graft polymerization of butyl and methyl methacrylate. methoxy poly(ethylene glycol) (mPEG) to the Injectable in situ gelling hydrogels were prepared by arginine residues of various proteins.1 We have mixing hydrazide-functionalized carboxymethyl evaluated the viscosity-reducing effect of PGO– cellulose with aldehyde-functionalized dextran using mPEG on a very high concentration solution of a double-barrel syringe equipped with a mixer. Both immunoglobulin G (IgG) as well as human serum temperature- and pulsed AMF-based drug release of albumin (HSA). To perform viscosity rhodamine B-loaded nanocomposite hydrogels was measurements, the concentrated yet isotonic tracked via fluorescence. solutions of the proteins (up to ~500 mg.mL–1) were Results: Temperature-based drug release formulated with a highly-sub-stoichiometric amount experiments indicated a 4-fold increase in rhodamine of the additive. release between the on-state (45°C) and off-state Results: Our data showed that extremely small (37°C). Pulsed AMF-based release studies showed amounts of PGO–mPEG (~5 μM), were able to 2-fold enhancement of rhodamine B release between reduce the viscosity of a very high concentration on-state (pulsed AMF) and off-state (no AMF). A (~460 mg.mL–1) solution of IgG by ~35%. Similar similar triggered release profile was attained when a results were obtained for HSA, where low pulsed AMF was applied after one week. All the concentration of the additive (500 μM) reduced the

96s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

viscosity of a highly concentrated HSA solution HPLC assay. (500 mg·mL–1) by ~20%. Interestingly, addition of Results: PK data showed that the oral bioavailability mPEG alone had no viscosity reducing effect on the of CEF in MMs was found to be (4.91 %) higher IgG solution, whereas the reducing effect was seen compared to the CEF in aqueous solution (1.30%). in HSA solution in the presence of mPEG. Cmax of CEF in MMs formulation was higher (1.08 ± Conclusion: Considering how little of PGO–mPEG 0.1 µg/ml) compared to CEF-MKC complex (0.69 ± additive was required to impart such a large effect 0.1 µg/ml) and CEF in aqueous solution (0.52 ± 0.1

on viscosity of protein solutions, these results are µg/ml). Similarly, the mean values for AUC0- of promising. The discrepancy seen in the effect of CEF in MMs formulation was higher (3.89 ± 0.9 mPEG on viscosity of IgG and HSA solutions, may h.µg/ml) compared to CEF-MKC complex (1.52 ± be attributed to unique interaction of mPEG with 0.2 h.µg/ml) and CEF in aqueous solution (1.03  each protein due to their structural differences and is 0.4 h.µg/ml, respectively). currently under investigation. Conclusions: The mixed micelles formulation Acknowledgements: This study was supported by composed of PPC and BS was able to increase the the Swiss National Science Foundation (ID intestinal epithelial cell efflux of drug and eventually 200021_137591) and the Natural Sciences and enhance the oral bioavailability of cefotaxime Engineering Council of Canada (NSERC; ID sodium up to 4-fold. STPGP_493874). HSA acknowledges a postdoctoral scholarship from NSERC. 1. Gong Y; et al. Chem. Sci., 2017;8: 4082. 24. A Mucoadhesive Lipidic Delivery System of the Adjuvant Innate Defense Regulator (IDR)-1002 23. The Enhancement of the Poor Oral Bioavailability of Cefotaxime Sodium using Ellen Wasan1, Jaweria Syeda1, Stacy Strom2, Nano-mixed Micelles Formulation Jacqueline Cawthray1, Kishor Wasan1, Volker Gerdts2 1 2 Mosab Arafat , Cathrin Kirchhoefer , Momir 1. College of Pharmacy and Nutrition, University of 3 1-4 Mikov , Muhammad Sarfraz and Raimar Saskatchewan, Saskatoon, SK, S7N 5E3, Canada Löebenberg4. 2. VIDO-InterVac, University of Saskatchewan, 1College of Pharmacy, Al Ain University of Science Saskatoon, SK, S7N 5E3, Canada 2 and Technology, Al Ain. Department of Chemistry, 3 The University of Warwick, UK. Department of Purpose: To design a mucoadhesive nasal Pharmacology, Toxicology and Clinical formulation of the vaccine adjuvant innate defense Pharmacology, University of Novi Sad, Serbia. regulator (IDR)-1002 peptide, previously used 4Faculty of Pharmacy and Pharmaceutical Sciences, systemically as a triple complex with poly(I:C) and University of Alberta, Edmonton, Canada polyphosphazene (TriAdj). Methods: The binding properties of the TriAdj Purpose: The main purpose for this study was to mixture were characterised by gel electrophoresis investigate the ability of mixed micelles formulation and fluorescence quenching using rhodamine- (MMs) made of phosphatidylcholine (PPC) and BS poly(I:C). Cationic liposomes comprised of (sodium deoxycholate) loaded with Cefotaxime didodecyl dimethylammonium bromide (DDAB), sodium (CEF) and 3α,7α-dihydroxy-12-keto-5β- dioleoyl phosphatidylethanolamine (DOPE) (60:40 cholanate (MKC) complex to enhance the oral mol:mol) and DDAB, L-α-phosphatidylcholine (egg bioavailability of CEF in rats. PC) and DOPE (45:45:10 mol:mol:mol) were Methods: thin-film hydration method was used to prepared by the thin-film extrusion method. The prepare CEF loaded MMs using different BS liposomes and TriAdj were combined by simple concentrations. MMs were characterized, and the mixing. The formed complex was characterized by oral bioavailability of CEF in MMs formulation was dynamic light scattering, zeta potential, mucin assessed, and the pharmacokinetic (PK) of CEF- binding and cytotoxicity in RAW267.4 macrophage loaded MMs in comparison with CEF-BS complex cells by MTS assay. Mice were administered the and CEF aqueous solution were evaluated using 24 complex intranasally with ovalbumin as antigen, and male Wistar rats. Blood samples were collected for the immunogenic response was measured by ELISA up to 24 h, and CEF analyzed using a validated (plasma IgG1, IgG2) and Elispot assays (spleen IL-

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5, INF-γ). then surface coating with type I collagen. The Results: IDR-1002 peptide, polyphosphazene and characteristics and In vivo efficacy of the fabricated poly(I:C) self-assembles in solution forming an scaffold evaluated. anionic complex, demonstrated by altered Results: G-CSF-loaded chitosan NPs with average electrophoretic mobility in agarose gel, co-elution on diameter of 180nm prepared. The nanofibers of size exclusion chromatography and fluorescence 400nm acquired by incorporating the NPs into the quenching of rhodamine-labeled poly(I:C). TriAdj+ PCL. The scaffold of nanofibers preserved the G- cationic liposomes were prepared at several molar CSF structure against the harsh condition of ratios to determine optimal size stability and desired electrospining process. It is considered nontoxic. positive charge. Stable particles (<200nm over 24h) The prepared scaffold not only could accelerated the showed mucin binding of DDAB/DOPE+TriAdj was wound healing by providing sustained release of G- greater than DDAB/EPC/DOPE (45/45/10)+TriAdj. CSF, it could also prevented further contamination Exposure of RAW267.4 cells to TriAdj alone vs. of the wound. lipid-complexed TriAdj indicated that DDAB/DOPE Conclusion: The designed scaffold showed suitable (60:40) and DDAB/EPC/Chol (45:45:10) proliferation of stem cells with well-adherent complexation reduced TriAdj toxicity. Mice morphology. The histopathological results revealed administered either TriAdj alone or the lipid- the significant acceleration in skin regeneration complex TriAdj indicated a significantly greater comparing to the control groups. The designed immune response with lipid complex-TriAdj (Fig 1), scaffold also showed some beneficial properties; i.e. with IgG1>IgG2, a dose-response with the IDR-002 superior fibroblast maturation, collagen deposition peptide content (2µg vs 10µg/dose), and a enhancement, and minimizing the inflammatory differential IgG1 vs IgG2 response based on the lipid cells. In general, the designed G-CSF loaded composition. nanofibrous system could develop a suitable Conclusion: A mucoadhesive cationic lipid-based supportive dressing for wound healing. formulation of the TriAdj IDR-002 peptide adjuvant Acknowledgment: This research has been published is a potential approach for nasal administration of a in the Journal of biomedical materials research part vaccine product. A, in October 2017, volume 105a, issue 10 and Acknowledgements: Funded by VIDO-Intervac pages 2830–2842. (VG) and the President’s NSERC Fund, University of Saskatchewan (EKW). 26. Segmented Intravaginal Ring for Dual Delivery of siRNA-encapsulated 25. In vivo Wound Healing Effect of G-CSF Nanoparticles and Hydroxychloroquine as a Loaded Nanofiber/Nanoparticle Composite Prevention Strategy for HIV Infection

Shima Tanha, Molood Vakilinezhad, Hamid Akbari Yannick Traore, Yufei Chen, Emmanuel Ho Javar Laboratory for Drug Delivery and Biomaterials, Department of Pharmaceutics, Faculty of Pharmacy, School of Pharmacy, University of Waterloo, Tehran University of Medical Sciences, Tehran, Iran Kitchener, Ontario, Canada

Purpose: Wound healing could be promoted by an Purpose: Microbicides are an excellent alternative extracellular matrix (ECM) that release the growth to condoms to help reduce transmission of human factors in the controlled manner. In skin regeneration immunodeficiency virus (HIV). An intravaginal ring process human granulocyte colony stimulating factor (IVR) would be a suitable platform that can provide (G-CSF) is considered as the prominent growth controlled delivery of drugs within the female factor. Herein we aimed to prepare chitosan genital tract. We propose to develop a segmented nanoparticles (NPs) as the framework for controlling combination IVR whereby one-half of the IVR will the release of G-CSF and then incorporated the be loaded with hydroxychloroquine (HCQ), an acquired NPs into the Poly (ε-caprolactone) (PCL) immuno-modulatory drug that can induce a nanofibers for wound dressing. quiescent state in T-cells and the other half will be Method: The G-CSF-loaded chitosan NPs prepared coated with a pH-responsive film for the rapid and then incorporated into the PCL nanofibers using release of small interfering RNA (siRNA)- suspension electrospinning method. The nanofibers encapsulated nanoparticles (siRNA-NP) targeting

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CCR5 gene, triggered by an increase in vaginal pH caprolactone) (PBCL) in micelles can induce further due to the presence of seminal fluid as a strategy for changes to the disposition of delivered diclofenac. preventing HIV infection. Methods: DFEE was encapsulated in traceable Methods: Solid lipid nanoparticle made of glyceryl (Cyanine-5.5 attached) PEO-PBCL (PBCL-TM) or monosterate and L-α-phosphatidylcholine was used PEO-PCL micelles (PCL-TM). The micelles were to encapsulate siRNA using double emulsion characterized for their size distribution, DFEE method, mixed with pH-sensitive polymer (Eudragit encapsulation, and in vitro release. Diclofenac L100) and used to coat a matrix-type IVR segment, pharmacokinetics and tissue distribution was studied fabricated by injection molding from polyurethane. at 24 h following intravenous administration of HCQ was loaded in a reservoir-type IVR segment. A micellar formulations or free diclofenac (n=3). release study was performed for each segment. The Excised organs were fluorescent imaged. biocompatibility of the IVR was evaluated on Results: An average diameter of 37.2±0.06 nm was cervicovaginal epithelial cell lines and on vaginal observed for PBCL-TM which was significantly flora Lactobacilli. smaller than that for PCL-TM (45.1±0.06 nm). The Results: IVR segments coated with a pH-sensitive diclofenac concentration was comparable for both polymer rapidly released fluorescent NP at pH8.2 PBCL-TM and PCL-TM in blood and kidneys, (12.81.7%) at 4 hours’ time point but negligible significantly higher than free diclofenac in blood amount at pH4.2 (0.260.042%). The reservoir-type (2.3±1.4 and 1.9±0.6 μg/mL for micelles, IVR segment containing HCQ continuously released respectively, vs below detection), and significantly drug up to 21 days with a near zero-order release lower than free drug in the kidneys (0.4±0.3, profile (R2 value =0.99) with a mean daily release of 0.5±0.5, vs 1.5±0.3 μg/g). In heart, PBCL-TM 17.013.6g/mL. The IVR segments were not toxic showed significantly lower diclofenac levels to the vaginal cells or microflora. The relative gene compared to PCL-TM and free diclofenac (0.3±0.03 expression of CCR5 in cells treated with the siRNA- vs. 0.5±0.1, 0.8±0.1 μg/g). In liver and spleen, NP was significantly reduced with 58.6017.36 % of treatments showed comparable diclofenac gene reduction. concentrations. Both micellar formulations similarly Conclusion: We describe an IVR system capable of reduced diclofenac partition in the heart and kidneys controlled release of HCQ and also siRNA-NP at (heart:blood ratios of 0.4±0.1, 0.7±0.2, and 4.4±0.7 high pH and non-cytotoxic towards lactobacilli and and kidney:blood ratios of 0.8±0.06, 1.2±0.4, and vaginal/cervical epithelial cells. 5.5±2.1 for PBCL-TM, PCL-TM, and free diclofenac, respectively). Near-infrared fluorescence images showed micellar carrier tissue accumulations 27. Pharmacokinetics and Biodistribution of in-line with those achieved for diclofenac. Traceable Poly(ethylene oxide)-block- Conclusions: PBCL based micelles further poly(ester) Based Micellar Formulations of improved the biodistribution of diclofenac compared Diclofenac: The Effect of Poly(ester) to PCL based micelles evidenced by reduced drug Structure accumulation in the cardiac tissue. Both micelles show strong potential for a cardiac-safe delivery of Hanan Al Lawati, Mohammad R. Vakili, Afsaneh diclofenac. Lavasanifar, Fakhreddin Jamali. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada

Purpose: Nonsteroidal anti-inflammatory drugs are associated with elevated cardiovascular (CV) risk, depending on the extent of their accumulation in the heart and kidneys. We have developed poly(ethylene oxide)-block-poly(-caprolactone) (PEO-b-PCL) micelles encapsulating diclofenac ethyl ester (DFEE) which favourably altered the pharmacokinetics and disposition of diclofenac in rats. Herein, we investigated whether modifying the PCL structure to poly(α-benzyl-carboxylate--

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28. Development of Mycophenolate Mofetil Acknowledgements: Funding support was provided (MMF) Immunosuppressant as Sustained by the College of Pharmacy and Nutrition, Release Oral Nanoparticles University of Saskatchewan (MM, EW) and by the Division of Nephrology, College of Medicine, Munawar Mohammed1, Holly Mansell1, Ahmed University of Saskatchewan (AS). Shoker2, Kishor Wasan1 and Ellen Wasan1. 1College of Pharmacy and Nutrition, University of Saskatchewan; .2Division of Nephrology, College of 29. Fluorescence De-quenching and Albumin- Medicine, University of Saskatchewan, Saskatoon, induced Fluorescence Enhancement Assays SK, Canada to Measure Liposomal Drug Release of Camptothecins and Protein Kinase Purpose: To reduce dosing frequency and improve Inhibitors drug adherence, mycophenolate mofetil was 1 1 formulated as sustained-release mucoadhesive oral Roger Gilabert-Oriol , Lina Chernov , Brent 1 1 1,2 polymeric nanoparticles (CS-PNPs). Sutherland , Malathi Anantha , Alessia Pallaoro , 1 1,3 Methods: MMF nanoparticles (CS-PNPs) were Wieslawa H. Dragowska , Marcel B. Bally 1 prepared by a modified single-emulsion solvent British Columbia Cancer Agency, Vancouver; 2 3 evaporation method with low, medium and high Simon Fraser University, Burnaby; University of molecular weights of acid-capped polylactic-co- British Columbia and Centre for Drug Research and glycolic acid (PLGA) or polylactic acid (PLA), Development, Vancouver, Canada coated with chitosan. Surfactant type, surfactant concentration and polymer concentration were Introduction: The development of liposomal varied in a limited matrix study to optimize particle formulations with improved stability rely on size, encapsulation efficiency and in vitro drug empirical data collected in animals. In vitro assays release in simulated gastric fluid (2h) followed by have been used to predict release rates and stability simulated intestinal fluid (22h). Encapsulation of various liposomal formulations, but these often efficiency and release of MMF were measured by are not accurate; sometimes under-predicting how HPLC. Differential scanning calorimetry (DSC), fast liposomal drugs are released in vivo. In this scanning electron microscopy (SEM) and mucin report, two in vitro fluorescence-based methods are binding by zeta potential were also conducted. presented; assays that produce reliable drug release Results: Nanoparticles of PLA (MW 18K-24K) and curves and accelerate the design of optimized polyvinyl alcohol 0.5% as the surfactant, achieved liposomal formulations of suitable fluorescent drug encapsulation efficiency of 71-97% at drug-polymer candidates. The methods are illustrated using ratios (w/w) of 1:3 to 1:7. Particle size varied by camptothecins and a protein kinase inhibitor. composition. Two optimal formulations [PLA 18- Methods: Drug release from liposomal 24K MW, medium MW chitosan, drug: polymer camptothecins was measured with a fluorescence de- ratio 1:7 (w/w) and PLGA 24-38K MW, high MW quenching assay. Camptothecin derivatives chitosan, drug: polymer ratio 1:7 (w/w)] had high (topotecan and irinotecan) are quenched when encapsulation efficiency (94.34% and 75.44% encapsulated at high concentrations (>10mM) inside respectively) and sustained drug release with a liposomes but fluoresce when released and are at minimal burst phase (Fig 1). DSC experiments low concentrations (<10 M). The method to study reveal crystalline to amorphous transformation of drug release from the liposomal protein kinase MMF in the optimal formulation. Surface inhibitor OTS964 relied on albumin-induced morphology of CS-PNPs shows spherical fluorescence enhancement. OTS964 fluorescence is nanoparticles with minimal porosity. Mucin binding low inside the liposomes and the liposomes are not was demonstrated by change in zeta potential. permeable to albumin added to the outside of Conclusion: Two CS-PNP formulations of MMF liposomes. Once OTS964 is released from liposomes containing PLA: medium molecular weight chitosan it binds to albumin and fluorescence augments. (1:7 w/w) and high MW PLGA: high MW chitosan Changes in fluorescence were measured by the (1:7 w/w) prepared by a solvent evaporation method fluorescence microscope IN Cell Analyzer 2200. is a potential approach towards achieving once, Results: Drug release of liposomal topotecan by the rather than twice daily oral sustained delivery of fluorescence de-quenching assay was approximately MMF. 60% at 4h and 80% at 8h; the same that was

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observed in vivo. In addition, stability studies with Results: Spray drying process at the lab scale was this method demonstrated higher release rates with successfully perfumed and critical process higher serum protein concentration and temperature. parameters optimized. The process was also Drug release of liposomal OTS964 by the albumin- successfully scaled-up at the pilot scale. Scanning induced fluorescence enhancement assay was 84% at Electron Microscopy imaging of the spray dried 4h after treatment with 5mg/mL octyl- powder showed spherical microcapsules with size glucopyranoside and 25% at 4h after administration ranging from 1 to 10 µm. The sphericity of of 0.4mg/mL saponin. The formulation was very microcapsules was better with increasing Xanthan stable with less than 10% release after 4 days in gum concentration. In-Vitro release kinetic at buffer only supplemented with albumin. pH=6.8 showed a slower release rate compared to Conclusion: The present assays will help physical mixture of polymers. developing formulations in a more efficient way and Conclusion: Starch based microcapsules were without raising ethical concerns associated to animal formulated and successfully manufactured using experiments. These methodologies also allow the spray drying at both lab and pilot scale. These quantification of drug inside and outside liposomes microcapsules represent a promising device for the and may be adapted to provide the necessary controlled drug delivery of drugs as well as for taste information to regulatory bodies in the process of masking. liposomal drug development.

31. Determination of the Effect of Patient 30. Pilot Scale-up and Evaluation of Starch- Posture and Fasting State on Digital Pulse based Spray Dried Microcapsules as Wave Features using a Novel Computational Controlled Drug Delivery and Taste Technique, Non Invasive Vascular Risk Masking Device Prediction System (NIVAR), and Potential Application for Assessment of Raynaud Christopher Gaudnik Larin, Nathaniel Wong, Phenomenon Miloud Rahmouni, Mohamed Nabil Khalid Biopharmaceutical Production Technology Edmond Zahedi1, Jochen Boehm1, David Holloway2, Department, John Abbott College, Sainte-Anne-de- Connie Evans3, Simin S.C. Jolfaee1, Tatiana Bellevue, Quebec, Canada Orlowski4, and Ellen Wasan4 1Dept. of Biomedical Engineering Technology, Purpose: To formulate, manufacture and evaluate British Columbia Institute of Technology, Burnaby, starch-based spray dried microcapsules at both lab BC; 2Dept. of Mathematics, British Columbia and pilot scale. The encapsulation of Acetaminophen Institute of Technology, Burnaby, BC; 3School of and Caffeine was developed to aid in the controlled Health Sciences, British Columbia Institute of release, enhance chemical stability and mask the Technology, Burnaby, BC; 4College of Pharmacy bitter taste. and Nutrition, University of Saskatchewan, Method: Starch 7.5% (w/w) was first dispersed in a Saskatoon, SK, Canada. phosphate buffer pH 6.8 using a low shear mixer. A second solution was prepared by dissolving Xanthan Purpose: A clinical trial was conducted to evaluate gum 1% (w/w) or a mixture of Kollidon VA64 and the effect of supine/upright and fed/fasted patient Cekol 150 into deionised water. Solutions were status on an index reflecting the state of the vigorously stirred using a low shear mixer. microcirculation at the tip of the finger, in the Acetaminophen and Caffeine were added to each context of validating a novel computational analysis solution with different drug loading (20 and 30% of the pulse oximetry waveform. A separate w/w). Finally, the two solutions were mixed and experiment was conducted to determine the ready for spray drying. Solutions were spray dried influence of cold challenge to the hands on pulse using a lab scale spray dryer, 1.25 L batch size. The waveform analysis by NIVAR in normal vs Raynaud process was then scaled-up at the pilot scale with Phenomenon patients. 22.5 L batch size. The resulting microcapsules at Methods: Non Invasive Vascular Risk Prediction both scales were collected and characterised using System (NIVAR) consists of an optical probe SEM and the In-Vitro release kinetic was then connected to a personal computer through a small- evaluated. size, custom-made front-end biosignal amplifier.

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Healthy subjects (9 male, 18 female, age 23-56) (APIs). Our proof-of-concept system is a pre-natal were recruited for a clinical trial approved by supplement containing eleven (11) APIs of varying BCIT’s Research Ethics Board. Groups: overnight hydro- and lipophilicity. fasting/supine, overnight fasting/seated, 1 h after Methods: Ternary Phase Diagram (TPD) mapping food/ supine, 1 h after food/seated. NIVAR analysis was conducted at room temperature and measurement was carried out twice/session for 3 37°C for a list of five finalized surfactants in monthly sessions. Statistical significance was Miglyol 812 to evaluate type IV ME formation determined by ANOVA (p<0.10, R statistical potential. Tensiometry studies using a Lauda T3 Du software, Bell Labs). Nouy Ring Tensiometer established critical micelle A demonstration cold challenge was performed on concentration and surfactant synergism. Promising two volunteers, including one with Raynaud surfactant candidates were mixed with Miglyol 812 Phenomenon, with NIVAR measurements before and water to form microemulsions into which all and after cold exposure. eleven (11) APIs (five lipophilic and six Results: The measured index was affected both by hydrophilic), were incorporated. Droplet size and fasting state and by posture. The most significant zeta potential measurements were then performed difference was the combination of fasting state and with a Malvern Zetasizer Nano ZS. posture changes: “Seated-Before Breakfast” and Results: TPD mapping identified a unique “Supine -After Breakfast” (males p< 1×10-5, females surfactant combination of 1:3 Cremophor RH 40: p< 0.3×10-5). NIVAR showed a greater change in the Polysorbate 80 as most promising for ME type IV volunteer with Raynaud Phenomenon compared to formation, with clear synergism demonstrated via the normal volunteer following cold challenge. tensiometry. Droplet sizes were approximately 50 Conclusions: NIVAR has potential to evaluate nm after incorporation of all five lipophilic APIs and digital blood flow in the clinical setting, which may 88 nm after additional incorporation of the be applicable to diagnosis and efficacy testing of remaining six hydrophilic APIs. Zeta potential topical treatments for Raynaud Phenomenon, a values were -15 mV and samples demonstrated 70- vasospastic condition of the extremities. Posture and 80% stability after rigorous centrifugation stress feeding state are important factors to control in such testing. assessments. Conclusion: To our knowledge, this is the first time Acknowledgments: This work was supported by a that microemulsion systems have been used in this grant from the VP Research Seed Fund, British capacity to simultaneously solubilize eleven (11) Columbia Institute of Technology, Burnaby, BC, APIs of varying hydrophilicity. This work serves as Canada. a pioneer in the development of a single dose multi- API, microemulsion delivery system for complex, chronic multi-drug therapies. 32. Microemulsions: A Cure for All Ills? References: 1. Public Health Agency of Canada (PHAC). 1 1,2 Shannon P. Callender and Shawn D. Wettig . Economic Burden of Illness in Canada, 2005–2008: 1 School of Pharmacy, Faculty of Science, University Protecting Canadians from Illness 2014, 1-93. 2 of Waterloo, Waterloo, Ontario, Canada; Waterloo 2. Callender, S., Mathews, J., Kobernyk, K., Wettig, Institute for Nanotechnology, University of S. Int J Pharm 2017, 1, 425-442. DOI: Waterloo, Waterloo, Ontario, Canada. 10.1016/j.ijpharm.2017.05.005

Purpose: There is a growing need for multi-drug therapies given the burden of concurrent disease in 33. Development of Novel Polymeric Micellar Canada.1 Current multi-drug delivery options are DACHPt for Enhanced Platinum Based limited and inefficient. Microemulsions (MEs), with Chemotherapy in Colorectal Cancer their nano-size droplets, thermodynamic stability and spontaneous formation, are an effective multi- Abdulsalam Alharbi, Mohammed Vakili and drug delivery tool; however, their formation Afsaneh Lavasanifar. behaviour especially with respect to emulsifying Faculty of Pharmacy and Pharmaceutical Science, agents is not well understood.2 This work explores University of Alberta, Edmonton, Alberta, Canada the capability of various emulsifying agents to solubilize multiple active pharmaceutical ingredients Purpose: The parent compound of oxaliplatin,

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dichloro(1,2-diaminocyclohexane)platinum(II) profiles for drug delivery to the posterior chamber of (DACHPt) is a potent chemotherapeutic agent with the eye can reduce the frequency of intravitreal wide spectrum of anticancer activity, and no cross- injections necessary to treat diseases like wet-age resistance with cisplatin Incorporation of DACHPt related macular degeneration (AMD). We are in polymeric micelles may lead to changes in developing smart, bio-responsive injectable physiochemical properties as well as the microspheres and hypothesize that these pharmacokinetics profile of the drug, leading to a polyelectrolyte-layered microspheres with shells of reduction in its unfavorable side effects; improved hyaluronic acid (HA) or alginate, modified with tumor accessibility and in vivo activity. complementary DNA oligomers containing aptamer Method: Poly(ethylene oxide)-b-poly-(α- sequences, will release encapsulated FITC-dextran carboxylate-€-caprolactone) (PEO-b-PCCL) diblock in the presence of specific proteins. copolymer was synthesized. Then, DACHPt was Methods: Hyaluronic acid (HA) and alginate are reacted with the polymer to form polymer-metal modified with DNA oligomers containing aptamer complex. The complex was dialyzed in water to sequences specific to lysozyme, used as the protein prepare DACHPt loaded micelles. The average size of interest for this proof-of-concept work. HA is first of the micelles, complexed levels of DACHPt and functionalized with maleimide using 2- platinum in vitro release from micelles was aminoethylmaleimide trifluoroacetate salt (AEM) measured. ICP-MS was used to measure and then modified with thiol-terminated oligomers encapsulated and released Pt levels. MTTs assay was by a Michael-type addition reaction. Alginate is used to measure the cytotoxicity of DACHpt and modified by reacting its carboxyl groups with DACHpt micelles against human colorectal cancer amine-terminated oligomers by a carbodiimide cell lines, HCT-116, SW-620 and HT29 for 24, 48 reaction. Electrosprayed calcium alginate and 72 hours. The results were correlated to microspheres (diameter < 250m) are then coated intracellular Pt levels. with poly-L-lysine and DNA-modified HA or Results: High drug loading was achieved reaching alginate. Swelling studies of the HA or alginate 50 % w/w (n=3) with a mean diameter size of 56 nm hydrogels are indicative of their modification. FITC- for DACHPt complexed micelles. The release dextran is loaded during synthesis then released into profile of DACHPt from its micellar complex was PBS. sustained (only 53.6% of DACHPt was released by Results: HA was reacted to have 10-13% 120 h) compared to the free drug (96.5 % release at modification of the carboxyl groups with AEM. 7.5 h). The IC50s for both DACHPt-micelles and the Lyophilized HA-AEM was then reacted with PEG- free DACHPt decreased as the incubation time dithiol to produce control gels. Swelling studies in increased. However, the IC50 ranges were higher in water showed that the water content was high at DACHPt-micelles than the free DACHPt in all the 96%  0.4%. Studies with calcium alginate three cell lines for all the incubation times. The polyelectrolyte-layered microspheres modified with cytotoxic drug levels were shown to be correlated aptamer-containing DNA oligomers have resulted in with intracellular Pt levels. a burst release of FITC-dextran when incubated in Conclusion: Prepared micellar formulation of lysozyme (in comparison to no changes with DACHPt has a high potential for targeted Pt controls). delivery. Acknowledgement: AA was funded by Conclusion: HA-AEM was successfully modified Umm Al-Qura University, Mecca, Saudi Arabia. with PEG-dithiol in a Michael-type addition reaction This research was supported by grants from NSERC. and will be further adjusted to develop DNA- modified microspheres for sustained delivery applications. Protein-triggered drug release was 34. Protein-triggered Sustained Release of observed from calcium alginate microspheres FITC-dextran from Microspheres Modified modified with DNA oligomers containing aptamers with Aptamer-containing DNA Oligomers in the presence of lysozyme.

Emily Baldwin, D’Arcy Turner and Laura Wells. Department of Chemical Engineering, Queen’s University, Kingston, Ontario, Canada.

