Drug Interactions with New and Investigational Antiretrovirals
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Kan Lu, PharmD New Antiretrovirals for Based on a presentation at prn by Roy M. Gulick, md, mph the Treatment of HIV: Kan Lu, PharmD | Drug Development Fellow University of North Carolina School of Pharmacy Chapel Hill, North Carolina The View in 2006 Roy M. Gulick, md, mph Reprinted from The prn Notebook® | october 2006 | Dr. James F. Braun, Editor-in-Chief Director, Cornell Clinical Trials Unit | Associate Professor of Medicine, Meri D. Pozo, PhD, Managing Editor. Published in New York City by the Physicians’ Research Network, Inc.® Weill Medical College of Cornell University | New York, New York John Graham Brown, Executive Director. For further information and other articles available online, visit http://www.prn.org | All rights reserved. ©october 2006 substantial progress continues to be made in the arena of cokinetics and a long extracellular half-life of approximately 10 hours antiretroviral drug development. prn is again proud to present its annual (Zhu, 2003). During apricitabine’s development, a serious drug interac- review of the experimental agents to watch for in the coming months and tion with lamivudine (Epivir) was noted. Although the plasma years. This year’s review is based on a lecture by Dr. Roy M. Gulick, a long- concentrations of apricitabine were unaffected by coadministration of time friend of prn, and no stranger to the antiretroviral development lamivudine, the intracellular concentrations of apricitabine were reduced pipeline. by approximately sixfold. Additionally, the 50% inhibitory concentration To date, twenty-two antiretrovirals have been approved by the Food (ic50) of apricitabine against hiv with the M184V mutation was increased and Drug Administration (fda) for the treatment of hiv infection. -
Ep 2531027 B1
(19) TZZ ¥_Z _T (11) EP 2 531 027 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/4985 (2006.01) A61K 31/52 (2006.01) 06.05.2015 Bulletin 2015/19 A61K 31/536 (2006.01) A61K 31/513 (2006.01) A61K 38/55 (2006.01) A61P 31/18 (2006.01) (21) Application number: 11737484.3 (86) International application number: (22) Date of filing: 24.01.2011 PCT/US2011/022219 (87) International publication number: WO 2011/094150 (04.08.2011 Gazette 2011/31) (54) Therapeutic combination comprising dolutegravir, abacavir and lamivudine Therapeutische Zusammensetzung enthaltend Dolutegravir, Abacavir und Lamivudine Combinaison thérapeutique comprenant du dolutégravir, de l’abacavir et de la lamivudine (84) Designated Contracting States: (74) Representative: Gladwin, Amanda Rachel AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GlaxoSmithKline GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Global Patents (CN925.1) PL PT RO RS SE SI SK SM TR 980 Great West Road Designated Extension States: Brentford, Middlesex TW8 9GS (GB) BA ME (56) References cited: (30) Priority: 27.01.2010 US 298589 P WO-A1-2010/011812 WO-A2-2009/148600 US-A1- 2006 084 627 US-A1- 2006 084 627 (43) Date of publication of application: US-A1- 2008 076 738 US-A1- 2009 318 421 12.12.2012 Bulletin 2012/50 US-A1- 2009 318 421 US-B1- 6 544 961 (73) Proprietor: VIIV Healthcare Company • SONG1 et al: "The Effect of Ritonavir-Boosted Research Triangle Park, NC 27709 (US) ProteaseInhibitors on the HIV Integrase Inhibitor, S/GSK1349572,in Healthy Subjects", INTERNET , (72) Inventor: UNDERWOOD, Mark, Richard 15 September 2009 (2009-09-15), XP002697436, Research Triangle Park Retrieved from the Internet: URL:http: North Carolina 27709 (US) //www.natap.org/2009/ICCAC/ICCAC_ 52.htm [retrieved on 2013-05-21] Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. -