Purpose: Improving upon sustained drug release

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35. Effect of Synthesis Conditions on the on the physiochemical properties, colloidal stability Properties of Bone-Targeting and magnetic behavior of 30 nm bisphosphonate- Bisphosphonate- Conjugated conjugated superparamagnetic iron oxide Superparamagnetic Iron Oxide nanoparticles. Nanoparticles (BP-SPIONs)

Waheed Asghar, Raimar Loebenberg, Carlos A. 36. Striking a Balance: Interactions of Pluronics Velázquez-Martínez, Michael R. Doschak and Gemini Surfactants for Gene Therapy Faculty of Pharmacy & Pharmaceutical Sciences, Nanoparticles University of Alberta, Edmonton AB Samantha Shortall and Shawn Wettig. Purpose: Superparamagnetic iron oxide School of Pharmacy, University of Waterloo, nanoparticles (SPIONs) are used in a variety of Waterloo, Ontario, Canada biomedical applications including diagnostic and medical imaging. Over the years, attempts were been Purpose: Recently, the non-ionic polyoxyethylene- made to improve the selectivity of SPIONs by polyoxypropylene-polyoxyethylene triblock conjugating targeting ligands onto their surfaces. In copolymer, Pluronic® F87 (BASF Corp.) was a similar attempt, we conjugated SPIONs with bone combined with cationic N,N'- seeking bisphosphonate drugs (BPs) e.g., bis(dimethylhexadecyl)-1,3-propanediammonium alendronate, to target them to sites of bone mineral dibromide gemini surfactant (16-3-16) to form self- turnover. However, due to the presence of large and assembled nanoparticles for gene therapy. Human highly polar BP molecule, the chemical and colloidal ovarian adenocarcinoma (OVCAR-3) cells were stability of the formulation required attention. The successfully transfected in vitro (albeit poorly) with aim of this study was to investigate the effect of less cellular toxicity than the commercial control, synthesis conditions and to test different choices of Lipofectamine® 2000. The transfection efficiency of organic acids to be used as linker to conjugate bone- this system might be improved by appropriate seeking bisphosphonate (i.e., alendronate) with changes to the formulation (e.g. polymer SPIONs. composition, or relative amounts of nanoparticle Method: SPIONs were made using a published components). The aim of this study was to method and their surfaces were modified using investigate the effect of Pluronic molecular weight different organic acids (e.g., citric acid, sodium and hydrophobicity on the interaction between the citrate, poly-lactic-glycolic-acid and oleic acid). N- Pluronic and gemini surfactant-plasmid DNA hydroxysuccinimide (NHS) in combination with 1- condensate (GS/pDNA) of the nanoparticles, and to Ethyl-3-(3-dimethylaminopropyl) carbodiimide determine the impact these interactions have on (EDC) was employed to make the amino groups in transfection efficiency. alendronate molecules react with the carboxylic Method: Pluronics differing from F87 by molecular groups in the acids molecules, coated onto SPION weight or hydrophilic/hydrophobic composition surfaces. The resulting BP-SPIONs were were combined with the GS/pDNA condensate. characterized by Fourier transform infrared Critical aggregation concentrations of spectroscopy, dynamic light scattering, transmission Pluronic/GS/pDNA mixtures (with varying Pluronic electron microscopy and magnetic resonance mole fraction), were determined by tensiometry, and imaging (MRI). The effect of various reaction used to estimate the mixing behaviour of each temperatures, molar ratios, pH values and dispersion system (e.g. synergism vs. antagonism, and the medium were studied for optimization purposes. strength of interaction). Dynamic light scattering and Results: We observed that choice of organic acid laser Doppler electrophoresis, provided size and can significantly impact the nanoparticle’s core size charge measurements, respectively, of the complete (describe); the hydrodynamic size and the amount of nanoparticles. In vitro transfection efficiency and acid adsorption by SPION surfaces is described by cell viability was quantified using flow cytometry. the coating temperature and the length of the Results: The previously tested F87/GS/pDNA aliphatic chain in these acids. Overall, the coating of systems have strong synergistic interactions SPIONs improved their stability. (interaction parameter, β = -18 to -27). The strength Conclusion: The effect of different coating of this attraction can be increased by decreasing the materials and synthesis conditions was investigated molecular weight or decreasing the hydrophobicity

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of the Pluronic component of these nanoparticles. In peptides. Ten compounds have been synthesized. vitro transfection efficiencies decreased with Conclusion: Ten compounds have been synthesized stronger synergistic interactions; however, a with modifications to the parent peptide. Future reduction in the system’s synergism or even slight plans involve screening of these compounds for their antagonism (by replacing F87 with L121) did not brain penetration. The results may inform rational increase transfection. design of prodrug chemistry to improve brain Conclusion: These results suggest synergism is delivery of small peptides. required for successful transfection with Acknowledgement: Anne Nguyen is the recipient Pluronic/16-3-16/pDNA systems. However, too of a 2018 GSK/CSPS National Undergraduate much synergism within the formulation may prevent Student Research Program Award. nanoparticle dissociation required for successful gene transcription. 38. Application of Design of Experiments for Optimizing Critical Quality Attributes of 37. Modulating Physiochemical Properties of a Scored Controlled Released Tablet Small Peptide Drug by Chemical Conjugation Miloud Rahmouni and Mohamed Nabil Khalid Biopharmaceutical Production Technology Anne Nguyen, KKR Viswanadham, Shyh-Dar Li. Department, John Abbott College, Sainte-Anne-de- Faculty of Pharmaceutical Sciences, University of Bellevue, Quebec, Canada British Columbia, Vancouver, BC, Canada Purpose: The purpose of this work is to use the Purpose: According to the National Institutes of design of experiments (DEO) to study the influence Health, one of three individuals suffer from a central of critical factors and their interactions on the nervous system (CNS) disorder each year, breaking accuracy, assay, dissolution, content constituting more than 20% of total health care uniformity, and other quality attributes of the scored spending in the United States. The brain is the center controlled released (CR) tablets. for a wide spectrum of psychiatric, neurologic, and Method: Scored CR tablets containing Caffeine as a or neurodegenerative disorders yet there are no model drug and Hydroxypropylmethyl-cellulose effective treatments for the majority of brain (HPMC) were prepared by direct compression using disorders. Neuropeptides present themselves as an instrumented tablet press (RoTab T, Luxner, attractive drug candidates due to their enhanced Germany). A three-factor, two-level, full factorial potency and low toxicity of their metabolites. design was used to investigate the effect of hardness, However, neuropeptides are not widely used to treat scoring line (one side vs two sides) and deepness of neurological diseases due to their limitation in the scoring line, on quality attributes of the scored targeted delivery to the brain. Two main factors CR tablets. Tablet hardness was measured using a prevent sufficient delivery of intact and viable hardness tester machine (Vector, USA), while peptides: low bioavailability and the presence of the friability was measured using a friabilator apparatus blood brain barrier (BBB). It is hypothesized that (Sotax, USA). Assay and content uniformity were chemical modifications of side chains of a small determined on 10 tablets using a UV-spectroscopy peptide will change its physiochemical properties to technique. Dissolution test was evaluated using a improve its membrane permeability and ultimately USP dissolution apparatus type II at 50 rpm in brain penetration. The goal of this project was to phosphate buffer pH 6.8. create a panel of compounds that represent various Results: Splitting of CR tablet generates higher chemical modifications of a small peptide in the weight variability as compared to the whole CR hope of improving the brain penetration. tablets. Tablets with 2 deep scoring lines are easy to Methods: Peptides were synthesized from C- break and show a good breaking accuracy compared terminus to N-terminus through acid-amide to one scoring line tablets. Assay and dissolution coupling. Modifications were made at the N- profile of splits tablets (2 deep scoring lines) were terminus by adding hydrophobic end groups. not significantly different compared to the whole Structure analysis was performed by H1-NMR. tablets, at high compression force (high hardness). Results: A robust platform was created for the Conclusion: Formulation composition, process introduction of chemical modifications to small manufacturing and other physical characteristics

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have greater influence on the accuracy and quality Pharmaceutical & Analytical attribute of scored CR tablets. Chemistry

39. Bisphosphonate Drug Alveolar Bone Burden in Osteoporosis 40. Lipid based Liposomal Formulation of Amel Hamza, David Wishart, Michael Doschak Phytosterols and Tocopherols into Faculty of Pharmacy and Pharmaceutical Sciences, Functional Food University of Alberta, Edmonton Asmita Poudel1, George Gachumi1, Zafer Dallal Purpose: Osteonecrosis of the jaw (ONJ), a severe Bashi2, Ildiko Badea1 and Anas El-Aneed1 bone disorder that leads to bone death is caused 1College of Pharmacy and Nutrition, University of mainly by nitrogen-containing bisphosphonate Saskatchewan, Saskatoon, 2Ministry of Agriculture, drugs. Recent observations suggest that the nature of Government of Saskatchewan ONJ is not an area of avascular necrosis, nor an osteomyelitis, but an inability of the alveolar bone to Purpose: Phytosterols and tocopherols, extracted respond to injury. Our study hypothesis was that the from canola oil waste stream can be a component of identification of new metabolites involved with the functional foods. They have cholesterol lowering pathogenesis of ONJ may serve as a diagnostic abilities and antioxidant properties. However, their mechanism for measuring the extent of ONJ present lipophilic nature as well as heat and light sensitivity in the bones of patients following long-term makes it challenging to incorporate them into bisphosphonate therapy. We used a metabolomics functional food. The aim of this study is to develop profiling approach, to observe metabolic changes in bifunctional liposomes of phytosterols and plasma and urine in an established rat model of tocopherols and integrate them into functional food. osteoporosis. The commercially available Biocrates Method: Liposomes containing phytosterols and kit was used as a tool in order to provide new tocopherols were creating using three different information on the alteration in metabolite level and approaches: homogenization, ultrasonication and to determine the potential therapeutic insight offered heating methods. Liquid chromatography- tandem by metabolomics profiling following bisphosphonate mass spectrometry (LC-MS/MS) quantitative drug intervention. method was developed and validated to determine Methods: The study subjects were divided into four the incorporation efficiency of phytosterols and experimental groups: control rats dosed with vehicle, tocopherols into liposomes. rats dosed with 0.12mg/kg Alendronate twice Results: The particle size was significantly larger Weekly, third group dosed with active vitamin D when employing the heating method (258nm) (100ng/kg) and a combination group receiving both compared to homogenization (192nm) and Alendronate and vitamin D. Plasma and urine from ultrasonication (195nm) method. Whereas zeta the four groups of rats were collected at baseline, 4 potential were comparable among the three week and 8 week study endpoint and subjected to formulations (-15mn to -18mv). Linearity (R2= metabolomic analysis and in vivo Micro CT scan 0.998) and adequate sensitivity (0.005µg/ml) was measurement of bone volume. achieved by quantitation method. In addition, the Results: Preliminary results by micro-CT confirmed method was validated as per the FDA guideline, an osteopenic phenotype developing in the ensuring robustness of analytical platform. trabecular bone of all OVX rats. A distinct Incorporation efficiency of the phytosterols and metabolite “fingerprint” was measured following tocopherols was around 95% with homogenization drug treatment between control and treated groups, method. with key metabolites detected in Alendronate-dosed Conclusion: All three-formulation strategies groups compared to the other groups. showed size and zeta potential suitable for colloidal Conclusions: These findings suggest that the use of stability and oral drug delivery. Robust analytical a metabolomic approach would be of value to method was developed and validated and applied to dentists attempting to alleviate symptoms associated measure incorporation efficiency. The optimized with osteonecrosis of the jaw induced by liposomes will be incorporated into orange juice. bisphosphonate drug therapy. Formulation stability in pasteurized orange juice will

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be evaluated for 60 days. 42. FOXM1 Inhibitors: A Structural Activity Relationship Study

41. The Quantitative Analysis of Titanium Seyed Amirhossein Tabatabaei Dakhili1, David Dioxide in Commonly used Sunscreen Perez Gomez1, Keshav Gopal, John R. Ussher, Cosmetics by Ultraviolet-visible Carlos A. Velázquez-Martínez1 Spectroscopy 1Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada. Masood Bhatti, Nalliah Theivendra, Mohsen Farazmand. Purpose: The FOrkhead boX M1 (FOXM1) is a Alpha Healthcare, Toronto, Ontario, Canada transcription factor essential for normal activation of the cell cycle and replication. However, increasing Purpose: Frequent exposure to UV radiation has evidence links its overexpression with cancer pronounced harmful effects on human health. To development, poor prognosis and drug resistance prevent skin damage from the sun’s radiation, many which makes it an interesting drug target. Based on a skin care products, such as moisturizing creams, previously performed molecular modeling and body sprays, lipsticks, makeup foundations, and face molecular dynamics simulations, we hypothesised lotions contain titanium dioxide as sunscreen to that the current FOXM1 inhibitor (FDI-6) binds to block UV radiation. The Industrial Pharmaceutical the FOXM1 DNA binding domain mainly by Laboratories Division at the Toronto facility of forming a pi-sulfur interaction and a Halogen Alpha Healthcare has developed and validated a bonding with its 4-fluorophenyl to the ARG287 of simple and sensitive method for the determination of the FOXM1 DNA binding domain. Titanium Dioxide in human Sunscreen Lotion by Method: To test this hypothesis, we employed FDI- Ultraviolet Visible spectrophotometer (UV/VIS). 6 as a scaffold, to synthesize different derivatives by Methods: 2.0 g of sample was weighed on an Ash- removing or replacing different groups at 4-fluoro less filter paper (70 mm) and placed in an 800 mL phenyl position. We used the MTT method to Kjeldahl flask. To this, 6 g of Ammonium Sulphate compare the cytotoxicity level of the synthesized and 30 mL of Sulphuric Acid was added. The compounds with the FDI-6 (7c) in two FOXM1 mixture was heated gently on an electric heater until expressing cell lines (MDA-MB-231 and MCF-7). the sample was completely carbonized. The mixture Next, we determined the level of nuclear FOXM1 was then heated at a higher temperature (400C) until expression on triple negative breast cancer cell line the sample was yellowish or brown in color. The (MDA-MB-231) followed by making the sample was let cool, added 200 mL of water, recombinant FOXM1-DBD to perform quantitatively transferred the contents into a 500 mL ElectroMobility Shift Assay (EMSA). volumetric flask and diluted to volume with water. Results: The experimental results provide evidence The solution was filtered through Whatman #4 filter supporting the hypothesis describing an essential paper. Three calibration standards and one blank halogen-Arg297 binding interaction exerted by the sample were also prepared simultaneously using the FOXM1 inhibitor. The biological evaluation of drug same method. The absorbance of sample, standards molecules, especially the measurement of nuclear and blank was measured at Wavelength 410 nm FOXM1 levels in MDA-MB-231 triple negative using 1 cm cuvette cell by Perkin Elmer LAMBDA breast cancer cells line and EMSA, are in 25, UV / VIS spectrophotometer. accordance with theoretical (calculated) binding free Results: The method produces acceptable linearity energy calculations, showing the importance of this 2 (r = more than 0.999) precision (CV= less than 2%) halogen-Arg297 interaction in the overall and accuracy (recovery= 100+2.0%) to a minimum compounds suppressing ability. concentration of 30 microgram per mg in human Conclusion: We hope that the results presented in sunscreen lotion. this investigation provide essential insights to Conclusion: The method is very simple, rugged, and elucidate the mechanism of action exerted by convenient. It can be used to analyze titanium FOXM1 inhibitors at this protein’s DNA binding dioxide in human sunscreen lotion with no domain. Finally, we also propose that these observable matrix interferences. structural requirements may be used to design (future) more potent and selective FOXM1 inhibitors in Medicinal Chemistry.

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Pharmacokinetics & hypoxanthine concentrations were significantly higher in the DOX treated group (p < 0.05). Pharmacodynamics Conclusion: Acute cardiovascular toxicity induced by DOX and ISO may be measured by changes in hemodynamics and breakdown of ATP and adenosine in the circulation albeit a notable 43. Assessing Cardiovascular Toxicity of qualitative and quantitative difference was observed Doxorubicin and Isoproterenol by (supported in part by funding from Dalhousie Hemodynamics and in vivo Catabolism of Faculty of Health and Pharmacy Endowment Adenosine 5-‘triphosphate Foundation).

Pollen K. Yeunga, Sheyda Mohammadizadeha, Fatemeh Akhoundia and Thomas Pulinilkunnilb 44. Effects of Tacrolimus on Mycophenolic Acid aPharmacokinetics and Metabolism Laboratory, Exposure in de novo, Steroid-Free Adult College of Pharmacy and Department of Medicine, Kidney Transplant Patients Faculties of Health Professions and Medicine, Dalhousie University, Halifax, NS, Canada B3H Yan Rong1 and Tony K.L. Kiang1 4R2 Faculty of Pharmacy and Pharmaceutical Sciences, bFaculty of Medicine (NB Campus), Department of University of Alberta, Edmonton, Alberta, Canada Biochemistry and Molecular Biology, Dalhousie University, Saint John, NB, Canada Purpose: Mycophenolic acid (MPA) is commonly dosed empirically in combination with tacrolimus Purpose: Previous studies have shown catabolism (FK), with or without corticosteroids, for the of adenosine 5’-triphosphate (ATP) in systemic prevention of graft rejection in transplant recipients. blood is a potential surrogate biomarker for FK has been known to decrease the intrinsic cardiovascular toxicity. We compare the acute clearance of MPA in various in vitro models, but toxicity of high dose of doxorubicin (DOX) and conflicting clinical drug-drug interaction data have isoproterenol (ISO) on hemodynamics and ATP been reported. Because the majority of MPA catabolism in circulation. pharmacokinetic and drug interaction studies have Method: Sprague Dawley (SD) rats were each given been conducted in subjects on steroid-based either a single dose of 30 mg/kg ISO, or twice daily pharmacotherapy, we hypothesized that FK can dose of 10 mg/kg of DOX or normal saline (control) affect the exposure of MPA in adult kidney for 4 doses by subcutaneous injection. Blood transplant patients on steroid-free regimens. samples were collected up to 6 hours for measuring Methods: Open label, prospective, observational concentrations of ATP and its catabolites. cohort study involving patients (N=49) on steroid- Hemodynmics was recorded continuously. free MPA/FK. The following clinical variables were Difference was considered significant at p < 0.05 collected: sex, age, weight, height, body surface area (ANOVA). (BSA), serum creatinine (SrCr), albumin, and Results: Mortality was 1/8, 5/11 and 0/11 for the FK/MPA concentrations. MPA and FK exposures DOX, ISO and control groups, respectively. Systolic (area under the concentration-time curve, AUC) blood pressure was significantly lower in the DOX were calculated using the trapezoidal rule or limited and ISO treated rats than in the control measured at sampling strategies, depending on data sampling the last recorded time (76  9 for DOX vs 42  8 for intensity. ISO vs 103  5 mmHg, p < 0.05 for all). Blood Results: Parameter values were: sex (N=27 pressure fell gradually after the final injection for females), age (50±13 years, mean±SD), weight both DOX and control groups, but abruptly after ISO (71.8±18.2 kg), height (166.9±9.7 cm), BSA followed by a rebound and then gradual decline till (1.82±0.26 m2), SrCr (1.2±0.3 mg/dL), albumin the end of the experiment. Heart rate was (4.0±0.5 g/dL), FK trough concentration/dose significantly higher after ISO, but no difference (1.46±0.72 μg/L/mg), FK exposure/dose (25.0±14.4 between the DOX and control rats (p > 0.05). RBC μg·h/L/mg), MPA dose (1.62±0.50 g/day) and MPA concentrations of ADP and AMP, and plasma exposure/dose (25.3±11.0 mg·h/L/g). Using log- concentrations of adenosine and uric acid were transformed data, initial simple linear regression significantly higher in the ISO group. In contrast, analyses indicated that MPA exposure was only

108s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

associated with “weight”, “BSA”, and “MPA daily obtained with other PK parameters. dose”. Stepwise multiple regression models, using Conclusion: The correlation between PopPK model various combinations of clinically relevant variables, and NCA outcomes using rich or sparse data was identified “BSA” and “MPA daily dose”, but not similar. Therefore, PopPK models are well suited for “FK AUC”, as predictors of MPA exposure. individual PK estimation with few observations and Moreover, when patients were sub-categorized based limited sampling analysis is a useful diagnostic tool on FK AUC or post-transplant time (where < 1 year that assesses the efficiency of limited sampling was associated with higher FK AUC), no significant strategies. differences in MPA exposure were observed. [1] Zhang Y, Roberts J, Tortorici M, Veldman A, St Conclusion: Our novel findings indicate that a Ledger K, Feussner A, Sidhu J. Population clinically significant drug-drug interaction between pharmacokinetics of recombinant coagulation factor FK and MPA was not clearly evident in this patient VIII-SingleChain in patients with severe hemophilia population. Further analyses using non-linear mixed- A. J Thromb Haemost 2017; 15: 1106–14 effects modeling are ongoing.

46. Impact of Inflammation on the Expression of 45. Comparison of Population PK and Non- Renal Drug Transporters in Pregnancy compartmental Analyses for Tailoring PK in Hemophilia A with Limited Sampling Navaz Karimian Pour, Micheline Piquette Miller Leslie Dan Faculty of Pharmacy, University of Pierre Chelle1, Alanna McEneny-King1, Yejin Yun1, Toronto, Toronto, Ontario, Canada Alphonso Iorio2, Andrea N. Edginton1 1School of Pharmacy, University of Waterloo, Purpose: To examine the impact of viral-induced Waterloo, Ontario; 2McMaster University, Hamilton, inflammation on key drug transporters in the kidney. Ontario Pregnant women are frequently exposed to viral infections including cytomegalovirus, herpes Purpose: Hemophilia A is a bleeding disorder simplex, HIV, and hepatitis. These patients are on characterized by the deficiency of coagulation factor antiretroviral medications, many of which are VIII. Standard treatment to prevent bleeds aims at excreted renally. It is well known that infection and infusing the patient with the missing factor to target inflammation impose changes in the expression and a trough FVIII level above 1%. Individual activity of drug transporters in several tissues which pharmacokinetic (PK) estimation is essential to tailor can lead to altered drug disposition. However, there treatment and usually performed by blood sampling is scarcity of knowledge about the effect of and non-compartmental analysis (NCA). NCA inflammatory stimuli on renal drug transporters. requires many blood samples whereas population Methods: Pregnant Sprague-Dawley rats received pharmacokinetic (popPK) modelling requires fewer single intraperitoneal doses of viral mimetic samples and might be better suited to this task. The polyinosinic/polycytidylic acid [poly(I:C)] (5.0 objective was to assess if a popPK model provides mg/kg) or saline at gestation day 18 (n = 8/group). equivalent PK estimates to NCA with limited Kidneys were collected 24 h later. mRNA and samples. protein expression of transporters were measured Methods: A virtual dataset was created with 1000 using quantitative RT PCR and Western blot. subjects having observations at predose, Results: As compared to saline controls, Mrp2, 1,3,6,12,24,48 and 72h post infusion (rich data) Bcrp, Octn1, Oat1, Oat2, Oat3, Urat and Oatp4c1 based on a popPK model [1]. PK parameters were mRNA levels were downregulated by 38-52% (p < estimated and compared between NCA and Bayesian 0.05) and the transcript level of Ent1 was increased forecasting from the popPK model. Data subsets by 75%. While protein expression of Bcrp, Urat1 having only 3 observations (sparse data) were also and Pept2 were significantly reduced, decreases in compared. Mrp2, Oat2 and Oat3 protein expression did not Results: Comparison between the methods using on reach significance. Transcript levels of Mdr1a, rich data led to a 7% median error and R2 of 0.68 for Mdr1b, Mrp4, Oct1, Oct2, Oct3, Octn2, Mate1, Ent2 half-life. Using sparse data at predose, 48 and 72h or and Pept1 were unchanged. predose, 1 and 48h led to a median error lower than Conclusion: Viral-induced inflammation mediates 10% and R2 higher than 0.62. Similar results were significant changes in the expression of several key

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drug transporters in the kidney of pregnant rats. phosphate buffer). A range of propofol Many clinically important endogenous and concentrations (5 - 1000 M) was used. After 10 exogenous compounds are substrates of these min, the reaction was stopped by the addition of transporters, therefore, inflammation-mediated acetonitrile and the tubes were centrifuged to alterations in transporter expression could affect remove protein. HPLC was used to assay propofol their maternal disposition and fetal exposure. remaining in the solution. Results: Each of the groups fitted well to the simple Michaelis-Menten relationship except for the HFCS 47. The Impact of Diet Induced Obesity on the group, which had a very different profile that fit best Microsomal Glucuronidation of Propofol in to a one enzyme system with a shape factor. For the Rats other groups, the HF treated rats had the lowest measures of Vmax and CLint (the ratio of Vmax to Hamdah M. Al Nebaihi, Dion R. Brocks km). We also compared the velocity of formation of Faculty of Pharmacy and Pharmaceutical Sciences, glucuronidated propofol at the highest concentration University of Alberta, Edmonton, AB, Canada of 1000 M for all groups. In that comparison, the data indicated that for the HFCS treated animals, Purpose: To investigate the functional changes in there was a higher rate of formation of the glucuronidation caused by diet-induced weight gain glucuronide metabolite than other groups. using the commonly used anesthetic/sedative agent, Conclusions: Diet-induced obesity was associated propofol. Propofol is a known substrate for with a general reduction in the hepatic microsomal glucuronidation. rate of glucuronidation of propofol when fat alone Methods: Liver microsomes were harvested from was incorporated into the diet. Interestingly, the male Sprague–Dawley rats given for 14 weeks either kinetics in rats given HFCS alone or in combination normal rodent chow with water (controls); normal with fat appeared to have a higher rate of chow and high fructose corn syrup water (HFCS); glucuronidation based on Vmax, and when given as 45% high fat diet (HF) chow with water; or a HFCS without fat, a profound change in the kinetic combination of HFCS and HF. Propofol was profile of glucuronide formation. incubated with the microsomal protein in incubation media (microsomal protein, UDPGA, MgCl2 in

110s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

CSPT Poster Session 1

Wednesday, May 23

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CSPT Posters - Session 1

Wednesday, May 23

Furthermore, our results indicated that exogenous 48. Using the Wet Bridge Transfer System to surfactant was an effective delivery vehicle for many Assess Exogenous Surfactant as a antimicrobial and anti-inflammatory therapeutics. Pulmonary Drug Delivery Vehicle Keywords: Surfactant, Drug Delivery, Bacterial Infection, Inflammation, Wet Bridge Transfer 1,3 1,2,3 Brandon J. Baer , Cory Yamashita , and Ruud A. System 1,3 W. Veldhuizen 1Department of Physiology and Pharmacology, Western University, London, Ontario; 2Department 49. Gene Expression of Solute Carrier of Medicine, Western University, London, Ontario; Transporters in Multidrug Resistant Breast 3Lawson Health Research Institute, London, Ontario, Cancer Cells Canada Leah Bennett, Steve Hall, Mark Issa, and Kerry Background: Due to its complex branching Goralski structure, drug delivery to the remote areas of the College of Pharmacy, Dalhousie University, Halifax, lung is a major challenge. Consequently, most Nova Scotia, Canada therapies, such as those treating pulmonary infection and inflammation, utilize large systemic dosing, Background: Jadomycins are natural products that with the potential for adverse side effects. A novel retain their cytotoxic properties in multi-drug alternative strategy is to use exogenous surfactant, a resistant (MDR) breast cancer cells by avoiding material capable of distributing throughout the lung, efflux through ATP-binding cassette (ABC) efflux as a pulmonary drug delivery vehicle. transporters. It is necessary to understand Objectives: Utilize an in vitro transferring system to jadomycins’ cellular uptake mechanisms in order to assess exogenous surfactant (BLES) as a pulmonary better utilize these compounds. We hypothesize that drug delivery vehicle. solute carrier organic anion (SLCO) transporters are Methods: An in vitro technique was developed to responsible for jadomycin uptake; therefore, the simultaneously study surfactant delivery and drug gene expression of these transporters must be efficacy. This Wet Bridge Transfer system consisted evaluated in breast cancer cells. of two connected wells in which drugs were instilled Objectives: To evaluate the gene expression of 11 into an administration well and function was tested SLCO transporters in a panel of breast cancer cell in a remote well. The distal wells were seeded with subtypes. either bacteria or stimulated macrophages. Then Methods: The mRNA expression of 11 SLCOs was therapeutics were administered to the delivery well quantified using quantitative polymerase chain alone or in combination with BLES. Outcomes reaction (qPCR) in drug sensitive MCF7-CON and involved spot plating for bacterial killing and taxol-, etoposide-, and mitoxantrone- resistant cytokine analysis for anti-inflammatory effects. MCF7 breast cancer cells which overexpress Results: Administering any of the antimicrobial or ABCB1, ABCC1, and ABCG2 efflux transporters, anti-inflammatory drugs alone to the delivery well respectively. Comparisons were also made between elicited no change for outcomes in the remote well. BT474, SKBR3, and MDA-MB-231 breast cancer However, bacterial growth in the remote well was cell lines and non-cancerous MCF-10A breast reduced by several BLES/antibiotic preparations and epithelial cells. a few BLES/anti-inflammatory mixtures lowered its Results: SLCO4A1 and 3A1 were expressed pro-inflammatory cytokine concentrations. significantly higher than other transporter genes in Conclusions: The Wet Bridge Transfer system can drug resistant MCF7 cells. There was significantly be used to rapidly assess and screen surfactant-based higher expression of SLCO4A1 compared to several therapies prior to their assessment in vivo. other transporters in MCF-10A cells and SKBR3

112s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

cells; and SLCO1C1 compared to several other similar non-significant trend occurred in EtOH- transporters in MCF7-CON cells. There were no exposed fetal brains. Esr1 expression was increased significant differences when comparing the in fetal brains of EtOH-exposed Ogg1 -/- vs +/+ transporters in BT474 and MDA-MB-231 cell lines. progeny at 6 and 24 h (p<0.05), and compared to Conclusions: SLCO4A1 and 3A1 were expressed at saline-exposed Ogg1 -/- progeny at 24 h (p<0.01). significantly higher levels versus the other An increased association of the repressive mark transporter genes in MDR MCF7 cells. These H3K27me3 occurred in EtOH- vs saline-exposed transporters could serve as a conserved transport Ogg1 +/+ progeny (p<0.05), with a similar non- mechanism for intracellular delivery of anti-cancer significant trend in Ogg1 -/- fetal brains. drugs, suggesting they may be responsible for the Conclusions: The DNA lesion 8-oxodG and/or lack cellular uptake of jadomycins. of OGG1 results in epigenetic changes that may Keywords: Breast cancer, multi-drug resistance, contribute to the neurodevelopmental abnormalities jadomycins, solute carrier organic anion seen in Ogg1 KO progeny (Support: CIHR, UofT transporters. Faculty of Pharmacy) Keywords: DNA oxidation, Epigenetics, Estrogen Receptor, Ethanol, FASD 50. Gene-specific Epigenetic Modifications May Contribute to Postnatal Neurodevelopmental Deficits in OGG1 KO Mice Exposed to 51. An Investigation into T-cell-mediated Drug Ethanol in utero Hypersensitivity Reactions

Shama Bhatia1 and Peter G. Wells1,2 Christine C Caron1,4, Abdelbaset A Elzagallaai2,3,4, 1Department of Pharmaceutical Sciences and Centre and Michael J Rieder1,2,3,4,5 for Pharmaceutical Oncology, Faculty of Pharmacy, 1Department of Pathology and Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada; Western University, London, Ontario; 2Department 2Department of Pharmacology & Toxicology, of Pediatrics, Western University, London, Ontario; Faculty of Medicine, University of Toronto, 3Department of Physiology and Pharmacology, Toronto, Ontario, Canada Western University, London, Ontario; 4Robarts Research Institute, Western University, London, Background: Oxidative DNA damage and Ontario; 5Division of Clinical Pharmacology, epigenetic changes occur in the brains of children Department of Medicine, Schulich School of exposed to ethanol (EtOH) in utero. We previously Medicine and Dentistry, London, Ontario, Canada reported that reactive oxygen species-initiated DNA damage in fetal brains, and postnatal learning and Background: Delayed drug hypersensitivity memory deficits were enhanced in EtOH-exposed reactions (DHRs) are T-cell-mediated idiosyncratic oxoguanine glycosylase 1 (Ogg1) -/- knockout (KO) reactions that can erupt days to weeks after initial progeny, which cannot repair the pathogenic DNA drug exposure. Many drugs can cause these reactions lesion 8-oxo-2’-deoxyguanosine (8-oxodG). that commonly presenting in skin. Previous research Objectives: We are investigating the role of 8- into the pathophysiology often groups clinical oxodG-dependent epigenetic changes in the presentations together, however there is some mechanism of EtOH-enhanced postnatal evidence suggesting that cutaneous reactions have neurodevelopmental abnormalities in Ogg1 KO different T-cell subset involvement, and therefore mice. different underlying mechanisms. Methods: Global DNA 5-methylcytosine (5-mC) Objective: Our objective is to address this issue, and levels, mRNA expression of Esr1 involved in determine pathophysiology in context of drug type learning and memory formation, and the association and resulting clinical presentation. of histone marks with the Esr1 gene promoter via Methods: Peripheral blood mononuclear cells ChIP-qPCR, were measured in saline- or EtOH- (PBMCs) are isolated from peripheral blood of exposed (2 g/kg single i.p.) fetal brains extracted 6 patients with confirmed drug allergy and healthy and 24 h post maternal treatment on gestational day controls, and stimulated with the culprit drug in 17. presence of autologous dendritic cells. T-cell subsets Results: 5-mC was increased by 50% in saline- are assessed by measuring surface markers, and exposed Ogg1 -/- fetal brains (p<0.05) at 24 h. A secreted effector cytokines using flow cytometry,

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ELISA and ELISpot techniques. Autologous paradigm) and motivation to consume alcohol dendritic cells will be derived from monocytes. A (assessed by a computer-assisted intravenous alcohol biobank of isolated PBMCs from affected patients self-administration paradigm under a progressive and healthy controls will be generated. ratio schedule). Results: Preliminary results include optimizing Results: Preliminary data show no differences in proliferation and staining of isolated lymphocytes [11C]-(+)-PHNO binding between AUD subjects and and different techniques to generate autologous controls. Exploratory analyses in the AUD group dendritic cells. Tritiated thymidine (H3) for revealed no relationship between self-administration measuring T-cell proliferation and percoll method peak blood alcohol concentration and [11C]-(+)- for isolation of monocytes have provided PHNO binding. However, there was a positive satisfactory results. It is anticipated that different association between craving score increases and clinical presentations occur due to response of [11C]-(+)-PHNO binding in several brain regions different T-cell subsets and effector cytokines. (e.g., globus pallidus, r=0.74, p<0.05; dorsal Conclusions: This study will provide insight into striatum, r=0.89, p <0.001; ventral striatum, r=0.75, the underlying pathophysiology of DHRs while p<0.05). aiming at developing reliable tests for prediction and Conclusions: While these data show no differences diagnosis. We aim to help lessen patient suffering in D3R binding between AUD subjects and controls, and associated healthcare costs, by improving this early data does suggest a role of D2/3R in accurate prediction and early diagnosis of DHRs. alcohol craving. Keywords: Drug; Hypersensitivity; Skin; Flow Keywords: Dopamine, PET, PHNO, AUD, D3 cytometry; T-cell

53. BRCA1 Protects the Embryo from Oxidative 52. The Role of the Dopamine D3 Receptor in DNA Damage in Brca1 Knockout Mice Alcohol Use Disorder Danielle M. Drake1 and Peter G. Wells1,2 Chidera C. Chukwueke1, Saima Malik2, Christina N. 1Department of Pharmaceutical Sciences and Centre Nona2, Esmaeil Mansouri2, Christian Hendershot1,2, for Pharmaceutical Oncology, Faculty of Pharmacy, Isabelle Boileau1,2, and Bernard Le Foll1,2 University of Toronto, Toronto, Ontario, Canada; 1University of Toronto, Toronto, Ontario; 2Centre 2Department of Pharmacology and Toxicology, for Addiction and Mental Health, Toronto, Ontario, University of Toronto, Toronto, Ontario, Canada Canada Background: Although primarily associated with Background: While animal models have implicated cancer, the breast cancer 1 (Brca1) gene also the dopamine D3 receptor (D3R) in alcohol use, provides embryoprotection from reactive oxygen AUD research in humans provides limited species (ROS). Brca1 regulates important cellular understanding with respect to the specific role of pathways, including DNA repair, and the D3R in AUD. This project aims to extend on homozygous knockout (KO) is embryolethal. preclinical research by investigating D3R in human However, heterozygous (+/-) progeny are thought to AUD subjects. develop normally. Objectives: 1. to examine the regulation of D3R Objectives: (1) Characterize the level of BRCA1 levels in AUD subjects (compared to previously protein deficiency in +/- Brca1 KO embryos vs. acquired controls); and 2. to explore how craving wild-type (+/+) littermates and adult brain; and, (2) and motivation to consume alcohol relate to D3R determine if KO embryos exhibit enhanced DNA levels. We hypothesize an upregulation of D3R in damage with or without in utero exposure to the AUD subjects as well as a positive association ROS-enhancer ethanol (EtOH). between D3R levels and our behavioral measures. Methods: +/- Brca1 KOs were mated, and pregnant Methods: D3R levels in AUD subjects (n=10) (and dams were either untreated or treated on gestational healthy controls, n=18) were estimated using day (GD) 12 with EtOH (4 g/kg i.p.) or saline. Positron Emission Tomography (PET) along with a Embryos were collected 6 hours later. BRCA1 D3R preferring radiotracer, [11C]-(+)-PHNO. D3R protein was measured in untreated embryos via levels in the AUD group were then correlated with western blot. Treated embryos were assessed by measures of craving (assessed by a cue-exposure ELISA for the DNA lesion 8-OH-2’-

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deoxyguanosine, and by western blot for γH2AX, 2011 (the war year) and statistical lower rates in indicating DNA double strand breaks. multiple births comparing to the previous two years Results: BRCA1 levels were reduced by 58% in (2009 and 2010). Brca1 +/- embryos vs. +/+ littermates (p<0.0001), Conclusions: Based on these results war stress may and by a lesser 38% in +/- adult brains compared to increase the rate of CHD. While multiple births is a +/+ brains (p<0.05). DNA damage was increased in major risk factors for prematurity and this was saline-exposed +/- embryos vs. +/+ littermates reduced in the war year the results may suggest the (p<0.05), and was exacerbated by EtOH exposure cause of prematurity was due to war stress. More (p<0.01). research is needed to further evaluate if any Conclusions: Modest BRCA1 deficiencies of either relationship truly exists. genetic or epigenetic origins may constitute a risk Keywords: Stress, Pregnancy Outcome, Congenital factor for abnormal development, suggesting a role Heart Defect for BRCA1 beyond cancer. These results may be relevant to autism spectrum disorders (ASD) and fetal alcohol spectrum disorders (FASD). (Support: 55. Optimizing Chronic Hepatitis C Treatment CIHR, Faculty of Pharmacy) in a Canadian Cohort Keywords: Breast cancer 1, BRCA1, DNA damage, 1 2 DNA repair, teratogenesis, autism spectrum Jennifer J. Lin , Catrina M. Loucks , Jessica N. 3 4 disorders, ethanol, fetal alcohol spectrum disorders Trueman , Britt I. Drögemöller , Galen E. B. 5 6 7 Wright , Eric M. Yoshida , Samuel S. Lee , Alnoor Ramji6, Edward Tam8, Colin J. Ross4, and Bruce C. 54. The Effects of War Stress on Pregnancy Carleton1,2, and The Canadian Pharmacogenomics Outcomes During the Conflict in Tripoli, Network for Drug Safety Consortium Libya 1Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia; Fatma Etwel, Gideon Koren, and Michael J. Rieder 2Department of Pediatrics, University of British Schulich School of Medicine and Dentistry, Western Columbia, Vancouver, BC; 3Pharmaceutical University, London, Ontario, Canada Outcomes Programme, BC Children’s Hospital, Vancouver, BC; 4Department of Pharmaceutical Background: Prolonged, severe stress is unhealthy Sciences, University of British Colombia, for pregnancy. There are limited studies evaluating Vancouver, BC; 5Centre for Molecular Medicine the potential adverse effects of war on pregnancy Therapeutics, University of British Columbia, outcomes. On February 17, 2011, a civil conflict Vancouver, BC; 6Division of Gastroenterology, erupted in Libya. Major stress factors in Tripoli University of British Columbia, Vancouver, BC; during the war were: bombing of the military centers 7Division of Gastroenterology and Hepatology, in the city and low quality of life. However, there University of Calgary Liver Unit, Calgary, Alberta; was no destruction of medical buildings. Updated 8LAIR Centre, Vancouver, BC, Canada health records were investigated to determine the effect of war stress on pregnancy outcomes. Background: Chronic Hepatitis C virus (HCV) Objective: The objective of this study is to infection is a major cause of cirrhosis and liver investigate the influence of war on pregnancy disease, making it a leading indicator for liver outcomes during the 2011 conflict in Tripoli, Libya. transplantation. In the era of direct acting antiviral Methods: All the neonatal records that were therapy, ribavirin is still used to improve outcomes admitted to the neonatal intensive care unit at the for difficult to treat patients and shorten therapy Archives Department at the Tripoli Medical Center length. However, ribavirin can cause serious for the period covering 2009, 2010 and 2011 were anemia, requiring dose reductions to prevent further reviewed. The following data was collected: date of harm to the patient. This can compromise treatment admission, gestational age, days in hospital, success, resulting in longer treatment periods and diagnosis with congenital heart defect (CHD) and higher costs. causes of death. Objectives: We aim to validate previously identified Results: No statistical difference between the years genomic variants, and discover novel variants on the rates of prematurity and infant death. associated with ribavirin-induced anemia in However, there was statistical higher rate of CHD in Canadian patients and develop a pharmacogenomic

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prediction model to identify patients most likely to approximately 400,000 deaths globally occurred due develop anemia. to complications of chronic hepatitis C infection. A Methods: We have recruited patients treated for new wave of highly effective drugs, collectively chronic HCV infection across Canada and genotyped called direct acting antivirals (DAAs), promise the them for ~700,000 variants across the genome. A elimination of hepatitis C-related complications with genome-wide association study will be conducted to reported cure rates over 95%, yet these rates may not uncover novel genomic predictors of ribavirin- adequately represent real-world patients with induced anemia by adjusting for significant difficult-to-cure infections. associations with previously identified variants. Objectives: Genomic differences influence the Results: Currently, we have recruited 189 patients likelihood of curing hepatitis C, and we aim to who have completed ribavirin-containing therapy. uncover genomic predictors of treatment failure Of these, 67 developed clinically diagnosed anemia, associated with these new DAAs. These predictors with a median hemoglobin decline of 35.5g/L and an can be used to further improve cure rates through increased likelihood of having lower baseline genomics-informed treatment optimization. hemoglobin levels. Methods: Given that sofosbuvir is the most Conclusions: Knowing in whom serious anemia to commonly used DAA in Canada, we have recruited ribavirin is likely to occur via precision medicine patients treated with sofosbuvir-containing regimens approaches will allow for tailoring of therapy to from five Canadian sites. We are collecting individual patients. This will therefore increase the comprehensive clinical and genomic data, which probability of treatment success and minimize the will be used in logistic regression analyses to likelihood of anemia, all which would decrease both uncover genomic predictors of sofosbuvir-based economic and psychological burdens on affected treatment failure. families. Results: We have recruited 380 patients treated with Keywords: Hepatitis C, ribavirin, anemia, sofosbuvir-containing regimens. Of the 226 patients pharmacogenomics who have completed therapy, 22 failed to eradicate the hepatitis C virus, representing a cure rate of only 90% in our real-world cohort. Genomic DNA from 56. Towards Reducing the Burden of Hepatitis the patients has been extracted and is available for C-related Complications through Genomics- high-throughput genotyping. guided Treatment Optimization Conclusions: Understanding how genomic differences contribute to failure of DAA-based 1 2 Catrina M. Loucks , Jennifer J. Lin , Britt I. regimens could lead to personalized treatment 3 2 Drögemöller , Galen E. B. Wright , Eric M. decisions and a reduced burden of hepatitis C-related 4 5 4 Yoshida , Samuel S. Lee , Alnoor Ramji , Edward complications. 6 3 1,2 Tam , Colin J. Ross , and Bruce C. Carleton , and Keywords: Hepatitis C, genomics, sofosbuvir, The Canadian Pharmacogenomics Network for Drug treatment failure Safety Consortium 1Department of Pediatrics, University of British Columbia, Vancouver, BC; 2Department of Medical 57. Targeting Metabotropic Glutamate Genetics, University of British Columbia, Receptor 5 (mGluR5) Ameliorates Vancouver, BC; 3Faculty of Pharmaceutical Huntington’s and Alzheimer’s Disease Sciences, University of British Colombia, Pathology via Activating Conserved Vancouver, BC; 4Division of Gastroenterology, Mechanisms of Autophagy University of British Columbia, Vancouver, BC; 5Division of Gastroenterology and Hepatology, Khaled S. Abd-Elrahman, Alison Hamilton, University of Calgary Liver Unit, Calgary, Alberta; Shaunessy R. Hutchinson, and Stephen S. G. 6LAIR Centre, Vancouver, British Columbia, Ferguson Canada University of Ottawa Brain and Mind Institute, Department of Cellular and Molecular Medicine, Background: The World Health Organization has University of Ottawa, Ottawa, Ontario, Canada identified viral hepatitis as a public health threat, with an estimated 71 million people living with Background: Huntington’s disease (HD) and chronic hepatitis C infection globally. In 2015, Alzheimer’s disease (AD) are neurodegenerative

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disorders that are characterized by progressive We previously reported [1] important accumulation of proteotoxic aggregates, mutant pharmacogenetics differences among Pakistani huntingtin in HD and amyloid β in AD. Genetic breast cancer patients and compared them with allele deletion of mGluR5 reduced disease pathology in frequencies in Africa, China, Europe, North HD and AD by enhancing the clearance of America, and other regions as represented in proteotoxic aggregates via a mechanism that was not HapMap database. Most striking difference was very described. Pharmacological blockade of mGluR5 high ALDH3A1 variant allele frequency. Later, we had favorable outcomes in AD mice. explored additional genotypes in healthy adults from Objectives: We tested whether the inhibition of different population subgroups at Karachi which mGluR5 will be effective in delaying the remained unreported so far. progression HD by activating the autophagy and Objectives: 1. To estimate ALDH3A1 variant allele whether this autophagic clearance of aggregates frequency among healthy Pakistanis. 2. To validate mechanism is conserved in AD. previously reported ALDH3A1 allele frequency Methods: zQ175 HD, APPSwe/PSEN1dE9 and among Pakistani breast cancer patients. 3xTg-AD mice were treated with the highly specific Methods: We included 155 healthy adults after mGluR5 negative allosteric modulator CTEP for 12 informed consent and institutional approval. The weeks. zQ175 mice were assessed for changes in DNA was extracted from saliva collected and stored motor and cognitive function. Autophagy markers in Oragene-DNA® kits. Several SNPs involved in were assessed in brain slices and lysates from HD drug metabolism and transport were genotyped. and AD mice. Here we present the pyrosequencing data of Results: CTEP improved in grip strength, latency on ALDH3A1 genotyping done at our collaborating rotarod, novel object recognition scores and % error institution (Institute of Clinical and Experimental in limb placement during ladder task in zQ175 mice. Pharmacology, University of Kiel, Germany). This was paralleled by an enhanced clearance of Results: The ALDH3A1 (985 C>G) variant allele huntingtin aggregates and a GSK3β-dependent frequency was 67% among our population which is degradation of ZBTB16 and stabilization of the significantly higher than all ethnic groups in autophagy adaptor ATG14. CTEP also activated HapMap database (Figure-1), which is similar to our ULK1 resulting in phosphorylation and activation of previously reported 63% among Pakistani breast the autophagy adaptor ATG13. Interestingly, CTEP cancer patients. Healthy Europeans in HapMap activated similar pathway in APPSwe/PSEN1dE9 database had lowest variant allele frequency (29%). and 3xTg-AD mice. Conclusions: ALDH3A1 variant allele is very Conclusions: we provided the first description of frequent in our population. Implications include mGluR5 signaling via a conserved autophagic (Figure-2) increased susceptibility of suffering from, mechanism in two neurodegenerative diseases. Our (a) diseases like atherosclerosis, cancer, cataracts, findings indicate that mGluR5 negative allosteric infertility, neurodegeneration, (b) hazards related to modulators can be repurposed clinically to improve mitochondrial dysfunction, oxidative stress, HD and AD progression. smoking, environmental pollutants, and (c) reduced Keywords: mGluR5, Autophagy, Huntington’s efficacy to cyclophosphamide, nitroglyderin, disease, Alzheimer’s disease, ZBTB16 tretinoin and others. Keywords: Aldehyde dehydrogenase, Environmental hazards, Non-communicable 58. Aldehyde Dehydrogenase – A Real diseases, Pharmacogenomics, Toxicogenomics Pharmacogenomic and Toxicogenomic Crossroad

Nasir Ali Afsar Department of Pharmacology, Jinnah Medical and Dental College, Karachi, Pakistan, and Department of Pharmacology, Alfaisal University College of Medicine, Riyadh, Saudi Arabia

Background: The xenobiotic response may be influenced by polymorphic metabolizing enzymes.

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59. Development and Implementation of Keywords: Pharmacogenomics, Oncology, Pharmacogenomic Risk Prediction Models Precision Medicine, Adverse Drug Reactions in Pediatric Oncology

Tessa A. Bendyshe-Walton1, Shahrad R. Rassekh2, 60. Association of Nicotine Metabolism Ratio 11 Gabriella S. Groeneweg3, Colin J. Ross4, and Bruce with [ C]-(+)-PHNO PET Binding in C. Carleton3 Tobacco Smokers 1Department of Medicine, University of British 1 4-7 Columbia, Vancouver, BC; 2Division of Pediatric Patricia Di Ciano , Rachel F. Tyndale , Esmaeil 3 4,7 Hematology/Oncology, BC Children’s Hospital, Mansouri , Christian S. Hendershot , Alan A. 4,5,7,8 1 4,5,7,8 Vancouver, BC; 3Department of Pediatrics, Wilson , Dina Lagzdins , Sylvain Houle , 2,3,4,5,7,8 1,2,4,6-8 University of British Columbia, Vancouver, BC; Isabelle Boileau , and Bernard Le Foll, 1 4Faculty of Pharmaceutical Sciences, University of Translational Addiction Research Laboratory, British Columbia, Vancouver, BC, Canada Centre for Addiction and Mental Health, Toronto, 2 ON; Addictions Division, Centre for Addiction and 3 Background: Adverse drug reactions (ADRs) are Mental Health, Toronto, ON; Addiction Imaging increasingly recognized as important and sometimes Research Group, Centre for Addiction and Mental 4 irreversible complications of cancer treatment. Health, Toronto, ON; Campbell Family Mental Anthracyclines and cisplatin are effective Health Research Institute, Centre for Addiction and 5 chemotherapeutic agents, but their use can be limited Mental Health, Toronto, ON; Research Imaging by cardiotoxicity (anthracyclines) and ototoxicity Centre, Centre for Addiction and Mental Health, 6 (cisplatin) in up to 60% of patients. Genetic variants Toronto, ON; Department of Pharmacology and that can be used to predict who is most at risk of Toxicology, University of Toronto, Toronto, ON; 7 developing these ADRs have been discovered and Department of Psychiatry, University of Toronto, 8 replicated. Toronto, ON; Institute of Medical Sciences, Objectives: To create pharmacogenomic risk University of Toronto, Toronto, ON, Canada prediction models for anthracycline and cisplatin toxicities and discuss results with oncologists to Background: The rate at which nicotine is facilitate incorporation into treatment decision- metabolized can be measured by the nicotine making when appropriate. metabolism ratio (NMR). Fast metabolizers (FM) Methods: Risk prediction models were developed tend to smoke more and have a harder time quitting from the linear regression of strongly-predictive than slow metabolizers (SM). We have previously genomic variants (odds ratios ≥ 3) discovered and shown that smoking a cigarette can produce replicated in at least three patient populations. increases in DA in the ventral striatum (VS) and These models were used to assess an individual ventral pallidum (VP). Further, DA D2 receptors patient’s genomic risk of developing cardiotoxicity maybe down-regulated in nicotine dependence. from anthracyclines or hearing loss from cisplatin. Objectives: The purpose of the present study was to Results: 241 patients have been genotyped and had determine whether SM and FM would have different their genetic risk results returned to their levels of D2 and/or D3 receptor levels and different oncologists. The first 140 patients have been smoking-induced increases in DA in the VS and VP. characterized to determine the impact these test Methods: Participants (15 FM and 13 SM) 11 results have had on their clinical care. Families and underwent two PET scans with [ C]-(+)-PHNO: one oncologists have described results as being valuable after 48 hours of abstinence from smoking, and the for decision-making in all cases. Additionally, for other after smoking a cigarette. patients in the most extreme risk groups (highest and Results: D2 receptor levels were approximately 10- lowest risk), a change in treatment plan was ordered 13% lower in SM as compared to FM during 30% of the time for cisplatin patients and 35% of the abstinence (p=0.024); there were no differences in time for anthracycline patients. D3 receptor levels. After smoking a cigarette, DA Conclusions: Pharmacogenomic information is was elevated by approximately 10% in the VS highly utilized in patients’ treatment decisions and (p<0.001) and VP (p=0.001) of both groups of better informs patients about their risk of serious smokers, with no differences between FM and SM. drug toxicity.

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Conclusions: Future studies will need to determine Methods: Extensive clinical and demographic data whether these changes are pre-existing or differ as a were collected for 229 testicular cancer patients function of NMR by smoking history. treated with cisplatin. Patients were genotyped for Keywords: Neuroimaging, Addiction, Nicotine two variants, ACYP2 rs1872328 and WFS1 rs62283056, that have previously been associated with hearing loss in cisplatin-treated patients. 61. Careful Investigation of Pharmacogenomic Analyses were performed to investigate the Phenotypes to Uncover the Roles of ACYP2 association of these variants with ototoxicity in this and WFS1 in Cisplatin-induced Ototoxicity. cohort of adult testicular cancer patients. Results: Pharmacogenomic analyses revealed that 1,2 3 Britt I Drögemöller , Beth Brooks , Carol ACYP2 rs1872328 was significantly associated with 4 5 2,6 Critchley , José G. Monzon , Galen E. B. Wright , cisplatin-induced ototoxicity (P=2.83x10-3, 7 8 Geoffrey Liu , Daniel J. Renouf , Christian K. OR[95%C]:14.7[2.6-84.2]). WFS1 rs62283056 was 8 9 Kollmannsberger , Philippe L. Bedard , Michael R. not significantly associated with ototoxicity caused 2,6 8,* Hayden , Karen A. Gelmon , Bruce C. by cisplatin (P=0.39); however, this variant was 10,11,* 1,2,* Carleton , and Colin J. D. Ross associated with hearing loss attributable to any cause 1 Faculty of Pharmaceutical Sciences, University of (P=5.67x10-3, OR[95%CI]:3.2[1.4-7.7]). 2 British Columbia, Vancouver, BC; BC Children’s Conclusions: This study has provided the first Hospital Research Institute, Vancouver, BC; evidence for the role of ACYP2 rs1872328 in 3 Audiology and Speech Pathology Department, BC cisplatin-induced ototoxicity in testicular cancer 4 Children’s Hospital, Vancouver, BC; Neuro- patients. These results support the use of this Otology Unit, Vancouver General Hospital, information to guide the development of strategies to 5 Vancouver, BC; Tom Baker Cancer Centre, prevent cisplatin-induced ototoxicity across cancers. 6 Calgary, AB; Department of Medical Genetics, Further, this study has highlighted the importance of Centre for Molecular Medicine and Therapeutics, phenotypic differences in replication studies and has Faculty of Medicine, University of British provided further evidence for the role of WFS1 7 Columbia, Vancouver, BC; Medical Oncology and rs62283056 in susceptibility to hearing loss, which Hematology, Department of Medicine, Princess may be worsened by cisplatin treatment. Margaret Cancer Centre – University Health Keywords: ACYP2, cisplatin-induced ototoxicity, Network and University of Toronto, Toronto, ON; pharmacogenomics, testicular cancer, WFS1 8 BC Cancer Agency and University of British Columbia, Vancouver, BC; 9Princess Margaret Cancer Centre and University of Toronto, Toronto, 62. Sapropterin Prevents Coronary Artery ON; 10Division of Translational Therapeutics, Malformations Induced by Pregestational Department of Pediatrics, Faculty of Medicine, Diabetes University of British Columbia, Vancouver, BC; 11Pharmaceutical Outcomes Programme, BC Anish Engineer, Yong Jin Lim, Xiangru Lu, and Children’s Hospital, Vancouver, BC, Canada. Qingping Feng * These authors jointly supervised this work Department of Physiology and Pharmacology, Western University Background: Adverse drug reactions such as ototoxicity, which occurs in approximately one fifth Background: Coronary artery development in the of adult patients who receive cisplatin treatment, can embryonic heart involves epithelial to mesenchymal incur large socio-economic burdens on testicular transition (EMT) and cell differentiation. cancer patients who develop this cancer during early Hyperglycemia-induced oxidative stress can lead to adulthood. Recent genome-wide association studies the inactivation of endothelial nitric oxide synthase have identified genetic variants in ACYP2 and WFS1 (eNOS), vital for heart development. Sapropterin that are associated with cisplatin-induced (BH4), an antioxidant, is the co-factor for eNOS. ototoxicity. Treatment with BH4 has been shown to improve Objectives: We sought to explore the role of these vascular endothelial function in diabetes. genetic susceptibility factors to cisplatin-induced Objectives: Investigate the effect of sapropterin on ototoxicity in testicular cancer patients. embryonic coronary artery development during pregestational diabetes (PD).

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Methods: Diabetes was induced by streptozotocin to diabetic nephropathy (DN) and early DN presents (50 mg/kg, IPx5) to adult female C57BL/6 mice. as mild kidney disease. The impact of DN on BH4 (10 mg/kg/day) was orally administered to CYP3A and CYP2C mediated drug metabolism is pregnant mice. Fetal hearts were collected at E18.5 unknown. for coronary artery analysis and 3D reconstruction. Objectives: Evaluate the impact of diabetes and DN EMT and oxidative stress were examined at E12.5 on expression and activity of hepatic CYP3A and 2C via immunostaining and qPCR. Immunoblotting enzymes. determined enzyme activity. Methods: Experimental groups were given five Results: BH4 treatment to diabetic dams decreased consecutive daily 50 mg/kg injections of the incidence of coronary artery malformations streptozotocin (STZ) to induce diabetes and controls (CAMs) in offspring from 47.4 to 23.3%. Decreases were injected with sodium citrate. C57BL/6 mice in coronary artery luminal diameter, volume and were sacrificed 16 weeks following STZ and abundance in hearts from diabetic mothers, were humanized CYP3A4 mice were sacrificed after 2 prevented with BH4. Diabetes reduced embryonic weeks. CYP3A and CYP2C expression was expression of EMT regulators , including Snail1/2 determined by real-time PCR and Western blotting. and WT1, and increased epicardial cell to cell Metabolic activity of liver microsomes was assessed connections, which were all reestablished to normal by measuring testosterone metabolites using LC- with BH4. Akt and eNOS activity was reduced in MS. embryonic hearts from diabetic dams, and was Results: Diabetic C57BL/6 mice showed no returned to normal with BH4. Finally, oxidative differences in Cyp3a11 and Cyp2c29 mRNA stress was elevated in diabetic hearts and reduced expression, and Cyp3a11 protein expression, with BH4. compared with controls. Diabetic humanized Conclusions: Sapropterin treatment prevents CAMs CYP3A4 mice showed no differences in CYP3A4 induced by PD. BH4-mediated increase in mRNA expression compared with controls. Akt/eNOS activity and reduction in oxidative stress Conclusions: Despite pronounced decreases in CYP during cardiac angiogenesis provides insight into expression and activity in moderate and severe factors contributing to CAMs. BH4 may have CKD, diabetes or mild CKD induced by DN does therapeutic potential in PD. not impact hepatic CYP3A or CYP2C enzyme Keywords: Sapropterin, Diabetes, Coronary Artery, expression. Enzymatic function, expression of Heart Development, eNOS transcription factors and drug transporters will be investigated in future studies using this diabetic model. 63. Expression of Hepatic Cytochrome P450 Keywords: Diabetes, diabetic nephropathy, Drug-Metabolizing Enzymes in Diabetes and cytochrome P450, drug metabolism Diabetic Nephropathy

Cheng J. Fang1, Dylan Burger2, Chet E. Holterman2, 64. The Effect of Maternal Nicotine Exposure on Chris R. Kennedy2, Jean-Francois Thibodeau2,3, and Fetal Heart Development Brad L. Urquhart1,4 1Department of Physiology and Pharmacology, Elizabeth R. Greco, Anish Engineer, Tana Saiyin, Western University; 2Kidney Research Centre, MengQi Zhang, Xiangru Lu, Douglas Jones, and Ottawa Hospital Research Institute; 3ProMetic Qingping Feng BioSciences, Inc.; 4Department of Medicine, Department of Physiology & Pharmacology, Division of Nephrology, Western University Collaborative Program of Developmental Biology, Schulich School of Medicine and Dentistry, Western Background: Polypharmacy, along with a high risk University, London, Ontario, Canada of adverse drug reactions, is common in diabetic patients. Many drugs are metabolized by hepatic Background: Cigarette smoking during pregnancy cytochrome P450 (CYP) enzymes such as CYP3A is a risk factor for congenital heart defects (CHDs). and CYP2C. These enzymes are reduced in Many women still smoke before pregnancy (25%) moderate and severe chronic kidney disease (CKD), and during pregnancy (12%). These women resort to leading to altered drug pharmacokinetics. nicotine replacement therapies or e-cigarettes to aid Approximately 40% of all CKD cases are attributed in smoking cessation. Many people believe these

120s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

alternatives are safer compared to cigarette smoking, Background: Factor Xa inhibitor, apixaban, belongs because they do not expose the fetus to the many to an increasingly prescribed class of direct-acting toxins found in tobacco smoke. However, e- oral anticoagulants used for stroke prevention in cigarettes contain nicotine, and the safety of nicotine patients with atrial fibrillation (AF). Apixaban is on fetal heart development is not known. predominately metabolized by hepatic and intestinal Objectives: Determine if maternal nicotine exposure cytochrome P450 3A enzymes (CYP3A4/5). To (MNE) during pregnancy leads to CHDs in the date, the relationship between apixaban blood offspring of mice. concentrations and endogenous markers of CYP3A Methods: C57BL/6 adult female mice were treated activity among patients taking apixaban, has not with subcutaneous nicotine infusion at doses of 1.5 been determined. In humans, 4β-hydroxycholesterol mg/kg/day via osmotic pump (Alzet #2004), a (4β-OHC) is an endogenous oxysterol that is created human dose equivalent to 1-10 cigarettes per day. through the conversion of cholesterol by CYP3A Pumps were implanted 14 days prior to mating with enyzmes. a wildtype male, and nicotine exposure was Objectives: To compare plasma apixaban continued throughout gestation. Heart samples were concentrations in AF patients in relation to their collected at E18.5 for morphological analysis. plasma 4β-OHC concentration as surrogate marker Results: The incidence of CHDs in the E18.5 of CYP3A activity. offspring of dams exposed to nicotine was 45.5%. Methods: We determined 4β-OHC plasma The most prevalent defect observed was hypoplastic concentration in 136 AF patients taking apixaban left heart syndrome (36.4%). E14.5 hearts were with previously determined drug plasma stained with dihydroethidium probing for concentrations. Multiple linear regression analysis superoxide, a marker for oxidative stress. Fetal was used to test the relative contribution of 4β-OHC hearts exposed to nicotine had significantly higher concentration to the variability in apixaban levels of ROS compared to control. concentration while controlling for patient Conclusions: This research provides insight into the characteristics (age, weight, sex, serum creatinine, potential dangers of nicotine therapies during moderate CYP3A4/P-gp inhibitor use), ABCG2 pregnancy for the developing embryo. This could c.421C>A genotype, as well as apixaban dosing decrease MNE and reduced the incidence of regimen and time since last dose. reproductive abnormalities such as CHDs. Results: We observed a weak, inverse correlation (p Keywords: Nicotine, Cardiogenesis, Congenital = 0.016, r = -0.2063) between 4β-OHC and Heart Defect, Developmental Biology apixaban concentration. In our regression analysis, Oxidative Stress 4β-OHC concentration accounted for 16% of the explainable variation in apixaban concentration. Furthermore, higher apixaban concentrations were 65. 4-Beta Hydroxycholesterol as a Predictor of associated with increased age (p = 0.001), female Observed Apixaban Plasma Concentration sex (p = 0.002), elevated serum creatinine (p = among Atrial Fibrillation Patients <0.001), and amiodarone use (p = 0.024). Conclusions: Our findings demonstrate that CYP3A 1,2 1 1,2 Markus Gulilat , Wendy A. Teft , Ute I. Schwarz , activity as measured by 4β-OHC concentration is an 1,2 1,2 Rommel G. Tirona , and Richard B. Kim additional determinant of apixaban plasma 1 Division of Clinical Pharmacology, Department of concentration. Medicine, Western University, London, Ontario; Keywords: endogenous CYP3A activity biomarker, 2 Department of Physiology and Pharmacology, 4-beta hydroxycholesterol, apixaban, single time- Western University, London, Ontario, Canada point plasma concentrations

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Poster Session 2

CSPS and CC-CRS

Thursday, May 24

122s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

Posters - Session 2

Thursday, May 24

medium only. Uptake of daunorubicin into K562 cells treated with CPX-351 was significantly Biomedical Sciences decreased in the cells where expression of SR-BI was knocked down by siRNA, compared with cells treated with NC at 24, 48, and 72 h. A 75% 66. Scavenger Receptor Class B Type I (SR-BI) reduction in SR-BI gene expression (72h post Mediates the Cellular Uptake of CPX-351 siRNA transfection) resulted in a 30% reduction in into K562 Leukaemia Cells CPX-351 (50ng/mL) uptake. Conclusions: These preliminary studies suggest that Yunyun Di, Ellen K. Wasan, Jacqueline Cawthray, SR-BI may be one potential mechanism by which Kishor M. Wasan CPX-351 is taken up into K562 cells. College of Pharmacy and Nutrition, University of Acknowledgements: Funding for this project was Saskatchewan provided by Celator Pharmaceuticals Inc. prior to its acquisition by Jazz Pharmaceuticals. Purpose: The Scavenger Receptor class B type I (SR-BI) plays an important role in mediating the uptake of high-density lipoproteins. The purpose of 67. Effects of Diet-induced Diabetes on β-cell this study is to assess the role of the cell surface Specific Aryl Hydrocarbon Receptor lipoprotein receptor SR-BI in the uptake of CPX-351 Nuclear Translocator/Hypoxia-inducible liposomes (Jazz Pharmaceuticals) into K562 Factor-1β (ARNT/HIF-1β) Knockout Mice leukaemia cells. CPX-351 liposome formulation encapsulates a fixed ratio of daunorubicin and Monica Hoang, Jamie W. Joseph. cytarabine, and is approved for use in acute myeloid University of Waterloo, School of Pharmacy, leukaemia. Waterloo, Ontario, Canada Methods: K562 cells were treated with 10nM Stealth RNAi duplexes targeting the SR-BI gene Purpose: The transcription factor ARNT/HIF1β (SR-BI siRNA) or 10 nM low GC negative control plays a key role in maintaining pancreatic β-cell Duplexes (NC), premixed with Lipofectamine function. β-cell ARNT/HIF1β regulates glycolysis, + 2+ RNAiMAX reagent. Cells were collected every 24 anaplerosis, NADPH/NADP ratio, Ca influx and hours to determine the SR-BI gene expression levels has also been shown to be one of the most down by RT-PCR. Uptake of CPX-351 within K562 cells regulated transcription factors in islets from type 2 was determined using flow cytometry by tracking diabetic patients. Using a β-cell specific daunrobuicin. CPX-351 at concentrations of 10, 20, ARNT/HIF1β knockout (β-ARNT KO) mouse 30 and 50 ng daunorubicin/mL were incubated for model, we have shown a strong role for 24, 48 or 72 hours after siRNA transfection to ARNT/HIF1β in glucose sensing and insulin downregulate SR-BI. At each time point, cells were secretion in vitro. However, β-ARNT KO mice have no significant in vivo defects associated with glucose collected and analyzed at λex/λem=480/590 nm on a CytoFLEX Multicolour flow instrument to tolerance and insulin resistance. determine cellular uptake of daunorubicin. Method: In order to gain a better understanding of Experimental data were plotted as mean±SD using the role of ARNT/HIF1β in the development of GraphPad Prism (Version 5.0). Data were analyzed diabetes, we placed male β-ARNT KO mice on using two-way ANOVA with Bonferroni multiple either a chow diet consisting of 5.5% fat or a HFD comparisons. Significance was set at p<0.05. consisting of 58% fat with sucrose for 10 weeks. Results: The SR-BI gene expression levels were Results: The only in vivo significant difference seen significantly decreased by > 75% in the cells treated for β-ARNT KO mice on the HFD was that they had with 10 nM siRNA for at least 48 h, and maintained no impairment in glucose tolerance and had a up to 120 h, compared to K562 cells treated with significantly elevated plasma insulin during the

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ipGTT compared to HFD fed control mice. β-ARNT mass spectrometry (LC-ESI-MS). Cardiac KO mice had lower β-cell mass on a chow diet as hypertrophic markers and CYP1B1 were determined compared to chow fed control mice and showed no by real time-polymerase chain reaction and Western further impairment on the HFD. Isolated β-ARNT blot analysis, respectively. KO islets from chow fed mice and islets from HFD Results: Our results demonstrated that fluconazole fed control mice had impaired GSIS and glucose- was able to attenuate Ang-II-induced cellular stimulated NADPH/NADP+ ratio responses as hypertrophy as evidenced by a significant inhibition compared to control diet fed mouse islets. Isolated of hypertrophic markers, β-myosin heavy chain islets from β-ARNT KO mice on the HFD showed (MHC)/ α-MHC. The protective effect of an improvement in GSIS and NADPH/NADP+ ratio fluconazole was associated with a significant response to glucose suggesting that the defects seen decrease in the level of CYP1B1 enzyme and its in the control fed β-ARNT KO islets could be associated mid-chain HETEs metabolites induced by rescued by a HFD. Ang II. Furthermore, treatment of rats with Conclusion: We have shown a consistent role for fluconazole significantly decreased the expression of ARNT/HIF1β in the maintenance of β-cell function CYP1B1 enzyme and the formation level of in vitro and β-cell mass. cardiotoxic mid-chain HETEs metabolites. Conclusion: Our results provide the first evidence that fluconazole may be repurposed as a mid-chain 68. Fluconazole Protects Against Angiotensin II- HETEs formation inhibitor for the treatment of induced Cellular Hypertrophy through cardiac hypertrophy. Inhibiting Cytochrome P450 1B1 and its Associated Arachidonic Acid Metabolites in the Heart 69. Modeling the Dynamic Gating Mechanism and Small-molecule Binding in the CaV1.2 Ahmad H. Alammari, Zaid H. Maayah and Ayman Channel O.S. El-Kadi Faculty of Pharmacy and Pharmaceutical Sciences, Tianhua Feng1, Subha Kalyaanamoorthy1, Khaled University of Alberta, Edmonton, AB, Canada Barakat1,2,3 1Faculty of Pharmacy and Pharmaceutical Sciences, Purpose: Several studies have elucidated the role of University of Alberta; 2Li Ka Shing Institute Of cytochrome P4501B1 (CYP1B1) and its associated Virology, University Of Alberta; 3Li Ka Shing arachidonic acid (AA) metabolites in the Applied Virology Institute, University Of Alberta, development of cardiac hypertrophy. CYP1B1 has Edmonton, Alberta, Canada. been reported to have a major role in metabolizing AA into cardiotoxic metabolites, mid-chain Purpose: Voltage-gated calcium channels (CaVs) hydroxyeicosatetraenoic acid (HETEs). Recently, remain essential for normal cardiac functioning in fluconazole was shown to inhibit the formation of the human body. Any abnormalities in the mid-chain HETE metabolites. Therefore, we functioning of CaVs results in serious diseases, for investigated whether fluconazole confer example, cardiac arrhythmias and Timothy cardioprotection against angiotensin II (Ang II)- syndrome. Thus, CaVs are considered as one of the induced cellular hypertrophy. In an attempt to promising targets for the treatment of these diseases. determine whether similar effects will occur in vivo, Diverse types of small molecules, such as we examined the effect of fluconazole on CYP1B1 dihydropyridines and phenylalkylamine have been and its associated AA in rats. identified to modulate the activity of CaVs. Methods: Rat cardiomyocytes H9c2 cells were However, their mode and site of action are still treated with 10 μM Ang II in the absence and unclear. In order to understand how these drugs bind presence of 50 μM fluconazole for 24 hours. Also, and act on the CaV, it is necessary to have a high- Sprague Dawley rats (n=6) were injected quality three-dimensional structure of the human intraperitoneally with a single dose of fluconazole CaV channel. However, this has not been resolved (20 mg/kg) or saline and the heart tissues were yet. harvested 24 hours post-treatment. Thereafter, the Methods: We have used computational molecular formation of AA metabolites was measured using modeling to model the complete three-dimensional liquid chromatography-electron spray ionization- (3D) structure of the open and close CaV channel

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using homology modeling and threading approach. substrate uptake assay using various cell lines. Classical and advanced molecular dynamics Results: A competitive binding assay, simulations were carried out to explore the transactivation assay, and glucose uptake assay conformational transitions between the closed and revealed ENL as a PPARϒ partial agonist. ENL open state. The binding orientation and critical modulated cholesterol and lipid metabolism targets interactions that stabilize the known modulators (FASN, SREBPs, INSIG-1, LDLR, PPARϒ) and ER were identified using molecular docking and stress markers (ATF4, CHOP, GADD34 and binding-free energy methods. GRP58). ENL reduced mitochondrial redox function Results: Our molecular dynamics simulations reveal and caused mitochondrial toxicity. ENL enhanced the conformational changes in the pore and voltage- ability of select anticancer drugs (e.g: microtubule sensing domains of the CaV channel. The mode-of- inhibitors) to decrease cell viability. Fluorescently binding of Amlodipine, Nimodipine, and Verapamil labeled cholesterol treated cells along with ENL were identified. As expected, the relative binding revealed altered intracellular vesicular trafficking affinity calculations agree that both Amlodipine and linking the actin cytoskeleton. Verapamil have the high potential to block the CaV Conclusion: A novel role may exist between the channel. regulation of PPARϒ, lipid and cholesterol Conclusion: The conformational dynamics and the metabolism, and ER stress. These findings warrant interactions reported from our binding mode analysis further investigations to support FLN’s ability to will be useful for understanding the structure- modulate ER stress as the key mechanism involved function-dynamic relationship in the CaV channel in the disruption of dysregulated cellular signaling. and guiding future drug design. ER stress and PPARϒ mediated signaling can influence cholesterol and lipid metabolism and therefore are relevant targets in drug discovery. As 70. Molecular Mechanisms of Mammalian well, lignans are safe and therefore are good Lignan Enterolactone in Modulating candidates for adjuvant therapy that could improve Cellular Lipid Homeostasis patient longevity and quality of life.

Franklyn De Silva, Xiaolei Yang, Ahmed Almousa, Ahlam Hawsawai, and Jane Alcorn. 71. DOX-Vit D, A Novel Doxorubicin Drug Discovery & Development Research Group, Derivative, Inhibits Human Osteosarcoma College of Pharmacy and Nutrition, University of Cell Proliferation by Inducing Apoptosis Saskatchewan, Saskatoon, SK, Canada while Inhibiting Akt and mTOR Signaling Pathways Background: Dysregulated cholesterol homeostasis is a feature of both cardiovascular disorders and Zaid H. Maayah1, Ti Zhang2, M. Laird Forrest2, cancer progression. Furthermore, dysregulated cells Ayman O.S. El-Kadi1, Michael R. Doschak1 and can exhibit elevated endoplasmic reticulum (ER) Neal M. Davies1*. stress as an adaptive survival mechanism. A link 1Faculty of Pharmacy and Pharmaceutical Sciences, between flaxseed lignans (FLN) anti-cholesterolemic University of Alberta, Edmonton, AB, Canada; and anti-cancer effects might exist through the 2Department of Pharmaceutical Chemistry, School ability of FLNs to modulate both ER stress and of Pharmacy, University of Kansas, Lawrence, KS, cholesterol homeostasis as FLN are known to USA. modulate multiple targets in dysregulated cellular signaling pathways. Purpose: Doxorubicin (DOX) is a very potent and Purpose: This study aims to identify the molecular effective anticancer agent. However, the targets responsible for enterolacone’s (ENL) ability effectiveness of DOX in osteosarcoma is usually to modulate ER stress and cholesterol homeostasis in limited by the acquired drug resistance. Recently, dysregulated cell types (e.g. cancer). Vitamin D (Vit-D) was shown to suppress the Methods: Key targets involved in cholesterol growth of many human cancer cells. Taken together, metabolism, ER stress, cell survival, and vesicular we synthesized DOX-Vit D by conjugating Vit-D to cholesterol trafficking were evaluated using a battery DOX in order to mitigate the chemoresistance of in vitro assays such as qPCR, western blot, associated with DOX. The overall objectives of the fluorescence microscopy, gene reporter assay, and present study were to investigate the antiproliferative

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and apoptogenic effects of DOX-Vit D and the University Hospital Heidelberg, Germany. 4German possible mechanism involved in the human Center for Diabetes Research (DZD); 5Institute for osteosarcoma cancer cell line, MG63 cells. Diabetes and Cancer IDC Helmholtz Center Munich, Method: For this purpose, MG63 cells were treated Neuherberg, Germany and Joint Heidelberg-IDC with 10 µM DOX or DOX-Vit D for 24 hours. Translational Diabetes Program, Dept. Inner Thereafter, cell proliferation, apoptotic and oxidative Medicine I, Heidelberg University Hospital, stress genes were determined by 3-[4,5- Heidelberg, Germany. 6Neurobiology Laboratory, dimethylthiazol-2-yl]-2,5- National Institute of Environmental Health Sciences, diphenyltetrazoliumbromide (MTT) assay and real- North Carolina, USA and Institute for Biomedical time PCR, respectively. The protein expression level Research (BIOMED), School of Medical Sciences, of the phosphorylated-Jun NH2-terminal kinase (p- Catholic University of Argentina, Buenos Aires, JNK), p-p38, p-Akt and the mammalian target of Argentina. rapamycin (p-mTOR) was measured using Western blot analysis. Purpose: Diabetic retinopathy (DR) is induced by Results: Our results showed that DOX-Vit D, but an accumulation of reactive metabolites such as not DOX, significantly elicited apoptotic signal in ROS, RNS and RCS species, which were reported to MG63 cells extrinsically through a significant modulate the activity of cation channels of the TRPC activation of death receptor and intrinsically by a family. In this study, we use Trpc1/4/5/6–/– significant induction of oxidative stress genes (heme compound knockout mice to analyse the oxygenase-1 and NAD(P)H:quinone oxidoreductase- contribution of these TRPC proteins to diabetic 1). Consequently, DOX-Vit D caused a significant retinopathy. increase in the expression of caspase-3 and BCLxs Methods: We used qPCR-based analysis to genes and thereby suppressed the growth of MG63 determine mRNA levels of TRPC channels in cells. Mechanistically, the DOX-Vit D-induced control and diabetic retinae and retinal cell types. apoptogens and cell death was credited to the Chronic hyperglycemia was induced by activation of p-JNK and p-p38 signaling pathway. Streptozotocin (STZ) treatment. To assess the This was supported by the finding that blocking of development of diabetic retinopathy; vasoregression, p-JNK and p-p38 significantly attenuated the DOX- pericyte loss and thickness of individual retinal Vit D-mediated apoptosis. Furthermore, the layers were analysed. Plasma and cellular anticancer effect of DOX-Vit D against MG63 cells methylglyoxal (MG) levels, as well as Glyoxalase 1 was mediated by inhibiting the expression of (GLO1) enzyme activity and protein expression, proliferative proteins, p-Akt and p-mTOR. were measured in WT and Trpc1/4/5/6–/– cells or Conclusion: Our findings propose that DOX-Vit D tissues. MG-evoked toxicity was evaluated by MTT suppressed the growth of MG63 cells by inducing assay. apoptosis while inhibiting cell survival and Results: We find that Trpc1/4/5/6–/– mice are proliferative signaling pathways. protected from hyperglycemia-evoked vasoregression determined by the formation of acellular capillaries and pericyte drop-out. In 72. Loss of Cation Channels of the TRPC addition, Trpc1/4/5/6–/– mice are resistant to the Family Protects against the Development of STZ-induced reduction in retinal layer thickness. Diabetic Retinopathy in the STZ Model and The RCS metabolite methylglyoxal, was Accumulation of Reactive Metabolites significantly reduced in plasma and red blood cells (RBCs) of STZ-treated Trpc1/4/5/6–/– mice 1 2 Robin Sachdeva , Andrea Schlotterer , Dagmar compared to controls. GLO1 is the major MG 1 1 1 Schumacher , Christin Matka , Ilka Mathar , Nadine detoxifying enzyme, and its activity and protein 2 1 1 Dietrich , Rebekka Medert , Ulrich Kriebs , Jihong expression were significantly elevated in 2 1 3,4,5 Lin , Natasha Mahajan , Peter Nawroth , Lutz Trpc1/4/5/6-deficient cells, which lead to 6 3,4 Birnbaumer , Thomas Fleming , Hans-Peter significantly increased resistance to MG toxicity. 2 1 Hammes , Marc Freichel GLO1 activity was also increased in retinal extracts 1 Institute of Pharmacology, Heidelberg University, from Trpc1/4/5/6–/– mice. The TRPCs investigated 2 Heidelberg, Germany; Medical Faculty Mannheim, here are expressed at different levels in endothelial Heidelberg University, Mannheim, Germany; and glial cells of the retina. 3 Department of Medicine I and Clinical Chemistry, Conclusion: The protective phenotype in diabetic

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retinopathy observed in Trpc1/4/5/6–/– mice is help combat oxidative stress and neuroinflammation suggestive of a predominant action of TRPCs in in the brain. The blueberry extracts are also able to Müller cells and microglia because of their central provide significant protection compared to controls position in the retention of a proper homoeostasis of and effectively reduce neuronal and microglial cell the neurovascular unit. death, showing that their presence helps when cell death and damage is influenced by glutamate- mediated excitotoxicity or insoluble alpha-synuclein 73. Effect of Polyphenols on Markers of aggregates. Neurodegenerative Disease

Erin Kelly1, Poorva Vyas1,2, Rachel Ward1, Andre 74. Macro- and Micro-fabrication of Chitosan Igamberdiev2, and John T. Weber1. Hydrogels with Anisotropic Pores for School of Pharmacy1 and Department of Biology2, Biomedical Applications Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada Vahid Adibnia1, Marziye Mirbagheri2, Pierre-Luc Latreille1, Jimmy Faivre1,3, Thierry Delair3, Laurent Purpose: It is suggested that one of the main David3, Xavier Banquy1 mechanisms contributing to neurodegenerative 1Faculty of Pharmacy, Université de Montréal, diseases (NDD) is oxidative stress, which is caused Montreal, Quebec, Canada; 2Department of by the buildup of harmful reactive oxygen species Chemical Engineering, Ryerson University, Toronto, (ROS) in the brain. Neuroinflammation is also Ontario, Canada; 3Université de Lyon, Université accredited to causing many chronic NDD; when Claude Bernard Lyon 1, CNRS, Ingénierie des microglia are activated in response to the release of Matériaux Polymères Villeurbanne Cedex, France alpha-synuclein aggregates from damaged neurons, the activated microglia release inflammatory Purpose: The microstructure of hydrogels is mediators. NDD are linked to glutamate-mediated composed of micro- and nano-sized pores, with excitotoxicity as well, where cells are damaged by random shapes, sizes and orientations. However, in the excessive stimulation from glutamate via several biomedical applications, it is required to inadequate uptake by glial cells. Polyphenols, found adjust the pore geometry. For example, in 3D culture in very high levels in blueberries, are botanical of neural cells, the scaffolds should contain nutraceuticals which have antioxidant properties and cylindrical pores to promote directed axon may offer protection and intervention from regeneration. Fabrication of these non-random neurological disorders by managing ROS, reducing structures using self-assembly is a challenging task, the inflammatory response, and providing protection which is still preferred over bioprinting and in the brain from further degeneration. lithography due to biocompatibility. In this study, Methods: Biochemical analysis was performed after we exploit the self-assembly of anisotropic chitosan the extraction of frozen wild Newfoundland berries pores to design non-random microstructures with and leaves, Vaccinium angustiform spp., from four potential biomedical applications. different locations. We investigated the Method: The self-assembly of the anisotropic pores neuroprotective role of the blueberry fruits and is triggered by diffusion of a strong base to acidic leaves in cell cultures from mouse-pup brain chitosan solutions, which leads to the polymer dissections, and in pure cultures of rat neurons and coagulation and segregation in the diffusion microglia exposed to 100μM glutamate or 100ng/ml direction. The coagulated polymer forms a hydrogel alpha-synuclein for 24-hours. with double pore geometry, including random Results: It was determined that both blueberry fruits nanosized pores and anisotropic micron-sized and leaves contain high levels of polyphenols, cylindrical pores. The 3D structure of hydrogel was however the leaves contained significantly higher studied using fluorescent confocal microscopy. To levels for all of the locations. We have also observed test the application of the anisotropic pores, the an increase in the number of viable cells once hydrogels were formed in microchannels that were blueberry extract is added to cell cultures treated made using photolithography. with 100μM glutamate or 100ng/ml alpha-synuclein. Results: The dimensions and number density of the Conclusion: The blueberry extracts have high anisotropic pores were found to depend on the base antioxidant activity and therefore may be able to and chitosan concentrations as well as the

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geometrical features of the mold. The diameter of to the cortex in a highly reproducible manner. the capillaries is typically within 20-30 ߤm, while Analysis of caspase-3 null mice further demonstrates they can be longer than 10 mm. The hydrogel that loss of this executioner caspase activity confers containing these capillaries shows improved NP a significant protective effect against apoptotic cell diffusivity, measured using diffusive dynamic death, with the region of injury reduced by more microscopy. Various patterns and structures of the than half compared to wild-type littermates. hydrogel were formed and tested using Combinatorial inhibition of both caspase-3 and microfluidics. RIP1K demonstrates a still further reduction in the Conclusion: Chitosan hydrogels with self- size of cortical injury to near vehicle-treated levels. assembled anisotropic pores are an interesting Conclusion: These results demonstrate that under candidate for several biomedical applications. These conditions of cerebral ischemia in an improved hydrogels show enhanced diffusive properties that model of cortical stroke, apoptotic and necroptotic can be tuned by modifying the pore properties. In forms of programmed cell death constitute the addition, various patterns and structures that can be primary mechanisms by which the vast majority of made using these capillaries make the gel an ideal neurons die within the cortex in vivo. These findings material for tissue engineering applications. suggest that pharmacologic inhibition of caspase-3 and RIP1K can substantially reduce the level of cellular injury in the most common form of cerebral 75. Apoptotic vs. Necroptotic Cell Death stroke in humans. Analysis in an Endothelin-1 Model of Cerebral Ischemia 76. Binge Drinking During Adolescence Causes Chesarahmia Dojo Soeandy, Faraz Salmasi, and Persistent Behavioral Impairments and Jeffrey T. Henderson. Elevated Pro-Inflammatory Proteins in a Faculty of Pharmacy, University of Toronto, Rodent Model Toronto, Ontario, Canada Matthew G. Lamont and John T. Weber. Purpose: Stroke represents one of the leading School of Pharmacy, Memorial University of causes of long-term disability and death in North Newfoundland, St. John’s, Newfoundland, Canada America. The failure of a majority of human clinical trials aimed at improving stroke therapy highlights Purpose: Binge drinking among adolescents is an the need for more defined and anatomically ongoing public health concern. Although binge comparable animal models of stroke. We describe drinking can also be harmful to adults, the our investigations of an alternative murine model of adolescent population is more susceptible to aberrant stroke to middle cerebral artery occlusion (MCAO) neurological changes as their brains are still which more accurately models the most common undergoing significant development. The goal of this features of human clinical stroke. We also examined project is to provide firm evidence that there are the relationship which two key forms of changes occurring to physiology in the cerebellum programmed cell death (apoptosis and necroptosis) (an area of the brain important for motor play in this in vivo model. coordination and learning) and higher cortical areas Method: Induced ischemia/reperfusion in this after repeated episodes of binge drinking. murine stroke model is produced through the Methods: Groups of adolescent (PND 26) and stereotactic microinjection of endothelin-1, a periadolescent (PND 34) rats underwent a series of vasoconstrictor normally produced during acute behavioral tests designed to assess memory, anxiety cerebral infarct, into defined regions of the cortex. regulation, and motor function. Subjects were This technique is employed in both wild-type mice exposed to either ethanol or plain air through a and those lacking caspase-3 in the presence and vapour chamber apparatus for five consecutive days absence of the RIP1 kinase inhibitor Necrostatin-1 to (two hours per day). Western blot experiments were elucidate the contribution of both apoptotic and conducted using tissue from either the cerebellum or necroptotic forms of neural injury in regions of cerebrum to examine the role of NF-kB, PKC- cortical hypofusion. gamma, and caspase-3 (proteins associated with Results: This endothelin-1 model demonstrates inflammation and cell death) in this model. reduced infarct sizes that are geometrically defined Results: Behavioral testing showed significant

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differences between the groups up to 60 days after Results: Remarkably, LKO mice were protected treatment. Both age groups displayed a similar against HFD induced weight gain compared to their susceptibility to the effects of ethanol exposure. WT counterparts, with no difference in food intake. Western blot testing indicated significantly higher HFD-fed LKO animals had significantly improved levels of the caspase-3 pro-inflammatory protein in glucose and insulin tolerance compared to HFD-fed the cerebella of ethanol exposed rats, but not in the WT animals. LKO mice also showed increased cortical tissue. NF-kB was found to be elevated in energy expenditure compared to WT animals. When both brain regions. examining lipid metabolism, we found that HFD-fed Conclusion: Behavioral testing shows that there are LKO mice had significantly lower circulating several potential long-term problems associated with plasma and liver lipid levels compared to WT HFD- adolescent binge-drinking. Differences on tests fed animals. QPCR analysis revealed that genes related to motor coordination and object memory, involved in lipogenesis (Scd1, Srebp1c, Fas and which involve the cerebellar and hippocampal brain Acc) were significantly lower in HFD-fed LKO regions respectively, indicated a persistent mice. impairment. Protein quantification indicated the Conclusion: Overall, our data show that hepatic cerebellum is more susceptible to ethanol-induced ARGLU1 is an important mediator in the inflammation than the cerebrum. These experiments development of HFD-induced metabolic dysfunction indicate the potential dangers of binge-drinking and represents a potential drug target for the while the brain is still developing and indicate the treatment of obesity and non-alcoholic fatty liver need for future studies in this area. disease.

77. Arginine and Glutamate Rich 1 Knockdown is Protective Against High-fat Diet Induced Clinical Sciences & Pharmacy Obesity and Metabolic Dysfunction Practice Lilia Magomedova1, Stephanie Schroer-McFarland2, Ricky Tsai1, Minna Woo2 and Carolyn L. Cummins1 1Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON; 2Toronto General Hospital 78. Developing and Evaluating a Patient Research Institute, University Health Network, Decision Aid for Managing Surgical Toronto, ON, Canada Menopause: The Story Behind the “SheEmpowers” Patient Decision Aid (PDA) Purpose: ARGLU1, a glucocorticoid receptor (GR) Tasneem Siyam1; Sue Ross2; NeseYuksel1 coactivator, was recently found to play an important 1 role in hepatic glucose metabolism. Transcriptome Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada; analysis of primary hepatocytes lacking ARGLU1 2 revealed that in addition to gluconeogenic genes, Faculty of medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada ARGLU1 also basally regulates a subset of genes involved in lipid homeostasis. To gain insight into whether ARGLU1 is important in lipid metabolism Purpose: To systematically develop and evaluate an in vivo, we generated liver specific ARGLU1 evidence-based patient decision aid (PDA) to help knockout animals and challenged them with a women decide on hormone therapy (HT) to manage prolonged high-fat diet feeding. symptoms of early surgical menopause and long- Methods: Wild-type (WT) and ARGLU1 liver term risks. specific knockout (LKO) mice were fed a high-fat Methods: The PDA development was guided by the diet (HFD) for 14 weeks. Body weight and food Ottawa decision support framework and involved 3 intake were monitored weekly. Glucose and insulin phases: an exploratory phase to identify women tolerance tests were performed after 12 and 13 decisional needs; a development phase to identify weeks of diet, respectively. Liver gene expression evidence related to surgical menopause and was analyzed by real time qPCR. In a separate treatment options and draft an initial prototype; and cohort of mice, metabolic cages were used to an evaluation phase to evaluate the prototype and monitor energy expenditure and locomotor activity. elicit views on acceptability and usability in a non-

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clinical setting. For exploratory and evaluation that produced a cytokine cascade leading to the phases, we recruited women from the Edmonton hypersensitive reaction. menopause clinics. We searched Medline, TRIP, Methods: A 65 year old lady was hospitalized due Dynamed, and others for evidence to inform the to hepatocellular injury. Due to the appearance of content of the PDA. Data on HT outcome deep jaundice she was hospitalized. On history probabilities were evaluated using the Grading of ingestion of Herbalife tea and protein-shake was Recommendations Assessment, Development and noted. Evaluation (GRADE). All phases were driven by a Results: Liver biopsy revealed necrotizing multidisplinary group of researchers, clinicians and granulomatous hepatitis, apoptotic cells. PAS patient partners to ensure women priorities were diastase stain was showing cluster of foamy met. macrophages with ceroid pigment, characteristic of Results: Informed by identified needs from the toxicity. The severe HILI is consistent with a exploratory phase an initial prototype of the PDA cholestatic picture.Immunohistochemistry was drafted and had 4 components: facts about demonstrated bile duct loss. A lymphocyte toxicity surgical menopause and HT; HT outcome assay (LTA) was performed. LTA (% toxicity) was: probabilities to develop realistic expectations; a protein alone 20; tea alone 44; protein+ tea 66. values clarification section to make trade-offs and Jan Feb Mar clarify values associated with HT; and a component AST U/L 1319 606 69 on guidance in decision-making. We anticipate including supplemental information on other ALT U/L 1096 679 89 reasonable treatment options for women GGT U/L 697 899 218 consideration. We are currently reviewing the tool Bilirubin Total with our stakeholders to improve content and mg/dL 3.14 8.0 0.7 presentation and gain perspectives on tailoring to The proinflammatory cytokines and chemokine women’s needs. The evaluation of the PDA is still (pg/mL) in serum were elevated as follow: TNF pending. (tumor necrosis factor alpha) 842; IL1 (interleukin) Conclusion: Through our adopted, systematic, 254; IL6-65; IL13-102; IL8-187. Vascular evidence-based and multidisciplinary approach we endothelial growth factor was 5106 pg/mL. hope to develop a PDA than can empower women Mitochondrial markers M30 and M65 revealed a with early surgical menopause when making therapy predominant level of necrosis process versus decisions and offer them the information, resources, apoptosis. Discontinuation of the Herbalife products, and skills to effectively manage decision-making and treatment with both prednisone and urso- about HT and other options. deoxycholic acid resulted in slow resolution of her complaints and in biochemistry (ALT 41 U/L and GGT 49 U/L). 79. Phytotherapy-induced Hepatocytotoxicity Conclusions: Protein and herbal tea produce

mitochondrial toxicity and a strong T-lymphocyte-1 Manuela G. Neuman, Stephen Malnick, Marina response leading to HILI. This finding is consistent Somin, Yaacov Maor, Ehud Melzer Marius Braun, with the reports of combination of protein shake and Ana Tobar. tea-induced hepatocytotoxicity. In Vitro Drug Safety and Biotechnology and Department of Pharmacology and Toxicology,

University of Toronto, Toronto, Canada; Department of Internal Medicine C and Institute of

Gastroenterology and Liver Disease, Kaplan

Medical Center, Rehovot, Israel; Institute of Liver Disease and Department of Pathology, Rabin

Medical Center, Petach Tikva, Israel

Purpose: We report a case of severe-herbal-induced liver injury (HILI) due to Herbalife tea and protein- shake. We aim to show pharmaco-toxicologic and pathology evidence implicating an immune response

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80. Modulation of the Tumor Microenvironment incubation under hypoxia. MDNPs inhibited with Manganese Dioxide Nanoparticles to macrophage-mediated cell proliferation by 23%. At Re-educate Macrophages and Enhance 4 h post-MDNP treatment, DOX accumulation in Doxorubicin Efficacy tumor tissue was the highest, by two-fold, compared to DOX alone. MDNP increased DOX penetration Ho Yin Lip1, Mohammad A. Amini1, Azhar Z. distance by up to 20-fold compared to DOX alone. Abbasi1, Ping Cai1, Claudia R. Gordijo1, Jason Li1, IHC analysis showed upregulation of M1-related Li Zhang3,4, Andrew M. Rauth2, and Xiao Yu Wu1. CD86 cells (+51%) and downregulation of M2 1Leslie Dan Faculty of Pharmacy, University of marker CD163 (-47%). Toronto, Toronto, ON; 2Departments of Medical Conclusion: This study suggests that MDNP can Biophysics and Radiation Oncology, University of modulate macrophage polarization and enhance Toronto, Toronto, ON; 3Toronto General Research DOX efficacy. Institute, University Health Network, Toronto, ON; 4Department of Laboratory Medicine and Pathobiology, Department of Immunology, 81. Identification and Evaluation of the University of Toronto, Toronto, ON, Canada Prevalence of the Practice of Drugs and Opioids Abuse in Community Pharmacy Purpose: Hallmarks of tumor microenvironment 1 1 2 (TME), including hypoxia, oxidative stress, local Masood Ahmad , Tanveer Khan , and Salman Khan 1 acidosis, and tumor-associated macrophages, Faculty of Pharmacy, Jouf University, Sakaka, 2 promotes cancer escape from immune surveillance Kingdom of Saudi Arabia; Faculty of Applied and resistance to chemotherapy. Recently, our Science and Engineering, University of Toronto, laboratory has developed pharmaceutically Toronto, Canada. acceptable polymer-lipid encapsulated manganese dioxide nanoparticles (MDNPs) which accumulate Purpose: Drug addiction is a complex brain illness in tumor tissue and simultaneously modulate characterized by obsessive drug craving, often multiple factors in the TME by attenuating hypoxia irrepressible, which persists even in the face of and oxidative stress and neutralizing acidosis. The exceptionally negative consequences. The drug aim of this study was to investigate the effect of reliance becomes chronic, with relapses possible MDNPs on alleviating immunosuppression and even after extended periods of abstinence. Addiction enhancing doxorubicin (DOX) efficacy. is a significant problem which plagues all members Method: The effect of MDNPs on DOX uptake and of society including men and women, both young cytotoxicity in EMT6 murine breast cancer cells and old. were investigated under normoxia or hypoxia. The Method: The study was conducted in various tourist effect of MDNP on macrophage-mediated cancer cities of neighboring Himalayan countries. The cell proliferation was investigated in EMT6 cell and study data was based on a questionnaire document in RAW264.7 murine macrophage co-culture. which exclusion and inclusion criteria was set. The Orthotopic breast tumors were established by survey comprised of personal information including: injecting EMT6 cells into mammary fat pad of age, gender, status, occupation, and qualifications. female immunocompetent BALB/c mice. The Moreover, the questionnaire also gathered additional optimal window of TME modulation by MDNPs to information about drug use, family, social and enhance DOX penetration into tumor tissue was financial status, and their views on the effects of determined by treating mice with systemic drug addiction on society. administration of free DOX 2, 4, or 8 hours Results: The results were analyzed using statistical following intraveneous injection of MDNPs. To methods. 94.7% of the participants were between 11 investigate effect of MDNP+DOX therapy on and 20 years old, 55% were unmarried, 57.9% macrophage polarization, tumors were resected on declared their occupation as a student, and 34.2% Day 5 and analyzed for cytokine and nitric oxide had qualifications up to primary school. Teenagers expression and stained for M1 and M2 macrophage are the ones primarily involved in drug obsession. In biomarkers. addition, considering a group of marijuana users, Results: MDNP treatment enhanced DOX uptake which comprised of 68.4% of the participants, 50% and cytotoxicity in vitro by 190% and 42% consumed a maximum dose of 1 to 5 grams. 28.9% respectively compared to DOX alone after 4 h of this group’s use of drugs stemmed from curiosity

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and 57.9% of them sourced the drugs from their associated with altered metabolism or response to friends. Furthermore, with regards to the personals certain drugs. views of addict individuals, 36.8% described it as Conclusion: Based on these results and we initially anti-social while 57.9% stated that rehabilitation and will utilize a clinically validated targeted PGx treatment should be provisioned for them. testing, but as clinical genome sequencing will be Conclusion: By facilitating good governance and integrated into daily clinical care, we are planning to education for teenagers, the imminent issue of drug use this platform as well to generate PGx data for abuse and addiction can be solved progressively. our paediatric patients. Moreover, by implementing constructive outcome ventures, we can eradicate the drug craving problem in our society and form healthy nations. However, abstinence is the safest way to live a longer and Drug Delivery and healthier life. Pharmaceutical Technology

82. Implementing Pharmacogenomics Testing in Paediatric Care 83. Are Excipients Inert? Phenytoin: A Follow- Iris Cohn1,2, Tara Paton3, Miriam Reuter3, Stephen up Half a Century Later with New Scherer3, Lianna Kyriakopoulou4, Ronald D. Cohn5, Incompatibility Insights Shinya Ito1,2,5 1Division of Clinical Pharmacology and Toxicology, Daniela Amaral Silva, Raimar Löbenberg, Neal M. Department of Paediatrics, The Hospital for Sick Davies Children; 2Program in Physiology and Experimental Faculty of Pharmacy and Pharmaceutical Sciences, Medicine, The Hospital for Sick Children; 3The University of Alberta, Edmonton, AB. Centre for Applied Genomics, The Hospital for Sick Children; 4The Department of Paediatric Laboratory Purpose: Excipients are added to aid in the Medicine, The Hospital for Sick Children; manufacturing process and enhance stability, 5Department of Paediatrics, The Hospital for Sick bioavailability, safety, effectiveness and drug Children, Toronto, ON delivery. They are generally considered safe, but they may interact with the API. The 1968 phenytoin Purpose: The Hospital for Sick Children (SickKids) intoxication outbreak in Australia, is a classic has launched the Clinical Pharmacogenetics example of an API–excipient interaction. When Research Pilot study in a collaborative setting, administered with CaSO4 the absorption of which is available for ambulatory and inpatient phenytoin was reduced. When CaSO4 was replaced consultations within SickKids. The overall goal of by lactose, drug absorption was increased, resulting the pilot project is to serve as a test-bed to influence in the observed intoxication. It was hypothesized the design to plan for a future PGx service, that phenytoin was converted to a poorly soluble examining the clinical utility and feasibility of calcium salt. The purpose of this study was to implementing such a test into routine paediatric care. mechanistically investigate the interactions between Methods: We have previously demonstrated that excipients and phenytoin and to re-examine the genome sequencing technologies show high hypothesis and interpretation of the previous reports. correlation to targeted PGx testing panels in a Methods: Titration experiments with phenytoin, paediatric population. Furthermore, as part of the calcium salts and lactose were performed. NMR was Human Genome Project Canada, a set of 391 used to characterize the compounds. Isothermal variants associated with 14 pharmacogenes with micro calorimetry determined incompatibilities known drug- gene interactions were analyzed. between phenytoin - excipients and phenytoin-milk. Results: Most of the children tested had at least one Dissolution tests containing CaSO4, lactose or clinically actionable PGx variant, indicating that sorbitol as excipients were also performed. diagnostic genomic sequencing data can be used for Results: Calorimeter results indicate that phenytoin pre-emptive PGx screening. Moreover, each sodium interacts with CaSO4 in aqueous media participant in the Human Genome Project carried an forming a compound with low solubility, reducing average of 4 clinically relevant PGx variants the amount of dissolved drug available for

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absorption. Phenytoin sodium also interacts with transcripts (NAT’s) and upregulate endogenous lactose through a Maillard reaction that can occur at BDNF levels in the brain. body temperature. The dissolution profile show a Methods: In vitro uptake and transfection studies of higher release rate from the sorbitol containing Cy5-labeled AT and BDNF AT in saline and compared to calcium or lactose containing cationic liposomes were carried out in RT4-D6P2T formulations. In Canada and the USA, the reference rat schwannoma cells. Transfection efficiency was product contains lactose as an excipient, whereas the evaluated qualitatively by confocal microscopy and Canadian generic formulations do not contain quantitatively by qPCR and ELISA. In vivo, lactose. transnasal mucosal delivery of AT’s was achieved in Conclusion: Phenytoin is commercially available Sprague Dawley rat model by creating a surgical since 1938, much has been learned about API window in the BBB, which is repaired using nasal excipient interactions with this drug. After eighty mucosal grafts from donor rat. The graft was years of clinical use a new incompatibility between positioned on the craniotomy creating an internal phenytoin sodium and lactose was discovered and an reservoir directly above the graft. Upon instillation incompatibility with calcium was confirmed. This of Cy5-labeled and BDNF AT in saline and cationic might have important implications for a possible liposomal formulations, uptake and BDNF food effect with milk. expression levels in different parts of brain were carried out qualitatively by fluorescence microscopy and quantitatively by ELISA. 100 Results: The in vitro and in vivo uptake studies using confocal microscopy showed that cationic liposomal formulations resulted in better

50Diss.

% uptake compared to controls. The in vitro transfection in BDNF AT liposomes treated cells 0 resulted in significant increase in BDNF mRNA and 0 10203040Time (min) protein levels as compared to the controls. The in Figure 1. Dissolution profiles obtained for capsules vivo transfection study with BDNF AT in saline and containing phenytoin sodium with lactose (dashed liposomes resulted in four- and five-fold increase in line), phenytoin sodium with CaSO4 (solid line) and BDNF levels in substantia nigra, respectively, as phenytoin with sorbitol (dotted line) in water. compared to negative control. Conclusion: The results show that the novel trans- nasal mucosal delivery and liposomal delivery can 84. Transnasal Mucosal Delivery of Brain- help in transporting large molecular weight disease Derived Neurotrophic Factor AntagoNATs modifying therapies, such as BDNF AT’s, in in Rat Brain using Cationic Liposomal treatment of chronic neurodegenerative diseases. Formulation

1 1 2 Grishma Pawar , Neha Parayath , Benjamin Bleier , 85. Engineering Functionalized Diamond 1 and Mansoor Amiji . Nanoparticles for Drug/Gene Delivery: 1 Department of Pharmaceutical Sciences, School of Biodistribution Studies Pharmacy, Northeastern University, Boston, MA 2 and Massachusetts Eye and Ear Infirmary, Harvard Raj Rai, Saniya Alwani, Ed Krol, Humphrey Fonge Medical School, Boston, MA and Ildiko Badea. College of Pharmacy and Nutrition, University of Purpose: Brain-derived neurotropic factor (BDNF) Saskatchewan, Saskatoon, SK Canada. (14 kDa) has important therapeutic implications in chronic neurodegenerative diseases. Delivering Purpose: To engineer lysine-functionalized biological therapeutics, like BDNF protein across nanodiamonds (lysyl-NDs) as biocompatible and the blood-brain barrier (BBB) is one of the biggest efficient gene carriers. Optimization of the design challenges today. The main objective of this study was carried out by grafting histidine as an was to develop a trans-nasal mucosal approach for endosomal membrane destabilizer onto the lysyl- delivering BDNF specific AntagoNAT’s (AT’s) NDs (lysyl-histidyl-ND). However, their specific (oligonucleotides) that inhibit natural antisense interactions with the biological system are yet to be

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defined. Biodistribution studies will help to elucidate 86. Additive Polyplexes as a Non-viral Delivery their fate at organ levels and monitor their System for Combinational siRNA Therapy pharmacokinetics. A suitable chelating agent against CDC20 and Survivin in Breast (defroxamine, DFO) was attached to the Cancer and Non-malignant Cells functionalized NDs to assist with radio labelling with 89Zr to study the biodistribution in animal Manoj B. Parmar a, Raimar Löbenberga, Hasan models. Uludag a,b,c Method: 1HNMR was used to confirm synthesis of aFaculty of Pharmacy & Pharmaceutical Sciences, amino acid conjugates at all steps. The lys-NDs were U. of Alberta; bDepartment of Chemical & Materials characterized by size and zeta potential Engineering, Faculty of Engineering, U. of Alberta; measurements and thermogravimetric analysis. NDs cDepartment of Biomedical Engineering, Faculty of tagged with DFO moieties will be labeled with 89Zr Medicine & Dentistry, University of Alberta, for positron emission tomography in animal models. Edmonton, AB, Canada Results: Several batches of lys-NDs revealed a surface loading of 1.67 mmoles/gm of ND. The Purpose: Conventional breast cancer therapies such average particle size was 66 nm and zeta potential of as surgery, radiation and chemotherapy have +21 mV, showing consistency in all batches and inherent limitations and side effects that warrant a validating the reproducibility of the designed search for alternative therapies, and RNA protocol. 1HNMR revealed that the tagged NDs interference based on small interfering RNA show all DFO protons of the aliphatic chain along (siRNA) seems to be a promising approach. We with 4 protons of the benzene ring in the aromatic have developed a library of cationic polymers based region, confirming the DFO-lysine-linker on 1.2 kDa polyethylenimine (PEI) to transport conjugation. Similarly, lysyl-histidine chemical siRNA safely. In this study, we introduced additive moiety was synthesized and confirmed using polymers such as hyaluronic acid (HA), polyacrylic 1HNMR through characteristic peaks at δ 7.34, δ acid (PA), dextran sulfate (DS) and methyl cellulose 7.45 (t, 2H, imidazole side chain) as well as presence (MC) while making siRNA/PEI complexes to of 3 Boc protecting groups at δ 1.4 (s 27H). increase the efficacy of siRNA. Conclusion: This study establishes that lysyl- and Methods and Results: We prepared additive lysyl-histidine functionalized NDs, as potential polyplexes by first mixing siRNA and additive carriers for gene therapy, can be labeled with polymers followed by addition of PEI substituted radiotracers for assessment of biodistribution and with linoleic acid (PEI-LA). The physicochemical pharmacokinetic analyses. Understanding the in vivo characteristics of these polyplexes suggested similar behavior of the functionalized NDs is critical for size among different additive polymers, while zeta their translation from benchtop to clinical potential has decreased drastically with negatively- applications. charged additive polymers. A faster dissociation of O O complexes was evident with negatively-charged O N O additive polymers. The uptake of complexes NH N O NH determined by flow cytometry and confocal NH O O microscopy suggested higher uptake of siRNA with O NH additive polyplexes compared to regular siRNA/PEI

NH complexes. Combinational siRNAs against CDC20 O O and survivin were delivered in breast cancer cells, MDA-MB-231, SUM149PT, MDA-MB-436 and MCF7, and additive polyplexes with HA and PA

Bis boc histidine-mono boc were the most successful complexes with >40% of lysine-fmoc diaaminopropane Chemical Formula: C H N O cell growth inhibition. The cell growth of non- 45 63 7 10 Molecular Weight: 862.02 malignant cells, MCF10A and HUVEC were inhibited to some extent, while hBMSC and HEK293T were the least affected by the combinational siRNA therapy. Conclusions: A better dissociation of polyplexes with negatively-charged additive polymers, HA, PA and DS resulted into higher cell growth inhibition

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compared to without or neutral (MC) additive capsule (0.62± 0.09 µg/ml) and drug suspension polymer. Even though the combinational siRNA (0.13± 0.07 µg/ml). therapy showed improved therapeutic efficacy in Conclusion: The nano-sized droplets of the self- breast cancer cells, the side effects on nonmalignant emulsifying system was found to be able to increase cells were evident as well, and more selective targets the oral bioavailability of the BCS Class IV might be needed to minimize the side effects. chemotherapeutic agent etoposide up to 10.4-fold by enhancing the dissolution and absorption of the drug. 87. Nano-sized Droplets of Self-Emulsifying System for Enhancing Oral Bioavailability of Etoposide in Rats 88. Microwave Enhanced Protein Folding

Nayab Khalid1,2, Muhammad Sarfraz3,4, Mosab Ahlem Meziadi1, Marc A. Gauthier1 Arafat3, Muhammad Akhtar2, Nisar-Ur-Rahman1,2, 1Institut National de la recherche scientifique- Raimar Löbenberg4. Énergie Matériaux et Télécommunications 1Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad, Pakistan; Purpose: The refolding process is a competing 2Faculty of Pharmacy and Alternative Medicine, The reaction with misfolding and aggregation events. It’s Islamia University of Bahawalpur, Pakistan; guided by reversible electrostatic interaction and 3College of Pharmacy, Al Ain University of Science exchangeable disulfide bonds. Once protein folding and Technology, Al Ain, UAE; 4Faculty of is initiated from its unfolded state, it is a very rapid Pharmacy and Pharmaceutical Sciences, University process and can get stuck along the way into kinetic of Alberta, Edmonton, Canada. traps. In these traps, molecular dynamics are too slow or movement is blocked by entanglements, Purpose: This study was carried on to investigate preventing further evolution to the the ability of self- nano-emulsifying system to thermodynamically most stable structure. In this enhance the oral bioavailability of Etoposide. work we examined whether microwave irradiation Method: A series of self-emulsifying system can replace the need for chaperones promoting the formulations with etoposide were prepared reversibility of electrostatic interactions and also consisting of medium chain triglycerides, accelerate the disulfide isomerization process. Polysorbate 80, diethylene glycol mono-ethyl ether Method: Ribonuclease A (RNase A) was chosen as and propylene glycol monolaurate. Test formulation a model due to its peculiar catalytic activity that can was characterized in terms of globule size, zeta be exclusively observed if the folding is successfully potential, PDI, TEM images and in vitro drug release achieved, which allows monitoring of the kinetics of profile was evaluated in comparison with a drug refolding. We started by optimizing the enzymatic suspension and the commercial product VePesid® in assay of the native RNase A, then a first screen was simulated intestinal fluid medium, pH 6.8. The PK done by exposing the RNase A to a microwave with parameters and oral bioavailability of etoposide an integrated cooling system for 30 min at different suspension and etoposide in the self-nano- power while the temperature was kept constant. emulsifying system was assessed and compared with Successively, solutions of misfolded enzyme will be the commercial product (VePesid® capsule) using 30 exposed to different power levels and temperatures Male Sprague–Dawley rats. Blood samples were to determine whether folding can be, at least collected for up to 24 h, and VP-16 analyzed using a partially, reactivated due to stimulated molecular validated HPLC assay. dynamics. Results: Pharmacokinetics data showed that the Results: The catalytic activity of the ribonuclease A mean values for AUC of etoposide in nano-sized was not affected by microwave exposure. Our droplets of the self-emulsifying system was found to hypothesis is that the simultaneous cooling was be 6.4 folds higher than drug suspension and 2.4- responsible for avoiding damage to the enzyme. The folds higher compared to the commercial products targeted result is to establish microwave irradiation VePesid® capsule. Similarly, the mean values for and additive conditions to achieve high conversion Cmax of etoposide in nano-sized droplets of self- to the desired folded structure while maintaining the emulsifying system was found to be higher (1.13± biological activity of the enzyme. 0.07 µg/ml µg.h/ml) compared to the VePesid® Conclusion: The microwave irradiation at fixed

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temperature exhibited promising results as a new treated groups have significantly higher neuronal tool for enhancing the refolding process without the count than the control group. need of chaperones. Conclusion: The acquired results suggested the Acknowledgments: This study is supported by the suitability of formulations for brain delivery of their Natural Science and Engineering Council of Canada laden drug, their potential in improving the (RGPIN-2015-04254) cognition and preserving the hippocampus’ neurons of experimented animals. On the other hand, the functionalized SLNs could reduce the required 89. Phenylbutyrate Loaded Solid Lipid administration times and doses. Nanoparticles could Improve Cognition in Alzheimer’s Disease Induced Animal Model 90. Precise Orientation of Thermally-sensitive Molood Vakilinezhad, Shima Tanha, Hamid Akbari Biomolecules using DNA Nanostructures: Javar An Exploration of Non-thermal Techniques Department of Pharmaceutics, Faculty of Pharmacy, for Controlling DNA Nanoassemblies Tehran University of Medical Sciences, Tehran, Iran Andrea A. Greschner, X. Ropagnol, M. Kort, N. Purpose: Phenylbutyrate, a histone deacetylase Zuberi, J. Perreault, L. Razzari, T. Ozaki, M. A. inhibitor, considered to be effective in halting the Gauthier progression of Alzheimer’s disease by reducing Institut National de la Recherche Scientifique hyperphosphorylation of tau protein, preserving (INRS), EMT Research Center, Varennes, QC, neuronal cell density and preventing the formation Canada; Université Pierre et Marie Curie (UPMC), of intraneuronal A . To act efficiently, considerably Paris, France; Institut National de la Rechercher large dose of phenylbutyrate should be Scientifique (INRS), Institut Armand Frappier, administrated. Designing a sustained delivery Laval, QC, Canada system is a promising way to reduce the administration times. Considering the characteristics Purpose: The commercialization of synthetic DNA of various delivery systems, solid lipid nanoparticles strands has led to exquisite control over sequence (SLNs) were seemed suitable for such purpose. This design. With the predictability of the A-T, C-G study aimed to evaluate the biodistribution and DNA alphabet, many researchers have begun to effectiveness of the phenylbutyrate loaded design DNA nanostructures to precisely position functionalized SLNs. functional groups in 2D and 3D environments. This Method: Herein the phenylbutyrate loaded SLNs approach has been successful in positioning small were prepared and functionalized with molecules, fluorophores, polymers, etc. However, polysorbate80 (S80) or phosphatidylserine (PS) for many opportunities remain in the field of proper brain delivery. The effect of these delivery biomolecules, where enzymes, antibodies, and systems on memory-related behavioral of Alzheimer proteins could be arranged to create novel classes of induced animals (intracerebroventricular drugs. To date, such biomolecule-DNA streptozotocin injected model) were studied using nanoassemblies have been limited due to the high Morris water maze test. Their biodistribution in heat required to assemble DNA structures. Here, we brain were evaluated by DiR-fluorescent marker. pursue the use of non-ionizing radiation to control The hippocampal neurons were counted using the DNA assembly at room temperature. Cresyl violet staining. Method: Two sources of non-ionization radiation Results: The particle sizes of 154, 179 and 161nm were used: a THz pulse and a cooled microwave were acquired for non-functionalized, S80- reactor. Three different DNA nanostructures were functionalized and PS-functionalized SLNs, screened for both assembly and disassembly. A respectively. The significant improvement of variety of biomolecules (enzymes, antibodies, etc) memory-related behavioral had observed in animals were exposed to identical assembly/disassembly treated with functionalized SLN comparing to other conditions, and their activity evaluated following groups. Their higher brain concentration, in exposure. As a final test, a biomolecule was comparison to the non-functionalized SLNs, conjugated to one of the DNA strands required for suggested the efficacy of functionalization. In the nanostructure, and structure assembly and histopathological studies, the functionalized SLNs activity was evaluated.

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Results: Room-temperature microwave anneal was incorporate a large variety of molecules. Diffusion in found to produce the desired thermodynamic the donor compartments of caffeine through the structure with 82±8% yield (compared to ~30% Strat-M® was 1,7 times faster and 3 times higher for yield when no anneal was used). Exposure to THz the BMVTM system than the caffeine in solution. rapidly disassembled structures. Of the six After the wash out, 35% of the total diffused dose biomolecules tested, 5 retained 100% activity was recovered in the acceptor compartments following the microwave assembly. The sixth saw a between 8 and 24 hours suggesting a reservoir 25% reduction in activity. Assembly of a effect. The same diffusion rate and tank effect was nanostructure using a thermally-sensitive observed on human skin biopsies. biomolecule-DNA conjugate was successful. Conclusion: Strat-M® can be used as a non-animal Conclusion: We were able to both assemble and model to predict the permeability of BMVTM. disassemble DNA nanostructures using novel, Microparticles can be used to improve the skin biomolecule-friendly techniques. More importantly, diffusion of molecules and promote a reservoir we were able to assembly a biomolecule-labeled effect. Further studies with different molecules and nanostructure without denaturing the biomolecule – formulations are ongoing. something that would not be possible using traditional thermal assembly. 92. Photocleavable Hydrogel-Coated Upconverting Nanoparticles for On-Demand 91. Biomimetic Vector (BMVTM): An Innovative Drug Delivery of Ultra-small Gold- Skin Delivery System Doxorubicin Conjugates

Marie-Eve Leclaire, Katia Trudeau, Pierre Simard, Vivienne Tam1, Artiom Skripka2, Jalani Ghulam1, Marie-Hélène Dufresne, Karine Théberge Fiorenzo Vetrone2, Marta Cerruti1 Biomod concepts Inc., Sainte-Julie, Canada 1McGill University, Quebec, Canada; 2INRS, Quebec, Canada; Purpose: BMVTM is a proprietary delivery microsystem developed and patented by Biomod. It Purpose: Light-triggered drug delivery offers is composed of biomimetic ingredients and allows precise control of the dosage, timing and location of the incorporation, the protection and the transport of drug release in a non-invasive manner. However, the actives through the stratum corneum and deeper typical wavelengths used for photoreactions are in layers of the skin. The goal is to demonstrate that the ultraviolet (UV) or visible (Vis) range and have BMVTM improve the skin delivery of actives. limited penetration in biological tissues. Near- Methods: BMVTM microparticles were infrared light (NIR) can penetrate deep into living characterized: the size and the morphology were tissues, has a low autofluorescence background and visualized by optical microscopy, encapsulation of is non phototoxic. Lanthanide-based upconversion actives was demonstrated by laser scanning confocal nanoparticles (UCNPs) can absorb NIR light and re- microscopy, and active content was measured by emit the UV-vis light required for the photoreactions HPLC-UV. Caffeine was used as a model molecule to trigger drug release. Furthermore, ultra-small to study skin delivery. In vitro permeability assays gold-doxorubicin (Dox) conjugates have higher on Franz cells with Strat-M® membranes were cytotoxicity to apoptosis-resistant melanoma cells conducted to compare the diffusion of caffeine in than Dox alone. This research develops a solution (n=6) and loaded in the BMVTM technology photocleavable hydrogel coating on UCNPs for on- (n=3). Wash out of the donor compartments was demand delivery of such conjugates upon NIR performed at 8 hours to evaluate the reservoir effect radiation. of the microsystem. A comparable permeability Methods: LiYF4:Tm,Yb UCNPs were synthesized study was performed on human skin biopsies and coated with a hydrogel of nitrobenzyl assembly on Franz cells. photocleavable crosslinks. Doxorubicin was Results: The caffeine-loaded microparticles size conjugated to gold nanoparticles and loaded into the ranged from 2-15 m and are spherical. Coumarin-6 hydrogel. Its release was measured during either on (lipophilic) and Rhodamine-B (hydrophilic) were (1 min) or off (50 min) states of an NIR laser at 1.8 successfully loaded in the microparticles W/cm2. Drug release curves were then quantified. demonstrating the potential of the BMVTM to Results: As expected, the gold-Dox conjugates were

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released from the photocleavable hydrogel upon NIR measured. The efficacy of thermosensitive cisplatin radiation. The rate of drug release can be tuned via liposomes, non-thermosensitive cisplatin liposomes, laser power and irradiation time. or free cisplatin alone or in combination with Conclusions: Chemotherapeutic drugs can be hyperthermia was assessed in two orthotopic models released on-demand via NIR radiation from of triple-negative breast cancer. photocleavable hydrogel-coated UCNPs, thus Results: Hyperthermia-triggered drug delivery offering greater control over dosage, timing and significantly increased drug concentrations within location of chemotherapy drug release at tumor site. the tumor, while hyperthermia degraded BRCA1 and increased CDDP sensitivity of breast cancer cells. In both tumour models, thermosensitive cisplatin 93. Hyperthermia-mediated Drug Delivery liposomes in combination with hyperthermia Increases Cisplatin Sensitivity and provided the longest median survival times. Accumulation Resulting in Improved Conclusion: Cisplatin-containing thermosensitive Efficacy in Triple Negative Breast Cancer liposomes provided the longest median survival times in mice bearing tumors sensitive to cisplatin. 1 1 Michael Dunne , Yannan N. Dou , Danielle M. However, it was in mice with tumors less sensitive 1 1 2 Drake , Tara Spence , Sávio M.L. Gontijo , Peter G. to cisplatin that the combined effects of increased 1,3 1,4 Wells , Christine Allen tumor accumulation of cisplatin and impaired DNA 1 Leslie Dan Faculty of Pharmacy, University of damage repair mechanisms resulted in the greatest 2 Toronto, Toronto, Ontario, Canada; Faculty of increase in median survival for thermosensitive Dentistry, Universidade Federal de Minas Gerais, cisplatin liposome treatment compared to cisplatin 3 Belo Horizonte, Brazil; Department of alone. Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; 4Department of Chemical Engineering and Applied Chemistry, 94. Liposomal Delivery of a Doxorubicin and University of Toronto, Toronto, Ontario, Canada Niraparib combination for the treatment of High Grade Serous Ovarian Cancer Purpose: Triple-negative breast cancer accounts for more 15% of breast cancer diagnoses and an even Lucy Wang, James C. Evans, Christine Allen higher percentage of breast cancer-related morbidity. University of Toronto, Leslie Dan Faculty of However, triple-negative breast cancer patients do Pharmacy, Toronto, ON not benefit from recently developed targeted therapies and therefore novel treatments must be Purpose: Results from clinical trials investigating sought. Hyperthermia has shown promise in the safety and efficacy of PARP inhibitors (PARPi) sensitizing breast cancers to chemotherapy and in combination with PEGylated liposomal improving patient outcomes. The main goal of this doxorubicin (PLD) for the treatment of ovarian work is to assess the efficacy of hyperthermia- cancer (OC) have yielded promising results. triggered release of cisplatin from thermosensitive Consequently, the aim of this study was to liposomes and to relate the in vivo efficacy to in investigate the synergistic potential between vitro measures of toxicity. niraparib (NIR) and doxorubicin (DOX) at specific Methods: The in vitro sensitivity to hyperthermia, molar ratios. Following this, we aimed to formulate cisplatin, and the combination of the two these drugs into a liposomal nanoparticle. interventions was measured using monolayer cell Methods: A panel of five OC cell lines were viability assay, clonogenic assay, and multicellular selected to assess the effect of the DOX:NIR tumour spheroid assay. In vitro molecular biological combination. IC50 values were obtained for 11 response to hyperthermia was determined by DOX:NIR molar ratios and used to calculate the measuring heat shock protein mRNA expression combination index (CI) values as described by Chou using quantitative PCR and expression of BRCA1, and Talalay. NIR liposomes were synthesized via an important DNA damage repair protein, by ethanol emulsion followed by extrusion. Particle size western blot analysis. In vivo biological response to was measured using DLS and loading was hyperthermia was measured by determined using HPLC. In vitro release studies immunohistochemical staining of heat shock were performed under sink conditions with proteins. Tumour accumulation of cisplatin was also 50mg/mL BSA.

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Results: DOX:NIR was found to be synergistic at substituted Zn Ferrite particles. TEM micrograph of ratios of excess NIR and antagonistic at ratios of Gd-Zn-Fe nanoparticles showed a dispersion of excess DOX across all 5 cell lines. NIR-loaded spherical particles with a narrow size distribution, liposomes were 131.9  31.24 nm in size, with the with mean diameter of 5.5 ± 0.9 nm. The average concentration of encapsulated NIR being nanoparticles systems developed generated sufficient 2.39mg/mL. Release of NIR was sustained over a 5- heat and stopped heating at the measured Tc, which day period, with approximately 25% of drug is modulated by the fraction of the composition. The released. measured R1 and R2 values at different Conclusion: The results of this study have shown concentrations showed linear increase of the that DOX:NIR are synergistic at ratios where NIR is relaxation rate. The increase of r2 with temperature in excess. We hypothesize that this effect will also was relatively large and linear; while the increase in be seen in vivo if DOX:NIR are delivered to the r1 was small and exhibits poor linearity. tumor site at a synergistic ratio. As demonstrated Conclusion: The synthesized HMNs have the with the recent approval of Vyxeos, nanoparticles intrinsic ability to self-regulate their heating level to can deliver synergistic drug combinations to the the desired therapeutic range. The temperature of tumor site to yield a superior in vivo response. The HMN that have Tc in the therapeutic range will rise next steps of this study is to formulate a dual- only up to the Tc when the particles are subjected to encapsulated liposome of DOX:NIR at a fixed an oscillating magnetic field, and further increasing synergistic ratio and to assess efficacy in a relevant the intensity of the field will not increase heating bioluminescent model of HGSOC. beyond their Tc.

95. Stimuli-sensitive Theranostic Nanoparticles 96. Optimization of a New pH-Responsive Pore for Targeted Imaging-Guided Drug Delivery Former for Controlled Release Coating

1 1 1 Ousama Rachid1, Yousef Haik2, Reza Abdi3 Hao Han Chang , Kuan Chen , Alireza Shalviri , 1 2 1 1Qatar University, 2Hamada Bin Khalifa University, Jason Li , Anil Kane , and Xiao Yu Wu 1 3Harvard Medical School Leslie Dan Faculty of Pharmacy, University of Toronto, ON; 2Patheon Inc., Toronto Region Purpose: The existing delivery systems for insulin Operations (TRO), Mississauga, ON, Canada all suffer from inability to regulate insulin without patient intervention. Targeted drug carriers using Purpose: Many drugs exhibit pH-dependent polymeric nanoparticles holds particular promise to solubility and varying absorption along the GI tract, enhance the delivery of immunoregulatory agents to which may result in unexpected toxicity and reduced treat type 1 diabetes (T1D). The aim of this study efficacy. One approach to ameliorate this problem is was to synthesize and characterize stimuli- to utilize pH-responsive permeability modifiers (i.e. responsive, thermosensitive, immunoregulatory- pore formers) to compensate changes in drug bearing carriers for potential use in image-guided solubility. Previously, we demonstrated that pH- targeted delivery and on site controlled release of sensitive nanoparticles in ethylcellulose film could nanocongugates. provide pH-responsive drug release while mitigating Methods: Hyperthermia magnetic nanoparticles major drawbacks of conventional pore formers, (HMNs) made out of Gd-Zn-Fe were synthesized including high viscosity of the coating suspension with self-controlled Curie temperature (Tc) in the and leaching from the coating. In this work, we aim range of 39-40oC, using co-precipitation method. to optimize the composition of the nanoparticles to The characterization data of the Gd-substituted Zn maximize the pH-responsiveness and mechanical Ferrite particles with that of the Zn Ferrite particles strength while minimizing the leaching. were compared. Transmission electron microscopy Methods: The nanoparticles were synthesized by a (TEM) of Gd-Zn-Fe nanoparticles was evaluated. one-pot polymerization method with various molar The magnetic resonance imaging (MRI) relaxivities ratios of polysorbate 80 (PS80) and polymethacrylic of the HMNs were measured in the temperature acid (PMAA) grafted onto starch and cross-linking range 25-45oC. agent (MBA). A central composite design (CCD) Results: Addition of Gd in small amounts led to was used to optimize the MAA, MBA, and PS80 modulate Tc linearly with the amount of Gd- ratios in the feed. The experiments were performed

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based on a full 23 factorial design with six center withdrawn samples were appropriately diluted and point replicates and six axial points. The effects of calculated at different time points 30 min, 1, 2, 4, pH-responsive permeability, tensile strength, and and 6hrs using HPLC. leaching of the composite membranes were Result: The preliminary result of in vitro study evaluated using side-bi-side diffusion cells, tensile indicated that the foamable microemulsion system testing, and weight loss study, respectively. might be a candidate carrier for transdermal delivery Statistical analysis were conducted using JMP10 of Methimazole. Percentage release through software. hydrophobic synthetic membranes into the receptor Results: A response surface was constructed using a media were found to be 56.2%, 68.1%, 72.6% for CCD which the optimal composition was found and the following concentrations 0.25%, 0.5%, 1% verified with further experiments. From the analysis, respectively. the pH-responsiveness was found to be dependent on Conclusion: The microemulsion system appears to MAA and MBA ratio, tensile strength was be one of the promising tools for percutaneous dependent on MBA and its interaction with PS80, delivery of Methimazole. The release profiles and weight loss was dependent on MBA only. obtained from in vitro permeability tests might be Conclusion: Significant factors of each response used for predicting the in vivo permeability of the were found, and the optimized composite membrane formulation. Findings from the current research showed the most desirable pH-responsiveness and work suggested that the developed Methimazole tensile strength with minimum leaching. The loaded ME-based system might be potential vehicle influence of the optimized nanoparticle pore former for enhancing the topical penetration of on pH-dependent drug release profile will be further Methimazole. investigated using spray-coated bead formulation.

98. Affinity Based Release of Protein 97. Microemulsion-based System for Therapeutics to Treat Retinitis Pigmentosa Transdermal Drug Delivery of Methimazole in Cats Carter Teal1, Vianney Delplace2, Malgosia Pakulska2, Arturo Ortin-Martinez4, Samuel En-Leh Areej Alshikhey, Raimar Löbenberg, Michael Tsai3, Valerie Wallace3,4,5, Molly S. Shoichet1,2 Doschak 1Institute of Biomaterials and Biomedical Faculty of Pharmacy and Pharmaceutical Sciences, Engineering, University of Toronto, Toronto, ON; University of Alberta, Edmonton, AB 2Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON; Purpose: Hyperthyroidism is one of the most 3Department of Laboratory Medicine and common feline endocrine disorders due to excess Pathobiology, University of Toronto, Toronto, ON; production of active thyroid hormone in middle-aged 4Donald K. Johnson Eye Institute, Krembil Research cats. The management involves oral or transdermal Institute, University Health Network, Toronto, ON; antithyroid drug delivery. The use of transdermal 5Department of Ophthalmology and Vision Sciences, medications in cats has become popular in veterinary University of Toronto, Toronto, ON, Canada medicine due to the ease of administration compared to oral medications. Our hypothesis is that Purpose: Retinitis pigmentosa (RP) is a genetic microemulsion-based system can improve the in disease that causes rod photoreceptor degeneration, vitro flux of Methimazole using a Franz cell model. subsequently leading to the loss of cone Method: Different concentrations of 0.25%, 0.5%, photoreceptor cells, causing blindness. Ciliary and 1% of Methimazole were incorporated into neurotrophic factor (CNTF) and rod-derived cone Labrafac-based microemulsion formulations with viability factor (RdCVF) have the potential to treat Labrasol as surfactant and Plurol Oleique as patients affected by RP. However, topical cosurfactant to be used for transdermal delivery of applications and bolus injections of therapeutics may Methimazole. The in vitro studies were carried out be limited by drug clearance and overdose, using Franz cell apparatus with a diffusional surface respectively. To mitigate these risks, we developed area of 1.79 cm2 and synthetic membranes. Purified an affinity-based system for sustained protein water was used as the receptor fluid and the delivery. Specifically, an injectable physical blend of temperature maintained at 32 ± 0.5°C. The hyaluronan and methylcellulose was modified with a

140s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

peptide binding partner of the Src homology 3 (SH3) bioavailability of water-insoluble drugs, since domain allowing the controlled release of SH3- amorphous drug shows faster dissolution than its containing fusion proteins. crystalline counterpart due to higher free energy. Methods: The SH3 binding peptide was However, amorphous drugs tend to recrystallize in immobilized onto thiol-modified methylcellulose. SPD with time, negating the desired enhancement on The SH3-CNTF and SH3-RdCVF fusion proteins dissolution. It is also challenging to evaluate drug- were separately purified from E. coli. Using ELISA, phospholipid miscibility although various techniques the release of SH3-CNTF was investigated in vitro. have been used for this purpose. Therefore, the A TF1-α cell proliferation assay was performed to objective of this study was to investigate the evaluate bioactivity SH3-CNTF. Finally, both in feasibility of using fluorescence-based techniques to vivo bioactivity and controlled release of SH3-CNTF assess the drug-phospholipid miscibility, and to were evaluated in wildtype mice. probe the correlation between miscibility and Results: Purified CNTF-SH3 and RdCVF-SH3 physical stability. were verified using mass spectrometry. Maleimide- Methods: Autofluorescent indomethacin- functionalized SH3-binding peptides were grafted phospholipid (IDM-PL) thin films were prepared by onto the gel, and in vitro investigations drop casting method. The miscibility was demonstrated sustained SH3-CNTF release over 10 characterized by infrared (IR) spectroscopy, days. Furthermore, released samples maintained fluorescence spectroscopy and fluorescence bioactivity (≥ 75%) in vitro. In vivo, the intravitreal microscopy. The physical stability of IDM-PL stored sustained delivery of SH3-CNTF showed the at 40Ԩ was evaluated by fluorescence imaging and expected downregulation of visual cycle genes, correlated with the initial state of IDM-PL as demonstrating effective release and bioactivity. revealed by different spectra. Finally, morphology of the retina after 7 days Results: Doublet emission peaks were observed in confirmed the bioinertness of the vehicle. the fluorescence spectra of high drug-loading Conclusions: Our affinity-based system constitutes samples, suggesting the existence of two local a new intraocular delivery platform for the treatment polarity environments. Amorphous-amorphous of retinal degenerative diseases, and has prompted us separation and amorphous-crystalline transformation to apply this strategy to other therapeutics in the with storage time were visualized by fluorescence future. imaging using a monotonic method. The Acknowledgments: We are grateful to the Canada experimentally determined drug loading limit of First Research Excellence Fund of Medicine by IDM-PL system was 30%, above which amorphous- Design (to VW and MSS) and the NSERC CREATE amorphous separation was thermodynamically in M3 (to CT) for funding. favored, leading to the recrystallization of IDM in the drug-rich phase due to the loss of crystal inhibition effect rendered by phospholipid. The results showed good correspondence to IR, and Pharmaceutical and Analytical further confirmed the phase transformation suggested by such conventional techniques. Chemistry Conclusion: Fluorescence techniques were successfully used to evaluate drug-phospholipid miscibility for the first time. The miscibility and physical stability of IDM-PL system were 99. Investigating the Correlation between determined, visualized and correlated in this study. Miscibility and Physical Stability of Solid Fluorescence techniques show promise in evaluating Phospholipid Dispersions Using the interactions between autofluorescent drugs and Fluorescence-Based Techniques phospholipids, aiming to build robust SPDs that are

resistant to recrystallization during storage. Jiahao Huang and Shawn Wettig.

School of Pharmacy, University of Waterloo, Waterloo, Ontario Canada

Purpose: Amorphous solid phospholipid dispersion (SPD) has been widely used to enhance the

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100. Use of Confocal Fluorescence Imaging 101. Investigation into the Factors Associated Techniques to Understand Phase Separation with Anesthetic Failure of Hyperbaric Behaviour during Dissolution of Amorphous Bupivacaine, including the Potential Role of Solid Dispersions Cold Exposure on Bupivacaine Degradation

Yi Rang Han and Ping I. Lee Ellen Wasan1, Calen Sacevich2, Munawar Leslie Dan Faculty of Pharmacy, University of Mohammed1, Jaweria Syeda1, Erin Neville1, Tatiana Toronto, Toronto, Canada Orlowski1, Anas El-Aneed1, David Campbell2, Jonathan Gamble2 1College of Pharmacy and Purpose: For amorphous solid dispersions (ASDs) Nutrition, University of Saskatchewan, Saskatoon, to be effective, it should be stable not only during SK 2Dept. of Anesthesiology, College of Medicine, storage but also during dissolution. Ideally, one University of Saskatchewan and Royal University would want to maintain its high energy state in order Hospital, Saskatoon, SK to generate supersaturation during dissolution. Unfortunately, when highly water soluble polymers Purpose Hyperbaric bupivacaine (0.75% in are used as carriers for the formulation of ASDs, dextrose) is commonly used for spinal anesthesia in significant moisture absorption leads to moisture obstetrics. Occasional clusters of anesthetic failures induced phase separation. The aim of this study is to occur in this setting, not readily attributable to understand moisture induced phase separation for clinical factors. We hypothesized that exposure to different drug loadings through confocal cold temperatures is related to bupivacaine fluorescence imaging. instability. Method: Moisture induced phase behavior was Methods An electronic survey was distributed to studied using ASD systems: indomethacin-PVP Canadian anesthesiologists regarding spinal (IND-PVP) and ritonavir-PVP (RTV-PVP). Small anesthesia practice, and to invite submission of amount of Nile red dye was incorporated to stain the failed bupivacaine samples for analysis. A separate hydrophobic domain. Solid dispersions of different survey for hospital pharmacists focused on drug loadings were prepared by solution casting bupivacaine logistics. UV spectrometry, differential method. After drying, the ASD was exposed to scanning calorimetry and HPLC were used to water and then phase separation behavior was evaluate temperature effects on bupivacaine probed by confocal fluorescence imaging. stability. Mass spectrometry (MS) was used to Results: Clear phase separation was not visible observe bupivacaine degradation. Secondary through fluorescence imaging in IND-PVP samples, MS/MS analysis evaluated those peaks identified as possibly because the domain size of IND-PVP is being most common in the failed or temperature- smaller than the resolution of the confocal altered samples. microscope. In the case of RTV-PVP samples, as Results Canadian obstetric anesthesiologists report drug loading was increased from 10% to 50%, phase similar practice and mainly use hyperbaric separation domain size also increased. bupivacaine for spinal anesthesia. Pharmacists Conclusion: Confocal fluorescence can be used to surveyed indicated facility storage at room monitor moisture induced phase separation in ASDs. temperature but variability during shipping. No Higher drug loading led to larger domain sizes and standard procedure for failure reporting was such difference in phase behavior between different identified. Analysis of bupivacaine showed a slight drug loadings may help explain the difference in decrease in bupivacaine concentration or UV release rate. spectral changes when samples were incubated at temperatures ≤ 4°C. Mass spectrometric analysis was complex, with inconsistent ion formation for samples representing clinical failures that were different than the ions observed for cooled vs uncooled bupivacaine solutions. However, temperature-related changes were noted for dextrose in which dextrose-related ions were formed. Conclusions Canadian clinical practice and product handling of hyperbaric bupivacaine is fairly consistent. The effects of cold exposure and clinical

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handling produce a complex and possibly expression was the highest in liver, spleen, lung, and inconsistent reaction that will require further cerebrum. Heavy labeled peptides have been analysis on a larger sample size to elucidate the purchased for the NRs whose peptides have been mechanisms. Most respondents indicated they are validated in the method above. interested in a formal reporting and collection Conclusion: This assay will quantitate low process to better understand this issue. abundance NR proteins which are highly relevant Acknowledgements: Study funding from: College drug targets normally missed by untargeted of Pharmacy and Nutrition, University of proteomics. Saskatchewan (EKW) and by the Dept. of Anesthesiology, Royal University Hospital, Saskatoon, SK (CS, JG). Pharmacokinetics and 102. Developing an Assay to Quantify Nuclear Pharmacodynamics Receptors by Mass Spectrometry

Michael F. Saikali and Carolyn L. Cummins. Leslie Dan Faculty of Pharmacy, University of 103. In silico, in vitro and in vivo Pharmaceutical Toronto, Toronto, Canada Investigations of a Novel Skeletal Muscle Regenerator Purpose: Nuclear Receptors (NR) are a family of 48 Samaa Alrushaid1, Neal M. Davies2, Judy E. (49 in mice) ligand activated transcription factors 3 1 4 that control the expression of genes involved in a Anderson , Tyson Le , Jaime A. Yáñez , Zaid H. Maayah2, Ayman O.S. El-Kadi2, Ousama Rachid5, wide range of physiological processes and form one 6 2 of the largest classes of drug targets. To date, there Casey L. Sayre , Raimar Löbenberg , Frank J. Burczynski1,7 has not been any method to quantitatively compare 1 protein levels between different NRs. Our goal is to College of Pharmacy, Rady Faculty of Health generate a tissue-wide, quantitative NR protein Sciences, University of Manitoba, Winnipeg, MB; 2Faculty of Pharmacy and Pharmaceutical Sciences, expression profile using targeted proteomics. 3 Methods: A workflow was developed to tryptically University of Alberta, Edmonton, AB; Department digest all the NRs in silico and filter peptides for of Biological Sciences, Faculty of Science, and uniqueness, optimal length (6 – 20 AA long), and Department of Human Anatomy & Cell Science, absence of post-translational modifications. Using Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, the Global Proteome Machine (GPM) peptide 4 database, 8 peptides for each protein were chosen to MB; YARI International Group, New Brunswick, validate on a QExactive HF mass spectrometer. NJ, USA and INDETEC Corp., Lima Perú; 5Pharmaceutical Sciences Section, College of Validation was done by comparing HEK293 cells 6 transfected to overexpress a NR to a control. Pharmacy, Qatar University, Doha, Qatar; College of Pharmacy, Roseman University of Health Proteins were digested with Trypsin and Lys-C 7 using the FASP protocol. Tissues were isolated from Sciences, South Jordan, USA; Max Rady College of C57Bl/6 mice, homogenized and digested. Medicine, Rady Faculty of Health Sciences, Results: For the 49 NRs, our workflow identified University of Manitoba, Winnipeg, MB, Canada. 826 unique peptides meeting our criteria. 306 of the 826 candidate peptides were found in the GPM Purpose: A novel skeletal muscle-regenerating database, with 45 of the 49 receptors represented. compound MyoNovin was developed through We have acquired NR expression plasmids and synthesis of two nitro groups onto guaifenesin to overexpressed them in HEK293 cells. Using this deliver nitric oxide to skeletal muscle with a HEK293 system, peptides have been selected and potential to treat muscle atrophy. The purpose of this validated for 25 of the receptors to date. The protein study was to examine MyoNovin’s pharmacological expression profile of GR was performed across 9 effects and delineate for the first time an analytical different tissues (adrenal gland, liver, lung, spleen, assay to characterize pharmacokinetics and its single brain stem, cerebellum, cerebrum, hypothalamus, dose tolerability. and spinal cord). Among these tissues, GR Methods: In vitro cardiotoxicity was assessed using

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human cardiomyocytes (RL-14) while effects on typically achieve lower exposures when compared to CYP3A4 metabolic enzyme and antioxidant activity adults, while adolescents (12-18 years) do not. This were examined using commercial kits. A novel work explores the effects of growth and maturation HPLC assay was developed to measure MyoNovin on the PK of anti-TNF mAbs using a concentration in serum, and delineate initial physiologically-based pharmacokinetic (PBPK) pharmacokinetic and acute cardiac and renal toxicity modelling approach. after intravenous administration (20 mg/kg) to male Methods: A PBPK model was developed in PK-Sim Sprague-Dawley rats. In silico software packages and Mobi (open-systems-pharmacology.com) to were used to predict the physicochemical and describe the subcutaneous absorption, distribution biopharmaceutical properties. and elimination of anti-TNF mAbs in adults. The Results: An HPLC assay was successfully physiological parameters in the adult model were developed. MyoNovin was determined to have a then adapted to create a pediatric model with short serum half-life (t1/2) of 0.16 h, and a volume of anatomy and physiology according to known values distribution Vss of 0.62 L/kg. Biomarkers of in literature. Following evaluation of the pediatric MyoNovin cardiac and renal toxicity did not differ model using observed pediatric PK data, sensitivity significantly from baseline control levels. In vitro, analyses were performed to identify the key MyoNovin was not cytotoxic to cardiomyocytes at physiological parameters in the pediatric model that concentrations below 8 μM and did not inhibit were most influential for predicting exposure CYP3A4 or show antioxidant activity. MyoNovin differences between adults and children. showed relatively high lipophilicity with a LogP Results: The adult and pediatric PBPK models for value of 3.49, a 20-fold higher skin permeability adalimumab, infliximab and golimumab adequately (19.89 cm/s*107) compared to guaifenesin (0.66 predicted the observed PK data and associated inter- cm/s*107), and ~10-fold higher effective jejunal individual variability. Based on the sensitivity permeability (2.24 cm/s*104) compared to analysis, the fast rate of subcutaneous absorption in guaifenesin (0.26 cm/s*104). children was driven by a fast lymph flow rate. Conclusions: Pharmacokinetics following IV Differences in distribution were related to administration of MyoNovin were delineated for the differences in capillary surface area and leaky: tight first time in a rat model. Preliminary single 20 tissue mass ratios. Low concentrations of the mg/kg dose assessment of MyoNovin suggest no neonatal Fc receptor (FcRn) in the vascular influence on serum cardiac troponin or urine β-N- endothelium of young children may be responsible Acetylglucosaminidase. The predicted high for the PK differences in elimination. lipophilicity and skin permeability of MyoNovin Conclusions: A PBPK modelling approach to render it a potential candidate for transdermal pediatric PK prediction for anti-TNF mAbs was administration while its favourable intestinal demonstrated. Further research will be concerned permeation suggests it may be suitable for oral with extrapolating the PBPK model to infants. administration.

105. Correlating Protein Expression of Human 104. A Physiologically-based Approach to the Hepatic Uridine Diphosphate Pharmacokinetics of Anti-TNF Agents in Glucuronosyltransferases (UGTs): Pediatrics Implications for UGT Protein Co-regulation

Paul R.V. Malik and Andrea N. Edginton Yuejian Liu, Michael W.H. Coughtrie, and Abby C. School of Pharmacy, University of Waterloo, Collier. Kitchener ON Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Purpose: Monoclonal antibodies (mAbs) targeted Canada against tumour necrosis factor (TNF) are used in children as young as two years old for treatment of Purpose: Uridine diphosphate glucuronosyl- autoimmune diseases. Little is known about how transferases (UGTs) are Phase II conjugation growth and maturation may impact the enzymes involved in the metabolism of numerous pharmacokinetics (PK) of these agents. With the drugs, nutrients and environmental chemicals. same weight-based dose, young children (2-6 years) Accumulating evidence suggests that different UGT

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isoforms can physically associate with each other to 106. In silico Homology Modeling of Human increase activity and clearance capacity. UDP-glucuronosyltransferase 1A6 Methods: A protein expression data set containing (UGT1A6) reveals new Insights into UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 3A1, and 3A2 Structural Folding and Binding of Substrate was generated using the same western blot protocol, and Co-substrate and sampling a liver archive multiple times. We compared total abundance of UGT proteins and Alexander D. Smith, Abby C. Collier, and Michael correlation between pairs of isoforms. Age, body W.H. Coughtrie. mass index, ethnicity and sex were investigated as Faculty of Pharmaceutical Sciences, University of co-variables. Analysis was performed in GraphPad British Columbia, Vancouver, British Columbia, Prism 6 (La Jolla, CA). Canada Results: The most abundant isoforms in human liver are UGT1A4 and UGT2B7, except in age >65 where Purpose: UDP-Glucuronosyltransferase 1A6 UGT3A1 and 3A2 are upregulated. Protein (UGT1A6) belongs to the glycosyltransferase (GT) abundance and associations did not differ with sex, superfamily and uses UDP-glucuronic acid ethnicity or BMI. UGT1A1/1A6 and UGT1A6/1A9 (UDPGA) as co-substrate. It is responsible for always correlate with excellent correlation metabolism and detoxification of numerous natural coefficients, regardless of age (p<0.0001 both, compounds and xenobiotics. UGTs have two r=0.97 and 0.82, respectively). The UGT1A3 functional N- and C-terminal domains, with most of isoform was only analyzed in adults and highly the protein residing in the endoplasmic reticulum correlates with UGT1A1, 1A4, 1A6 and 1A9 lumen. A crystal structure of the presumed UDPGA (r>0.85, except 1A4 r=0.62, and p<0.0001 for all). binding region of human UGT2B7 shows high Some isoforms only correlate significantly in structural similarity to plant and bacterial GTs. No adolescence or adulthood (after 12 years old): complete UGT structure exists. We aim to produce a UGT1A1/1A4, UGT1A1/1A9, UGT1A4/1A6, and new homology model of UGT1A6 to further UGT1A4/1A9. Conversely, UGT1A4/2B7 and examine features involved in enzyme function and UGT1A9/2B7 only correlate significantly in substrate binding. children under 12 years old. None of the UGT1A Methods: Structural models of human UGT1A6 and 2B members correlates with UGT3A isoforms, were produced using I-TASSER with or without a but UGT3A1 and 3A2 are associated with each other guiding partial crystal structure template (UGT2B7, (p=0.028, r=0.32). PDB: 2O6L). Models were analysed and refined Conclusion: We have identified 13 pairs of UGT using BIOVIA Discovery Studio™. Residues known isoforms that demonstrate statistically significant or predicted to be important for substrate and co- positive correlations in protein expression. Positive substrate binding were used to define compound correlations might indicate co-regulation of UGT binding spheres. Sixty-two compounds were docked expression and provides further evidence for using both the Libdock and CDOCKER algorithms, cooperation between UGT isoforms in metabolism with UGT substrates docked in both the presence and clearance. That co-association of isoforms and absence of the co-substrate UDPGA. differs with age gives insight into intersection of Results: The highest ranked model (C-score, developmental and genetic regulation of UGT MODELER, Profiles-3D scores) utilized the guiding structure and function. template structure (59% aligned sequence identity), and closely matched other GT structures. Root Mean Square Distances (RMSD) over aligned residues ranged from 2.28 (Medicago truncatula UGT71G1, sequence ID 16.3%) to 3.55 (Streptomyces antibioticus glycosyltransferase OleI, sequence ID 19.2%) prior to full energetic minimization. Models could not be constrained for the presence of membrane, hence transmembrane and C-terminal domains are not accurately localized. Preliminary docking experiments indicate that UDPGA interacts with residues including His371 and Glu379, which are highly conserved and identified as important for

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glucuronidation. and were gestational age-matched with samples from Conclusion: Due to extensive functional and preterm pregnancies with no obstetric complications structural conservation within the GT superfamily, (controls, n=24). Meanwhile, BeWo cells were homology modeling may provide insight into the treated with sFlt-1 alone and with VEGF for 72 structure and function of UGTs in the absence of hours. Gene expression was measured via qRT-PCR. high-resolution crystal structures. Results: A significant 30-50 % downregulation of ABCG2, ABCC1, ABCC2, SLC22A1, SLC22A3, SLC22A11, and SLC29A2 was seen in placentas 107. Role of Elevated sFLt-1 on the Regulation of complicated by PE compared to healthy controls (p Placental Transporters in Women with Pre- < 0.05). mRNA levels of sFLT-1 were induced by eclampsia 2.5 fold in preterm placentas of women with PE, relative to preterm controls (p < 0.01). Likewise, Dea Kojovic, Micheline Piquette-Miller. BCRP protein expression was significantly Leslie Dan Faculty of Pharmacy, University of downregulated by 50% in PE compared to controls. Toronto, Toronto, Ontario, Canada. Administration of sFlt-1in cells resulted in an 85- 90% downregulation of ABCG2 transcript levels Purpose: Pre-eclampsia (PE), a prominent obstetric which was attenuated by VEGF. complication is associated with elevated levels of Conclusion: Our findings suggest that the protective sFlt-1, a soluble Vascular Endothelial Growth Factor function of the placenta is compromised during PE (VEGF) receptor. However, virtually no information with significantly altered the expression of clinically exists on the expression and regulation of human important transporters. Furthermore, our in vitro placental transporters in PE. Therefore, our objective results show that sFlt-1 is involved in the regulation was to explore the impact of PE and sFlt-1 on the of BCRP in placenta. As this may impact fetal health expression of transporters in human placenta, and and development, further studies are needed to elucidate the regulatory mechanism in vitro. determine the impact of PE-induced changes on fetal Methods: Human placental samples were collected exposure to their substrates. from preterm pregnancies diagnosed with PE (n=34)

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CSPT Poster Session 2

Thursday, May 24

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CSPT Posters - Session 2

Thursday, May 24

drugs in biological matrices, with numerous 108. Quantification of NSAIDs in Human Tissues applications in health research. with a Novel UHPLC/MS/MS Method Keywords: Analytical quantitation, NSAIDs, pharmacokinetics, screening, UHPLC/MS/MS 1 1 2 Hayley R. Price , Dickson Lai , Hugh Kim , Michael W. H. Coughtrie1, and Abby C. Collier1 1Faculty of Pharmaceutical Sciences, University of 109. Investigating the Mechanisms of Bile Acid- British Columbia, Vancouver, British Columbia; mediated Organ Toxicity in Ntcp (Slc10a1) 2Faculty of Dentistry and Blood Research Center, Knockout Mice University of British Columbia, Vancouver, British Columbia, Canada Laura E. Russell1, Crystal L. Schmerk1,2, Sara E. Mansell1,2, Ahmed A. Almousa1,2, and Richard B. Background: Nonsteroidal anti-inflammatory drugs Kim1,2 (NSAIDs) are analgesics with antipyretic and anti- 1Department of Physiology and Pharmacology, inflammatory effects. NSAIDs are one of the most Schulich School of Medicine and Dentistry, The commonly used drug classes in the world and this University of Western Ontario, London, Ontario; coupled with their side-effect profiles, and 2Division of Clinical Pharmacology, Department of contraindications, mean that a method for screening Medicine, Schulich School of Medicine and NSAIDs would be valuable in the fields of Dentistry, The University of Western Ontario, biomedical and environmental sciences. London, Ontario, Canada Objectives: We aim to develop a method that simultaneously detects the five most common Background: Na+-taurocholate cotransporting NSAIDs (salicylic acid (SA), diclofenac (DCF), polypeptide (NTCP) mediates uptake of conjugated ibuprofen (IBU), indomethacin (IND) and naproxen bile acids and drugs from portal circulation into the (NAP)) in biological matrices. liver. Published Ntcp knockout mouse data noted Methods: A novel UHPLC/MS/MS method for the hypercholanemia and significant alterations in bile simultaneous quantification of these five NSAIDs acid transporter mRNA expression in 30-35% of using aceclofenac as an internal standard was knockout mice. The mechanisms of bimodal developed. Pharmacokinetic analysis was performed phenotypes within the knockout population remain to determine for how long plasma levels of NSAIDs unclear and require further investigation. could be detected after ingestion. Objectives: Aim 1: Identify hypercholanemic and Results: In solvent, the limit of sensitivity is below normocholanemic mice in our previously 1 ng/mL for all samples, with linear range of 1-1000 uncharacterized Ntcp knockout mouse model. Aim ng/mL for all analytes except IBU (10 – 1000 2: Quantify expression of proteins involved in bile ng/mL). Lower limit of quantitation is 1 ng/mL for acid synthesis and transport in hypercholanemic DCF and SA, 2.5 ng/mL for NAP and 20 ng/mL for knockout, normocholanemic knockout, and control IBU and IND. Validation in plasma and other mice. biological matrices is ongoing. After a single oral Methods: Total serum bile acid levels were dose all NSAIDs would be detected within five half- quantified using an enzyme-cycling method. lives (0.4-4.2 days), with SA, IBU and NAP Individual serum bile acids will be quantified using detected for 10 half-lives (0.8-8.3 days). From LC-MS/MS. Hepatic, renal, and ileal mRNA steady-state, all NSAIDs could be detected 10 half- expression will be quantified using RT-qPCR. lives from last dose. Results: Approximately 25-30% of our Ntcp Conclusions: Our UHPLC/MS/MS method can knockout mice died 4-7 weeks after birth and were simultaneously quantitate five NSAIDs in human noted to have strikingly elevated total serum bile tissues and provides a novel screening tool for these acid levels (464.6  29.5M) compared to age-

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matched controls (3.37  0.71M). Upon wide analyses will be performed using logistic preliminary necroscopy, such knockout mice display regression, including significantly-associated clinical severe renal damage secondary to bile acid variables as covariates, to explore the role of known accumulation. and novel ACT-associated variants. Functional and Conclusion: Bimodal serum total bile acid biological relevance of candidate variants will be measurements in our Ntcp knockout mice are examined using computational annotation tools such consistent with the published findings. We are the as VEP, GTEx, and CADD, and associated genes first to report lethality of a hypercholanemic subset will be investigated for enrichment in specific of Ntcp knockout mice, likely due to bile acid- pathways. mediated kidney injury. Using RT-qPCR, we aim to Results: An extensive review of the literature has elucidate pathways responsible for morbidity in identified 20 genes that have been previously hypercholanemic mice and, alternatively, for associated with ACT, the role of which will be compensation in normocholanemic knockout mice. validated in our cohort through a targeted analysis. Keywords: NTCP, bile acid transport We will present the top candidate variants that reach statistical significance in both targeted and genome- wide analyses. 110. Genome-wide Association Study of Conclusions: The identification of genetic variants Anthracycline-induced Cardiotoxicity in associated with ACT will play an important role in Adult Cancer Patients improving the safety of anthracyclines and, ultimately, in reducing the burden on the healthcare 1,2 2,3 Erika N. Scott , Britt I. Drögemöller , Galen E. B. system as well as affected patients. 1,2 4 4 Wright , Karen A. Gelmon , Diego Villa , Jessica Keywords: Pharmacogenomics, Anthracyclines, 5 5,6 N. Trueman , Bruce C. Carleton , and Colin J. D. Cardiotoxicity, GWAS 1,2,3 Ross 1Department of Medical Genetics, University of British Columbia, Vancouver, BC; 2BC Children’s 111. Physician Feedback and Antibiotic Hospital Research Institute, Vancouver, BC; Prescribing Patterns 3Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC; 4Division of Gavin R. Sun1 and Michael Silverman2 Medical Oncology, BC Cancer, Vancouver, BC; 1Division of Clinical Pharmacology and Toxicology, 5Pharmaceutical Outcomes Programme, BC Department of Medicine, Western University, Children’s Hospital, Vancouver, BC; 6Department of London, Ontario; 2Division of Infectious Diseases, Pediatrics, University of British Columbia, Department of Medicine, Western University, Vancouver, BC, Canada London, Ontario, Canada

Background: Anthracycline agents, such as Background: Antibiotics have revolutionized doxorubicin and epirubicin, are commonly modern medicine and have transformed infections prescribed for a variety of cancers. Nevertheless, up with serious potential morbidity and mortality into to 18% of adult patients develop severe life- eminently manageable and survivable conditions. threatening anthracycline-induced cardiotoxicity However, in addition to the direct unnecessary costs (ACT). Clinical risk factors include cumulative from dispensing redundant therapy, inappropriate anthracycline dose, age, prior thoracic radiotherapy, antibiotic prescribing incurs substantial indirect and pre-existing cardiac disease. Germline genetic socio-economic costs related to the associated variants associated with a higher ACT risk in adults adverse side-effects and the promotion of the have not been identified. development of resistant organisms. Audit and Objectives: To replicate previous, and discover feedback (A&F) when well designed, presented, new, ACT-associated genetic variants in adult framed and implemented, has been shown to be a cancer patients to improve our understanding of the cost-effective and efficacious tool in influencing genetic causes of ACT. physician behaviour change. Methods: Genotyping of 1.7 million variants has Objectives: Assess the impact of audit and feedback been performed on 180 adult cancer patients (60 in antibiotic prescribing patterns cases, 120 controls) treated with anthracyclines and Methods: A literature review was conducted on rigorously assessed for ACT. Targeted and genome- Pubmed, searching for articles using the search

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terms “prescriptions”, “prescribers”, “antibiotic”, of times after inhaling LO, to keep them in their “audit and feedback” and “inappropriate refrigerators at home, and to bring them to the clinic prescribing”. after recovery. Fifty μL of each milk sample was Results: Four studies were identified for inclusion. pretreated by solid phase extraction method using An important distinction between effective and OASIS MCX (3cc/60mg), followed by measuring ineffective audit and feedback interventions in concentration of LO and LA in breast milk with antibiotic prescribing is related to the method and liquid chromatography-tandem mass spectrometry at context of framing an individual physician’s Pharmacokinetics and Bioanalysis Center, Shin behavior. When framed in context, audit and Nippon Biomedical Laboratories, LTD. The feedback has been shown to decrease inappropriate detection limit of both LO and LA is 1 ng/mL. antibiotic prescribing. Results: Twenty-seven pumped milk samples (half Conclusions: As the gate-keepers to antibiotic an hour to 48 hours after inhalation) from 5 patients prescriptions, targeting physician perception and were examined. None of them showed LO / LA level behavior with A&F has been shown in American over the detection limit. and British settings to be effective at altering Conclusions: Available data suggest that inhaled prescribing patterns. Given the incidence of LO by a lactating mother does not affect her baby inappropriate antibiotic prescribing in Canada and via breast milk, and seems safe. the consequent adverse socio-economic and medical Keywords: Laninamivir octanoate, Influenza, outcomes, there is a need to target and alter lactating women, breastfeeding, safety Canadian physician antibiotic prescribing behavior. Audit and feedback is imminently applicable to the Canadian context and, if implemented well, would 113. Single Time Point Sampling for Assessment yield widespread and long-term societal benefit of Fexofenadine as an In Vivo Drug Keywords: Audit, feedback, antibiotic prescribing, Transporter Probe physician 1 1 Nicholas C. Tonial , Thomas J. Velenosi , Thomas D. Nolin2, Benjamin K. Thompson3, Matthew A. 112. Safety of laninamivir Octanoate, a Weir3, Andrew A. House3, and Bradley L. Neuraminidase Inhibitor, in Lactating Urquhart1,3 Women with Influenza 1Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The Toshihiro Tanaka1, Yumiko Kobayashi2, and University of Western Ontario, London, Ontario, Takashi Nakano3 Canada; 2Department of Pharmacy and Therapeutics, 1Department of Pediatrics, Shizuoka Kosei Hospital; University of Pittsburgh School of Pharmacy, 2Mochizuki Pediatric Clinic; 3Department of Pittsburgh, Pennsylvania, USA; 3Division of and Pediatrics, Kawasaki Hospital, Kawasaki Medical Nephrology, Department of Medicine, Schulich School School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada Background: Both pregnant and lactating women are thought an important group to be treated with Background: In vivo probe substrates are used to anti-influenza virus drugs once they are symptomatic assess activity of hepatic metabolism and transport during flu season. Laninamivir octanoate (LO / to help delineate effects of disease and drug-drug Inavir®, Daiichi Sankyo Company, Limited), one of interactions on drug disposition. For example, the neuraminidase inhibitors, was developed in Japan non-sedating anti-histamine fexofenadine, is and has been on the market for 7 years. Information effective as a nonselective transporter probe but is on safety of the medication use in the group, limited in clinical use due to its relatively long half- especially lactating women, is insufficient. life (11-16 hours). Many patient groups are unable to Objectives: To assess whether LO is safe to use in undergo full PK characterization due to the large lactating women, the concentration of LO and its time commitment. active metabolite, laninamivir (LA), in breast milk Objectives: This study investigated relationships samples from patients who were diagnosed as between fexofenadine exposure, area under the influenza and inhaled 40mg of LO once. curve (AUC), and single time point fexofenadine Methods: Each patient was asked to milk a couple concentration. We hypothesized that a single time

150s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

point measurement would provide a good estimate engineered to give off light when bound by an of fexofenadine exposure. agonist. The assay was used to identify cholinergic Methods: Data was utilized from two published agonist binding and anticholinergic inhibition of studies that orally administered 120 mg of agonist binding. The muscarinic agonist used was fexofenadine. Nolin et al. (S1) and Thomson et al. acetylcholine, and the anticholinergic agents (S2) collectively studied 18 healthy controls and 24 investigated included; atropine, digoxin, famotidine, chronic kidney disease (CKD) patients. Serial blood and ranitidine. Each agent was assessed across a samples were drawn over 8 or 12 hours for S2 or S1, range of concentrations. A standard luminescence respectively. Linear regression was performed using plate reader (Biotek SynergyHT) was used to 1, 2, 3, and 4-hour time points plotted against measure light emitted at all wavelengths. Statistical

AUC0∞ (S1) or AUC08 (S2). analysis was completed using GraphPad Prism 5. Results: For S1, linear regression yielded R2 of Results: We used the muscarinic 1 receptor based 0.77, and 0.88 for 3-hour and 4-hour time points, assay to examine acetylcholine agonism and respectively (p<0.0001). Comparably, for S2, 3-hour calculated the EC50 as 9778 nM. Subsequent trials and 4-hour time points yielded R2 of 0.95, and 0.95 to investigate inhibition of the acetylcholine induced (p<0.0001). luminescence at a concentration corresponding to the Conclusions: Single-time point measurements of EC80 (115 600 nM) showed complete inhibition by fexofenadine are correlated to exposure when taken atropine at a concentration of 2.73x10-5 M and at 3 or 4 hours following dosing, including CKD partial inhibition by varying concentrations of patients. Ongoing research is utilizing single time digoxin, famotidine, and ranitidine. point measurements to determine dialysis-mediated Conclusions: A cellular reporter assay can be used changes in fexofenadine exposure in CKD patients. to measure anticholinergic activity. This objective Keywords: Chronic kidney disease (CKD), measure of anticholinergic activity may be helpful to fexofenadine, drug disposition, drug transport predict anticholinergic burden and help direct drug- therapy decisions. Keywords: Anticholinergic, GPCR assay, 114. Development of a Novel Cellular Reporter muscarinic 1 receptor Assay to Measure Anticholinergic Activity

Shanna C. Trenaman1, Melissa K. Andrew2, and 115. Swelling-induced Chloride Current in Kerry B. Goralski3 Glioblastoma Proliferation, Migration and 1Interdisciplinary PhD, Dalhousie University and Invasion Geriatric Medicine Research Unit, Nova Scotia Health Authority, Halifax, Nova Scotia; Raymond Wong1,2, Wenliang Chen1, Xiao Zhong1, 2Department of Medicine (Geriatrics), Dalhousie James T Rutka1, Zhong-Ping Feng2, and Hong-Shuo University and Geriatric Medicine, Nova Scotia Sun1,2 Health Authority, Halifax, Nova Scotia, Canada; 1Department of Surgery, University of Toronto, 3College of Pharmacy, Dalhousie University, Toronto, Ontario; 2Department of Physiology, Halifax, Nova Scotia, Canada University of Toronto, Toronto, Ontario, Canada

Background: Anticholinergic activity is an Background: Glioblastoma (GBM) remains the important contributor to serious adverse drug events, most common and aggressive malignant brain tumor especially in older adults. This has led to the originating in the central nervous system. Diagnosis development of numerous scales to quantify is lethal with a median survival of <15 months. anticholinergic activity; to date these have failed to Aberrant swelling-induced chloride channel ICl,swell garner widespread acceptance due to their subjective expression has been linked to GBM cellular nature. functions (i.e. proliferation, migration and invasion). Objectives: The objective of this study was to Objectives: We hypothesize that inhibition of the develop a cellular reporter assay that could swelling-induced chloride channel ICl,swell suppresses quantitatively measure anticholinergic activity. GBM cellular functions. The purpose is to establish Methods: The DiscoverX PathHunter® β-Arrestin ICl,swell as a potential drug target by evaluating eXpress GPCR Assay was used. This assay contains DCPIB, a specific antagonist for the swelling- human cells expressing the muscarinic 1 receptor induced chloride channel ICl,swell, on GBM cellular

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functions. Methods: CD34+ cells were isolated from Methods: We used the human GBM cell lines U251 mononuclear cells (MNCs) derived from healthy and U87. First, with the whole-cell patch-clamp volunteers. Protein and mRNA expressions of ACE2 technique to measure activity of ICl,swell. GBM and MasR were determined in cells after exposure to + proliferation and viability were assessed with MTT normoxia (20% O2) or hypoxia (1% O2). CD34 and colony formation assays. Moreover, GBM cells were transduced with lentiviral particles (LV) migration and invasion were assessed with scratch carrying either ACE2-, MasR- or scramble-3’-UTR wound and Matrigel invasion assays, respectively. fused downstream to firefly luciferase reporter gene. With Western immunoblots, we also assessed in Results: Hypoxia stimulated mRNA and protein GBM the protein levels of p-Akt/t-Akt, p-JAK2/t- expressions of ACE2 and MasR in CD34+ cells, but JAK2, and p-STAT3/t-STAT3 in order to examine not in MNCs. In the presence of hypoxia-inducible the underlying mechanism. factor-1α (HIF-1α) inhibitor, hypoxic upregulation Results: We demonstrated that DCPIB enhanced the of ACE2 or MasR was not observed. Luciferase endogenous swelling-induced chloride channel activity was increased by hypoxia, compared to ICl,swell. GBM proliferation and viability were normoxia, in either ACE2- or MasR-luciferase reduced with DCPIB treatment. DCPIB also expressing cells. Co-transfection experiments using suppressed GBM migration and invasion. We found ACE2 and MasR specific miRNA (miR-421 or miR- that DCPIB inhibited the JAK/STAT as well as the 143 for ACE2 and MasR, respectively) confirmed PI3k/Akt signaling pathways, which could that the observed luciferase activity in both potentially be the underlying swelling-induced normoxic and hypoxic condition was dependent on chloride channel ICl,swell-dependent mechanism. ACE2 or MasR, respectively. Conclusions: Because potentiated swelling-induced Conclusions: Collectively, these results provide chloride channel ICl,swell activity contributes to the compelling evidence for the hypoxic upregulation of devastating proliferative, migratory and invasive ACE2 and MasR in CD34+ cells, which largely characteristics of GBM, our study establishes the contribute to the revascularization of ischemic areas involvement of ICl,swell in GBM cellular functions. following vascular injury. + Keywords: Glioblastoma, ICl,swell, DCPIB Keywords: CD34 cells; Stem/progenitor cells; Hypoxia; MicroRNA; ACE2

116. Hypoxic Stimulation of Vasoreparative Functions in Human CD34+ Cells is 117. Characterization of the Metabolome and Mediated by Angiotensin Converting Renal Tubular Cisplatin Disposition in Enzyme-2 and Mas Receptor Cisplatin Induced Acute Kidney Injury

Shrinidh A. Joshi, Estelle Leclerc, and Yagna P. R. Yong Lim, Emily D. Hartjes, and Brad L. Urquhart Jarajapu Department of Physiology and Pharmacology, Department of Pharmaceutical Sciences, College of University of Western Ontario, London, Ontario, Health Professions, North Dakota State University, Canada Fargo, North Dakota, USA Background: Cisplatin-induced acute kidney injury Background: CD34+ hematopoietic stem/progenitor (AKI) is diagnosed by increased serum creatinine cells (HSPCs) have the propensity of re- (SCr), but nephrotoxicity develops before rises in endothelialization and vascular regeneration. SCr are detectable. Novel diagnostic/predictive Angiotensin Converting Enzyme-2 (ACE2) markers of AKI may explain why approximately 1/3 generates the heptapeptide, Angiotensin (Ang)-(1-7), of cisplatin patients get AKI while others do not. which produces vasoprotective effects by acting on FVB/N mice have greater susceptibility to cisplatin- Mas receptor (MasR). We have previously reported AKI than C57BL/6 mice and we used these strains that hypoxia stimulated vasoreparative functions of to model the variability of cisplatin nephrotoxicity. CD34+ cells, which was impaired in MasR-deficient Objectives: 1) Determine the effects of AKI on murine HSPCs. expression of renal transporters and enzymes Objectives: Current study tested the hypothesis that involved in cisplatin disposition; 2) Investigate hypoxic stimulation of HSPC functions are mediated metabolic differences between FVB/N and C57BL/6 by ACE2 and MasR. mice using metabolomics.

152s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

Methods: FVB/N and C57BL/6 mice were treated expression of key nutrient and neurotransmitter with 15 mg/kg cisplatin or saline. Mice were transporters was examined using qRT-PCR and sacrificed 1 or 3 days following treatment; gene Western blotting. expression was assessed using RT-PCR, and LC-MS Results: Poly(I:C) induced a 1.7-fold increase in was used for untargeted metabolomics. TAUT (Slc6a6) mRNA (p < 0.05). This induction Results: Renal expression of uptake transporter was accompanied by a trend towards a 1.6-fold Oct2 and metabolizing enzyme Ggt1 were 20% and increase in TAUT protein expression (p = 0.0617). 45% higher, respectively, in FVB/N mice compared mRNA levels of PCFT (Slc46a1) were also to C57BL/6 (p<0.05). Ggt1 expression was lower in significantly upregulated 1.2-fold (p < 0.05). A trend day 1 and 3 cisplatin-treated FVB/N compared to towards increased mRNA expression was observed saline (-44% and -50% respectively, p<0.05). for LAT1 (Slc7a5, p = 0.1502) and BGT1 (Slc6a12, Principle component analysis (PCA) of mouse p = 0.0999). plasma and kidney samples demonstrated metabolic Conclusions: Simulating viral infection during mid- differences attributed to both strain and cisplatin gestation in rats causes dysregulation of the treatment. expression of nutrient and neurotransmitter Conclusions: mRNA expression of Oct2 and Ggt1 transporters in the placenta. Since these transporters in FVB/N mice was higher compared to C57BL/6. have substrates involved in critical aspects of fetal PCA separation of untreated mice indicates strain neurodevelopment, their dysregulation may alter metabolic differences, while separation by treatment fetal access to these substrates which could have groups suggests that cisplatin alters the metabolic deleterious effects on fetal outcomes. profiles of the mice. Our data suggests differences in Keywords: Inflammation, transporters, pregnancy, expression of cisplatin transporters/metabolizing placenta, fetal outcomes enzymes, and metabolic profiles may explain strain dependent differences in susceptibility to cisplatin- AKI. 119. Impact of MS-induced Systemic Pro- Keywords: Metabolomics, acute kidney injury, inflammatory Cytokines on the Regulation cisplatin, biomarkers of Human Placental Transporters

Kamelia Mirdamadi and Micheline Piquette-Miller 118. Viral Mimetic Imposes a Dysregulation of Leslie Dan Faculty of Pharmacy, University of Nutrient and Neurotransmitter Transporter Toronto, Toronto, Ontario, Canada Expression in Rat Placenta Background: Placental drug transporters play a Eliza R. McColl and Micheline Piquette-Miller crucial rule in the transfer of nutrients to the fetus Department of Pharmaceutical Sciences, University and protection against xenobiotics. While of Toronto, Toronto, Ontario, Canada preclinical and clinical studies have shown that systemic inflammation cause dsyregulation of Background: Previous research has shown that placental drug transporters, the impact of elevated inflammation during late gestation can cause systemic levels of the pro-inflammatory cytokines, changes in the expression of ATP-Binding Cassette IL-17, IL-22 and IL-23 associated with MS, has not and Solute Carrier transporters located in the been studied. We hypothesize that MS associated placenta. It is unknown whether transporter cytokines will impact the expression of placental dysregulation also occurs during inflammation at drug transporters. mid-gestation, a critical time for fetal Objective: To examine the impact of IL-17, IL-22 neurodevelopment. and IL-23 on the expression of key placental Objective: To determine whether viral infection transporters in vitro in a human trophoblast cell line. during pregnancy impacts the expression of key Method: BeWo cells were grown to 80% placental nutrient and neurotransmitter transporters confluency. IL-17, IL-22, and IL-23 were added to at a time critical for fetal neurodevelopment. the cells at various concentrations (0, 0.5, 1, 10, Methods: Pregnant Sprague-Dawley rats were 50,100 ng/ml) for periods of 24, 48 and 72 hr. qRT- injected intraperitoneally with poly(I:C) (10 mg/kg) PCR was used to measure the gene expression of on gestational day 14. After 24 hours, dams were BCRP, MDR1, MRP1, MRP2, OATP2B1, OAT4. sacrificed and placentas were collected. The Results: As compared to controls, IL-17

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significantly decreased the mRNA of BCRP and Conclusions: Sympathetic tone increases in MRP2 after 24h (p<0.001) and increased levels of response to the rapid declines in SBP associated OATP2B1 after 24 and 72hr (p<0.01). IL-22 with rapidly increasing dihydropyridine significantly decreased the BCRP and OAT4 genes concentrations. There was no evidence of drug- (p<0.01) after 48 and 72 hours respectively. induced tachycardia following NXL morning Likewise, IL-23 significantly downregulated the dosing, consistent with the lack of sympathetic mRNA levels of OAT4 and OATP2B1 at 24 and activation observed by de Champlain. Doubling the 48hr, respectively (p<0.01). dose did not increase HR, consistent with both doses Conclusion: Exposure of human placental cells to producing concentrations < minimum required to IL-17, IL-22 and IL-23 imposed alterations in the effect rapid change in SBP. However, NXL retains expression of many clinically important placental its short half-life, allowing more rapid titration and drug transporters. As these cytokines are elevated in discontinuation. MS patients, they potentially impact fetal exposure Keywords: Nifedipine, Hypertension, Sympathetic to their substrates. Response. Key words: multiple sclerosis, systemic inflammation, placental drug transporters

120. Low-dose, Low-fluctuation Dihydropyridine Concentrations as Delivered by Nifedipine- Extended-release Tablets Do not Perturb Heart Rate

P. Timothy Pollak, Navdeep Dehar, and Mingkai Peng

Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada 121. Identifying the role of G-Protein Signalling Background: Dihydropyridine agents are highly Modulator 3 in GPCR signalling effective in antihypertensive therapy, with Anette A. Surmanski1, Peishen Zhao1,2, Alexey I. amlodipine and nifedipine-extended-release (NXL) 1 1,3 being the most commonly used. Tachycardia caused Pevererzev , Brad L. Urquhart , and Peter Chidiac1,4 by administration of nifedipine is highlighted in 1 older literature, but relates to formulations used prior Department of Physiology and Pharmacology, Western University, London, Ontario, Canada; to NXL. Despite longstanding evidence that NXL 2 has no effect on sympathetic activity (de Champlain Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia; J Hypertens 1998; 16: 1357), elevation of heart rate 3 (HR) is still cited as a consideration to avoid use of Department of Medicine, Division of Nephrology, Western University, London, Ontario, Canada; NXL. 4 Objectives: To examine the effects of NXL on HR Department of Biology, Western University, in data collected from 120 uniformly conducted London, Ontario, Canada ambulatory blood pressure monitoring (ABPM) studies. Background: G protein coupled receptors (GPCRs) Methods: HR data were analyzed from 24-h ABPM are the largest superfamily of mammalian cell studies conducted twice in 60 pts to examine systolic surface receptors and serve as targets for over 30% blood pressure (SBP) response to morning doses of of current pharmaceuticals. GPCRs activate G 2 differing NXL formulations of 30 mg or 60 mg protein heterotrimers (GαGDP/G) by promoting tabs. GDP dissociation and GTP association. GPCR Results: Mean HR ranged between 63-76 bpm on signalling is limited via G protein activity and 30 mg/d, and 62-74 bpm on 60 mg/d with tight interactions with -arrestins. G Protein Signalling standard deviation ranges (Fig HR mean ± SD). Modulator-3 (GPSM3) is a novel protein that

154s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

influences receptor signalling by binding to inactive Objectives: We evaluated the relationship between

Gi-GDP, limiting GDP dissociation from Gi and the pharmacokinetics of ATRA and central nervous also preventing Gi re-association to the G system (CNS) toxicity in children and adults with subunit. GPSM3 thus has the potential to prevent APL.

Gi-mediated signalling while prolonging G Methods: Six children (9.3±2.4 year-old) and eight signalling. adults (35.5±13.3) with APL were enrolled. All of 2 Objectives: To determine whether GPSM3 inhibits patients received oral ATRA (45 mg/m per day) and GPCR signalling. chemotherapy, and all of them achieved complete Methods: Real-time bioluminescence-based kinetic remission. The pharmacokinetics of ATRA was assays for cAMP production and -arrestin determined within one week of starting therapy. recruitment were used to study the effects of GPSM3 Results: The Cmax values of the children and mutants thereof on GPCR signalling in (352.0±173.6 ng/ml) were higher than those of the transiently transfected HEK-293H cells. adults (203.9±34.5), but the other parameters (AUC, Results: GPSM3 overexpression inhibited basal and half-life time, clearance, and volume of distribution) did not differ between these two age groups. Two agonist-stimulated -arrestin recruitment to Gi- children suffered from CNS toxicities but none of coupled α2A-adrenergic and -opioid receptors by 52% (p<0.0001), with no effect on recruitment to the adults had CNS toxicity. G - or G -coupled GPCRs. The effect of GPSM3 Conclusions: The bioavailability of ATRA was not s q/11 different in adults and children. The children had on α -adrenergic--arrestin diminished with 2A higher Cmax values than the adults. The partially inactive mutants of GPSM3 (p<0.001) and pharmacokinetic parameters of the children with not observed with fully inactive mutants. In cAMP CNS toxicity were not different from those of the assays, GPSM3 reduced forskolin potency on children without CNS toxicity. The incidence of endogenous HEK-293H adenylyl cyclase activity CNS toxicity in children is higher than adults (LogEC =-5.261) when compared with control 50 although its bioavailability between both groups is (LogEC =-5.916), but the reason for this decrease is 50 similar. Further studies are needed to determine the unclear (p<0.0001). optimum regimen for ATRA combined with Conclusions: The selective effect of GPSM3 on - chemotherapy in children with APL, in order to arrestin binding to G -coupled receptors is consistent i reduce ATRA - related neurotoxicity. with its greater affinity for Gi relative to other G Keywords: all-trans retinoic acid, acute protein subtypes, and suggests that G protein promyelocytic leukemia, pharmacokinetics activation may be a necessary step in GPCR-- arrestin recruitment. Keywords: G-Protein Signalling Modulator-3, 123. Insights into PAR4 Signaling and Biased GPCR, adenylyl cyclase, -arrestin Agonism

Pierre Thibeault1, Jordan Cole LeSarge2, D’Arcy 122. Comparing Pharmacokinetics of All-trans Arends1, Michaela Fernandes2, Len Luyt2, and Retinoic Acid Between Adults and Children Rithwik Ramachandran1 with Acute Promyelocytic Leukemia 1Department of Physiology and Pharmacology, University of Western Ontario; 2Department of Kimitaka Takitani, Akiko Inoue, and Hiroshi Tamai Chemistry, University of Western Ontario Department of Pediatrics, Osaka Medical College, Osaka Prefecture, Takatsuki, Japan Background: Proteinase-activated receptor 4 (PAR4) is a G-Protein Coupled Receptor activated Background: All-trans retinoic acid (ATRA) is a following proteolytic cleavage of the receptor N- key drug of differentiation therapy for acute terminus by enzymes such as thrombin, trypsin, and promyelocytic leukemia (APL). ATRA toxicity is Cathepsin-G. Proteolysis reveals a receptor well known to include differentiation syndrome and activating motif termed the tethered ligand (TL) neurotoxicity. The pharmacokinetics of ATRA has which binds intramolecularly to trigger receptor been reported previously, but the comparison of signaling cascades. Synthetic peptides derived from pharmacokinetics parameters between different ages the TL sequence can also activate PAR4. Here we has not been performed. examined PAR4 signaling following activation with

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a library of TL derived peptides to identify University of British Columbia, Vancouver, BC, compounds with novel pharmacological properties. Canada; 4Division of Translational Therapeutics, Objectives: To identify novel PAR4 activating Department of Pediatrics, University of British peptides that exhibit functional selectivity for beta- Columbia, Vancouver, BC, Canada; 5University arrestin or Gq coupled signaling pathways. Institute of Clinical Chemistry, Inselspital Bern Methods: The synthetic agonist peptide (AYPGKF- University Hospital, University of Bern, Switzerland NH2) and 35 novel derivatives of PAR4 agonist peptides were synthesized (<95% purity) using solid Background: Vincristine is an effective phase Fmoc-peptide chemistry, purified by chemotherapeutic drug that is used to treat various preparative high performance liquid chromatography cancers, including acute lymphoblastic leukemia (HPLC), and characterized by liquid (ALL). Unfortunately, clinical utility is restricted by chromatography mass spectrometry (LC-MS). We dose-limiting neurotoxicities that include sensory used calcium sensitive fluorescent dyes to monitor and motor neuropathies. The identification of elevations in intracellular calcium levels (Gq pharmacogenomic markers for vincristine-induced coupled), Bioluminescence Resonance Energy peripheral neuropathies (VIPN) is valuable to predict Transfer (BRET) to monitor beta-arrestin-1 and -2 individual susceptibility to this adverse event. recruitment, and western blotting to determine Objectives: We sought to determine the association activation of p44/42 MAPK and Akt following of VIPN with: a recently-identified risk variant, receptor activation. CEP72 rs924607, as well as pharmacogenomic Results: 22 of 35 peptides showed decreased beta- variants from drug absorption, distribution, arrestin recruitment compared to AYPGKF-NH2. A metabolism, and excretion (ADME) genes. subset of peptides also showed decreased calcium Methods: Pediatric ALL patients were recruited signaling compared to AYPGKF-NH2. Interestingly from seven healthcare centres across Canada and we identified 7 peptides that recruit beta-arrestins-1 were retrospectively graded for VIPN using an and -2 but are unable to trigger PAR4-dependent intervention-based grading scale. Patients were calcium signaling. genotyped for CEP72 rs924607 and 7,907 ADME Conclusions: We have identified novel biased genetic variants. This was followed by a meta- peptide agonists for PAR4 and further work is analysis of pharmacogenomic data from over 500 underway to understand the structural basis for this patients. bias and to understand the physiological Results: Sex, vincristine duration, and use of consequence of biased signaling through PAR4. nifedipine differed significantly between VIPN cases Keywords: Proteinase activated receptor 4 (PAR4), and controls. CEP72 rs924607 was significantly G-protein coupled receptor (GPCR), Biased associated with VIPN (P=0.02, OR 3.4). Top ADME -5 agonism, variants included ABCC1 rs3784867 (P=5.34 x 10 , -4 OR 4.9), and SLC5A7 rs1013940 (P=9.00 x 10 , OR 8.6); genes involved in vincristine transport and 124. Pharmacogenomics of Vincristine-induced inherited neuropathy, respectively. The meta- Peripheral Neuropathy Implicates analysis identified an association with an expression Pharmacokinetic snd Inherited Neuropathy quantitative trait locus-related variant for TTPA Genes (rs10504361: P=6.85 x 10-4, OR 2.0), a gene associated with a heritable neuropathy-related Galen E. B. Wright1,2,3, Ursula Amstutz2,4,5, Britt I. condition. Drögemöller2,5, Joanne Shih2, Shahrad R. Rassekh2,4, Conclusions: By confirming that CEP72 rs924607 Michael R. Hayden1,2, Bruce C. Carleton2,4, and contributes towards VIPN risk in pediatric ALL, our Colin J.D. Ross2,5, and The Canadian analysis provides essential corroboratory evidence Pharmacogenomics Network for Drug Safety for this biomarker. Further, this study provides Consortium evidence for the role of drug transporter and 1Department of Medical Genetics, University of inherited neuropathy genes in VIPN. British Columbia, Vancouver, BC, Canada; 2BC Keywords: Adverse drug reactions; cancer; Children’s Hospital Research Institute, Vancouver, pharmacogenomics BC, Canada; 3Faculty of Pharmaceutical Sciences,

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Index

Birnbaumer, Lutz, 126 Bleier, Benjamin, 133 A Boehm, Jochen, 101 Abbasi, Azhar Z., 131 Boileau, Isabelle, 114, 118 Abbott, Frank, 1, 2 Bou‐Chacra, Nadia, 95 Abd‐Elrahman, Khaled S., 116 Brocks, Dion R., 110 Abdi, Reza, 139 Brooks, Beth, 119 Abyaneh, Hoda Soleymani, 96 Bugden, Shawn, 6, 34 Adb‐Elrahman, Khaled, 7, 49 Burczynski, Frank J., 143 Adibnia, Vahid, 127 Burger, Dylan, 120 Afsar, Nasir Ali, 117 Ahmad, Masood, 131 C Akhoundi, Fatemeh, 108 Akhtar, Muhammad, 135 Cai, Ping, 131 Al Lawati, Hanan, 99 Callender, Shannon P., 102 Al Nebaihi, Hamdah M., 110 Campbell, David, 142 Alam, Camille, 87 Campbell, Scott, 96 Alammari, Ahmad H., 124 Carlen, Peter, 10 Alcorn, Jane, 2, 125 Carleton, Bruce C., 3, 10, 59, 78, 115, 116, 118, 119, 149, 156 Alharbi. Abdulsalam, 102 Caron, Christine C., 113 Allen, Christine, 1, 2, 5, 9, 24, 26, 70, 90, 138 Casey, Andrew, 5, 24 Almousa, Ahmed, 125, 148 Cawthray, Jacqueline, 94, 97, 123 Alqahtani, Zuhair, 92, 162 Cerruti, Marta, 4, 9, 72, 137 Alrushaid, Samaa, 143 Chamberland, Guy, 5, 28 Alshikhey, Areej, 140 Chang, Hao Han, 139 Alwani, Saniya, 133 Chelle, Pierre, 109 Amidon, Gordon, 2, 6, 41 Chen, Kuan, 139 Amiji, Mansoor, 133 Chen, Peter, 9, 70 Amini, Mohammad A., 131 Chen, Wenliang, 151 Amstutz, Ursula, 156 Chen, Yufei, 98 Anantha, Malathi, 100 Chernov, Lina, 100 Anderson, Judy E., 143 Chidiac, Peter, 154 Andrew Casey, 24 Cho, Tiffany, 91 Andrew, Melissa K., 151 Chretien, Marc, 8 Angers, Stephane, 87 Chukwueke, Chidera C., 114 Arafat, Mosab, 97, 135 Clark, Doug, 6 Årstad, Erik, 91 Clifford, Tammy, 7, 44, 45 Asghar, Waheed, 104 Cohn, Iris, 132 Azadian, Aras, 5, 9, 26, 70 Cohn, Ronald D., 132 Collier, Abby C., 144, 145, 148 Connelly, Caitlin, 9, 63, 64 B Cooper, David, 94 Badea, Ildiko, 106, 133 Coughtrie, Michael W.H., 144, 145, 148 Baer, Brandon J., 112 Coull, Jeffrey, 5, 29 Baker, Steven K., 89 Cranston, Emily D., 95 Baldwin, Emily, 103 Critchley, Carol, 119 Bally, Marcel B., 100 Crown, Natalie, 10, 77, 78 Banquy, Xavier, 127 Cuddihy, Grace, 2, 94, 95 Barakat, Khaled, 124 Cummins, Carolyn L., 87, 129, 143 Bashi, Zafer Dallal, 106 Bedard, Philippe L., 119 D Bendayan, Reina, 87, 88 Bendyshe‐Walton, Tessa, 7, 49, 118 Dancey, Janet, 9, 62, 65 Benger, Ann, 89 Daneshtalab, Noriko, 2, 86 Bennett, Leah, 112 David, Laurent, 127 Bhatia, Shama, 113 Davies, Neal M., 125, 132, 143 Bhatti, Masood, 107 De Jong, Stephanie, 2, 92

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De Silva, Franklyn, 125 Goldman, I. David, 87 Delair, Thierry, 127 Gomes, Tara, 6, 33 Delplace, Vianney, 140 Gomez, David Perez, 107 Di Ciano, Patricia, 118 Gong, Yuhui, 96 Di, Yunyun, 94, 123 Gontijo, Sávio M.L., 138 Dietrich, Nadine, 126 Goodwin, Susan E., 89 Doschak, Michael R., 4, 104, 106, 125, 140 Gopal, Keshav, 107 Dou, Yannan N., 138 Goralski, Kerry B., 1, 3, 6, 38, 112, 151 Dragowska, Wieslawa H., 100 Gordijo, Claudia R., 131 Drake, Danielle M., 114, 138 Greco, Elizabeth R., 7, 49, 120 Dresser, George, 3, 6, 8, 58 Greschner, Andrea A., 136 Drögemöller, Britt I., 7, 49, 115, 116, 119, 149, 156 Groeneweg, Gabriella S., 118 Dufresne, Marie‐Hélène, 137 Gulilat, Markus, 7, 49, 121 Dunne, Michael, 9, 75, 138 Dutcher, John, 5, 29 Dybka, Ed, 6, 36 H Haak‐Frendscho, Mary, 5, 24 E Haik, Yousef, 139 Hall, Steve, 112 Edginton, Andrea N., 109, 144 Hamilton, Alison, 116 El‐Aneed, Anas, 106, 142 Hammes, Hans‐Peter, 126 Elias, Cynthia B., 85 Hamza, Amel, 106 El‐Kadi, Ayman O.S., 85, 124, 125, 143 Han, Yi Rang, 142 Elzagallaai, Abdelbaset A., 113 Hartjes, Emily D., 152 Engineer, Anish, 7, 49, 119, 120 Hawsawai, Ahlam, 125 Etwel, Fatma, 115 Hayden, Michael R., 119, 156 Evans, Connie, 101 Hendershot, Christian, 114, 118 Evans, James C., 9, 90, 138 Henderson, Jeffrey, 7, 46, 48, 128 Hirano, Naoto, 8, 52 Ho, Emmanuel, 2, 4, 6, 38, 98 F Hoang, Monica, 123 Faivre, Jimmy, 127 Hoare, Todd, 4, 9, 72, 90, 96 Fang, Cheng J., 120 Hofstein, Raphael (Rafi), 5, 25 Fang, Jay, 7, 49 Holloway, David, 101 Farazmand, Mohsen, 107 Holterman, Chet E., 120 Feng, Qingping, 119, 120 Houle, Sylvain, 118 Feng, Tianhua, 124 House, Andrew A., 150 Feng, Zhong‐Ping, 151 Huang, Jiahao, 141 Ferguson, Stephen S.G., 116 Husereau, Don, 7, 42, 43 Fernandes, Michaela, 155 Hutchinson, Shaunessy R., 116 Finnell, Richard H., 87 Hwang, Dae Kun, 85 Fleming, Thomas, 126 Fonge, Humphrey, 133 I Forrest, M. Laird, 125 Fraser, Graeme A.M., 89 Igamberdiev, Andre, 86, 127 Freichel, Marc, 126 Inoue, Akiko, 155 Iorio, Alphonso, 109 Issa, Mark, 112 G Ito, Shinya, 132 Gachumi, George, 106 Gamble, Jonathan, 142 J Gauthier, Marc A., 4, 96, 135 Gelmon, Karen A., 119, 149 Jamali, Fakhreddin, 1, 2, 6, 41, 92, 99, 162 Georgiou, Constantine, 87 Javar, Hamid Akbari, 98, 136 Gerdts, Volker, 97 Jeffrey Coull, 29 Ghulam, Jalani, 137 Jolfaee, Simin S.C., 101 Gilabert‐Oriol, Roger, 100 Jones, Allyson, 93 Gillies, Elizabeth, 9, 72 Jones, Douglas, 120 Glaser, Matthias, 91 Joseph, Jamie W., 123 Glinter, Shawn, 5, 27 Joshi, Shrinidh A., 7, 49, 152

158s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

Juurlink, David, 6, 32, 33 Lim, Yong, 152 Lim, Yong Jin, 119 Lin, Jennifer J., 115, 116 K Lin, Jihong, 126 Kalber, Tammy, 91 Lip, Ho Yin, 131 Kalyaanamoorthy, Subha, 124 Liu, Geoffrey, 119 Kane, Anil, 139 Liu, Yuejian, 144 Kara‐Yacoubian, Nareg, 88 Löbenberg, Raimar, 2, 95, 97, 104, 132, 134, 135, 140, 143, 162 Karsan, Aly, 9, 62 Logan, Heather, 6, 35 Kelly, Erin, 86, 127 Loucks, Catrina M., 115, 116 Kelly, Melanie, 5, 28 Lu, Xiangru, 119, 120 Kelschenbach, Jennifer, 88 Luyt, Len, 155 Kennedy, Chris R., 120 Lythgoe, Mark, 91 Khalid, Mohamed Nabil, 101, 105 Khalid, Nayab, 135 M Khan, Salman, 131 Khan, Tanveer, 131 Maayah, Zaid H., 124, 125, 143 Khokhar, Jibran, 9, 68 MacKinnon, Stephen, 5, 26, 27 Kiang, Tony K.L., 108 Macleod, Graham, 87 Kim, Hugh, 148 Magomedova, Lilia, 87, 129 Kim, Richard B., 121, 148 Mahajan, Natasha, 126 Kirchhoefer, Cathrin, 97 Majcher, Michael J., 90 Kitselman, Kayla, 86 Mak, Tak, 8, 50 Kleinberger, Rachelle, 90 Malik, Paul R.V., 144 Kobayashi, Yumiko, 150 Malik, Saima, 114 Kojovic, Dea, 146 Malnick, Stephen, 130 Kollmannsberger, Christian, 119 Manderville, John, 93 Koren, Gideon, 115 Mann, Kelsey, 2, 93, 94 Kort, M., 136 Mansell, Holly, 100 Kostelnik, Thomas. I., 94 Mansell, Sara E., 148 Kriebs, Ulrich, 126 Mansouri, Esmaeil, 114, 118 Krol, Ed, 133 Maor, Yaacov, 130 Kropp, Rhonda, 7, 43 Marius Braun, Ehud Melzer, 130 Kuentz, Martin, 96 Mathar, Ilka, 126 Kyriakopoulou, Lianna, 132 Matka, Christin, 126 McColl, Eliza R., 7, 49, 153 McCoy, Kathy, 8, 56 L McEneny‐King, Alanna, 109 Lagzdins, Dina, 118 Medert, Rebekka, 126 Lai, Dickson, 148 Medhar, Albayada, 8, 59 Lam, Angus, 96 Meziadi, Ahlem, 135 Lamont,Matthew G., 128 Mikov, Momir, 97 Larin, Christopher Gaudnik, 101 Miller, Donald, 6, 40 Latreille, Pierre‐Luc, 127 Miranda, Allan, 5, 25 Lau, Catherine, 1, 2, 5, 8, 50 Mirbagheri, Marziye, 85, 127 Lavasanifar, Afsaneh, 4, 99, 102, 162 Mirdamadi, Kamelia, 7, 49, 153 Le Foll, Bernard, 9, 69, 70, 114, 118 Mohammadizadeh, Sheyda, 108 Le, Tyson, 143 Mohammed, Munawar, 100, 142 LeClair, Daniel A., 95 Monzon, José G., 119 Leclaire, Marie‐Eve, 137 Morshead, Cindi, 7, 46 Leclerc, Estelle, 152 Munafò, Marcus, 9, 69 Lee, Nana, 6, 31 Murphy, Wayne, 10, 79, 80 Lee, Ping I., 142 Lee, Samuel S., 115, 116 N Leen, Jessica, 6, 8 Lefebvre, Francis, 2, 7, 49, 89, 90 Nagy, Andras, 7, 47 Leroux, Jean‐Christophe, 96 Nakano, Takashi, 150 LeSarge, Jordan Cole, 155 Nawroth, Peter, 126 Li, Jason, 131, 139 Neary, John, 89 Li, Shyh‐Dar, 105 Nelson, Brad, 8, 51, 52 Lichty, Brian D., 95 Neschadim, Anton, 5, 29, 30

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Neuman, Manuela G., 89, 130 Ross, Sue, 129 Neville, Erin, 142 Russell, Laura E., 148 Neville, Heather, 93 Rutka, James T., 151 Nguyen, Anne, 2, 105 Niederquell, Andreas, 96 Nolin, Thomas D., 150 S Nona, Christina N., 114 Sacevich, Calen, 142 Sachdeva, Robin, 126 O Sadelain, Michel, 8, 51 Sadowski, Cheryl, 93 Ohashi, Pamela, 8, 51 Sadowski, Lukas P., 90 Omeragic, Amila, 88 Said, Somiraa, 96 Orlowski, Tatiana, 101, 142 Saikali, Michael F., 143 Ortin‐Martinez, Arturo, 140 Saiyin, Tana, 120 Orvig, Chris, 94 Salmasi, Faraz, 128 Ozaki, T., 136 Samaha, Anne‐Noël, 3, 10, 83 Samudio, Ismael, 8, 54 Sarfraz, Muhammad, 97, 135 P Sayre, Casey L., 143 Pakulska, Malgosia, 140 Scherer, Stephen, 132 Pallaoro, Alessia, 100 Schlotterer, Andrea, 126 Parayath, Neha, 133 Schmerk, Crystal L., 148 Parker, Catherine, 6, 35 Schroer‐McFarland, Stephanie, 129 Parmar, Manoj B, 134 Schumacher, Dagmar, 126 Paton, Tara, 132 Schwarz, Ute I., 121 Pawar, Grishma, 133 Scott, Erika N., 149 Pedley, R. Barbara, 91 Servant, Marc J., 89 Pelis, Ryan, 6 Shalviri, Alireza, 139 Pereira, Stephen, 91 Shen, Yen Ting, 90 Perreault, J., 136 Shih, Joanne, 156 Pevererzev, Alexey I., 154 Shoichet, Molly S., 140 Pierre Thibeault, 49 Shoieb, Sherif M., 85 Piquette‐Miller, Micheline, 1, 10, 76, 77, 90, 109, 146, 153 Shoker, Ahmed, 100 Platt, Robert, 7, 44 Shortall, Samantha, 104 Poudel, Asmita, 106 Silva, Daniela Amaral, 132, 162 Pour, Navaz Karimian, 109 Silverman, Michael, 8, 56, 149 Preciado, Nahieli, 96 Simard, Pierre, 137 Price, Hayley R., 148 Siu, Lillian, 8 Pulinilkunnil, Thomas, 108 Siu, Wendy, 2, 87, 88 Siyam, Tasneem, 129 Skripka, Artiom, 137 R Smeets, Niels, 96 Rachid, Ousama, 139, 143 Smith, Alexander D., 145 Rahmouni, Miloud, 101, 105 Soeandy, Chesarahmia Dojo, 128 Rai, Raj, 133 Somin, Marina, 130 Rajakulendran, Nishani, 87 Spatz, Alan, 9, 64 Ramachandran, Rithwik, 155 Spence, David, 8, 56, 57 Ramji, Alnoor, 115, 116 Spence, Tara, 138 Rao, Praveen P. Nekkar, 92 Spreekmeester, Emma, 6, 34 Rassekh, Shahrad R., 118, 156 Stephen MacKinnon, 5, 26, 27 Rauth, Andrew M., 131 Stover, Harald, 90 Razzari, L., 136 Strom, Stacy, 97 Renouf, Daniel J., 119 Sun, Gavin R., 3, 8, 60 Reuter, Miriam, 132 Sun, Hong‐Shuo, 151 Rieder, Michael J., 3, 10, 81, 113 Surette, Michael, 8 Robson, Mathew, 91 Surmanski, Anette A., 7, 49, 154 Rong, Yan, 108 Sutherland, Brent, 100 Ropagnol, X., 136 Syeda, Jaweria, 97, 142 Ross, Colin J.D., 115, 116, 118, 119, 149, 156 Ross, Ruth, 9, 67

160s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada

T Vyas, Poorva, 86, 127 Tabatabaei Dakhili, Seyed Amirhossein, 107 W Tabrizchi, Reza, 86 Taddio, Anna, 10, 82, 83 Waldman, Stephen D., 85 Takitani, Kimitaka, 155 Wallace, Valerie, 140 Talachian, Kaivan, 9, 71 Wang, Jean, 7, 46, 47 Tam, Edward, 115, 116 Wang, Jian, 8, 54 Tam, Vivienne, 137 Wang, Lucy, 90, 138 Tamai, Hiroshi, 155 Wang, Susie, 91 Tanaka, Toshihiro, 150 Ward, Rachel, 2, 86, 127 Tanha, Shima, 98, 136 Wasan, Ellen K., 94, 97, 100, 101, 123, 142 Teal, Carter, 140 Wasan, Kishor M., 94, 97, 100, 123 Teft, Wendy A., 121 Weber, John T., 86, 127, 128 Thayumanavan, Sankaran, 9 Weinshilboum, Richard, 10, 76 Théberge, Karine, 137 Weir, Genevieve, 5, 30 Theivendra, Nalliah, 107 Weir, Matthew A., 150 Thibeault, Pierre, 7, 49, 155 Wells, George, 7, 42 Thibodeau, Jean‐Francois, 120 Wells, Laura, 103 Thompson, Benjamin K., 150 Wells, Peter G., 113, 114, 138 Thompson, Michael R., 95 Wettig, Shawn D., 6, 39, 102, 104, 141 Thomson, Jonathon, 2, 93 Wilson, Alan A., 118 Tirona, Rommel G., 121 Wishart, David, 106 Tobar, Ana, 130 Wolfram, Joy, 6, 40 Tong, Tiffany, 91 Wong, Nathaniel, 101 Tonial, Nicholas C., 150 Wong, Raymond, 151 Tonikian, Raffi, 9, 66 Wong‐Rieger, Durhane, 6, 37 Trang, Tuan, 6, 7, 32, 49 Woo, Minna, 129 Traore, Yannick, 98 Wright, Galen E.B., 3, 7, 8, 49, 60, 61, 115, 116, 119, 149, 156 Trenaman, Shanna C., 151 Wu, Xiao Yu, 131, 139 Trevors, Christopher, 10, 79 Trudeau, Katia, 137 Trueman, Jessica N., 115, 149 X Tsai, Ricky, 129 Xing, Zhou, 95 Tsai, Samuel En‐Leh, 140 Tsao, Ming, 9, 62 Tyndale, Rachel, 9, 67, 68 Y Tyndale, Rachel F., 118 Yamashita, Cory, 112 Yáñez, Jaime A., 143 U Yang, Andy, 87 Yang, Xiaolei, 125 Uetrecht, Jack, 91 Yavitt, Francis M., 90 Uludag, Hasan, 134 Yeung, Karen, 91 Urquhart, Bradley, 1, 8, 55, 57, 120, 150, 152, 154 Yeung, Pollen K., 108 Ussher, John R., 107 Yong Jin (James) Lim, 49 Yoshida, Eric M., 115, 116 V Yun, Yejin, 109 Vakili, Mohammad R., 99 Vakili, Mohammed R., 102 Z Vakilinezhad, Molood, 98, 136 Zahedi, Edmond, 101 Vassileva, Vessela, 9, 66, 91 Zappitelli, Mike, 10, 81 Velázquez‐Martínez, Carlos A., 104, 107 Zhang, Li, 131 Veldhuizen, Ruud A.W., 112 Zhang, Liangfang, 9, 74 Velenosi, Thomas J., 57, 150 Zhang, MengQi, 120 Venkatraman, Subramanian, 9 Zhang, Ti, 125 Vetrone, Fiorenzo, 137 Zhao, Peishen, 154 Villa, Diego, 149 Zhong, Xiao, 151 Viswanadham, KKR, 105 Zuberi, N., 136 Volsky, David J., 88 Zuo, Jieyu, 95

Translating Innovative Technology to Patient Care | 161s

Selected Articles Published in Journal of Pharmacy & Pharmaceutical Sciences

Analysis of patients with hypomagnesemia using the Japanese Adverse Drug Event Report database. Hiroyuki Tanaka et al. http://dx.doi.org/10.18433/JPPS29692

Functionalized Caprolactone-Polyethylene Glycol Based Thermo-Responsive Hydrogels of Silibinin for the Treatment of Malignant Melanoma. Afsaneh Lavasanifar et al. DOI: http://dx.doi.org/10.18433/jpps29726

Evaluation of the Benefits of De-Escalation for Patients with Sepsis in the Emergency Intensive Care Unit. Takahiro Niimura et al. DOI: http://dx.doi.org/10.18433/jpps29737

A Survey of the Regulatory Requirements for BCS-Based Biowaivers for Solid Oral Dosage Forms by Participating Regulators and Organisations of the International Generic Drug Regulators Programme . Joy Elizabeth van Oudtshoorn et al. DOI: http://dx.doi.org/10.18433/J36S7D

Effect of Cytochrome P450 (CYP) 2D6 Genetic Polymorphism on the Inhibitory Action of Antidepressants on CYP2D6-Mediated Dopamine Formation from p-Tyramine Toshiro Niwa et al. DOI: http://dx.doi.org/10.18433/jpps29673

Considerations and Pitfalls in Selecting the Drug Vehicles for Evaluation of New Drug Candidates: Focus on in vivo Pharmaco-Toxicological Assays Based on the Rotarod Performance Test. Mariana Matias et al. DOI: http://dx.doi.org/10.18433/jpps29656

Targeted Delivery of Amantadine-loaded Methacrylate Nanosphere-ligands for the Potential Treatment of Amyotrophic Lateral Sclerosis. Zamanzima Mazibuko , Sunaina Indermun , Mershen Govender , Pradeep Kumar , Lisa C du Toit et al. DOI: http://dx.doi.org/10.18433/jpps29595

Clinical Outcomes of Aspirin Interaction with Other Non-Steroidal Anti-Inflammatory Drugs: A Systematic Review. Zuhair Alqahtani , Fakhreddin Jamali. DOI: http://dx.doi.org/10.18433/jpps29854

Are Excipients Inert? Phenytoin Pharmaceutical Investigations with New Incompatibility Insights. Daniela Amaral Silva, Raimar Löbenberg, Neal Davies. DOI: http://dx.doi.org/10.18433/jpps29745

Treating Children with ASD: The Perspective of Caregivers Noor Breik et al. DOI: http://dx.doi.org/10.18433/jpps29829

162s | CSPS/CSPT/CC-CRS Conference 2018, Toronto, ON, Canada