Microbicides 2008
State of the Network Ian McGowan & Sharon Hillier Annual Meeting March 14th, 2016 HIV Infection in the US HIV Infection in US MSM HIV Infection in US Women Global HIV Infection HIV Incidence Rates in ASPIRE & RING Studies ASPIRE Study RING Study 10 8 6 4 2 HIV Incidence Rates (%) Rates Incidence HIV 0 <21 years > 25 years 18-21 years22-26 years27-45 years 21-25 years The PrEP Landscape in 2016 (1) • Oral PrEP – Optimization of Truvada delivery – Increasing availability – US, Canada, France, South Africa, Kenya, Israel – 2nd generation regimens being evaluated • Maraviroc combinations • Tenofovir alafenamide – New molecules • EFdA (Merck) The PrEP Landscape in 2016 (2) • Injectable PrEP – Rilpivirine & Cabotegravir • Intravaginal rings – Phase 3 • Dapivirine – Phase 1/2 • Tenofovir • Tenofovir disoproxil fumarate • Vicriviroc + MK 2048 • Dapivirine + Levonorgestrol The PrEP Landscape in 2016 (3) • Rectal microbicides – Phase 2 • Reduced glycerin tenofovir gel – Phase 1 • Maraviroc • Dapivirine • Griffithsin • MIV-150 / Carageenan / Zinc • Implantable PrEP MTN Highlights from the Past Year The MTN Portfolio 2015 / 2016 Studies in Ongoing development: Completed studies MTN-026 studies MTN-030 MTN-015 MTN-031 MTN-017 MTN-016 MTN-032 MTN-020 MTN-023 MTN-033 MTN-024 MTN-027 MTN-028 MTN-034 MTN-029 MTN-035 MTN-036 MTN-037 Intravaginal Ring Studies • Dapivirine • Vicriviroc / MK-2048 – MTN-020 – MTN-027 & MTN-028 – MTN-023 • Dapivirine 200 mg – MTN-025 (HOPE) IVR – MTN-029 – MTN-036 / IPM 047 – MTN-031 – MTN-034 • Dapivirine / Levonorgestrel – MTN-030 / IPM 041 Rectal Microbicide Studies • Tenofovir gel – MTN-017 • Dapivirine gel – MTN-026 – MTN-033 – MTN-035 CHARM-02 Study (Hiruy H et al. -
Semen-Mediated Enhancement of HIV-1 Infection Markedly Impairs the Antiviral Efficacy of Microbicides
Institute of Molecular Virology Ulm University Medical Center Prof. Dr. Frank Kirchhoff Semen-mediated enhancement of HIV-1 infection markedly impairs the antiviral efficacy of microbicides Dissertation to obtain the Doctoral Degree of Human Biology (Dr. biol. hum.) at the Faculty of Medicine, University of Ulm presented by Onofrio Zirafi Heidenheim an der Brenz 2014 Present Dean: Prof. Dr. Thomas Wirth 1st reviewer: Prof. Dr. Jan Münch 2nd reviewer: Prof. Dr. Barbara Spellerberg Date of graduation: 5th December 2014 TABLE OF CONTENTS III TABLE OF CONTENTS ABBREVIATIONS ............................................................................................................. V 1 INTRODUCTION ....................................................................................................... 1 1.1 HIV LIFE CYCLE AND ANTIRETROVIRAL DRUGS .......................................................... 2 1.2 HIV TRANSMISSION ................................................................................................... 4 1.3 FACTORS IN SEMEN MODULATING HIV-1 INFECTION .................................................. 5 1.4 MECHANISM OF INFECTION ENHANCEMENT BY SEMINAL AMYLOIDS ........................... 6 1.5 COUNTERACTING AMYLOID-MEDIATED ENHANCEMENT OF HIV-1 INFECTION ............ 6 1.6 STRUCTURE-BASED PEPTIDE INHIBITORS OF AMYLOID FORMATION ............................. 7 1.7 MICROBICIDES ............................................................................................................ 8 1.8 SCIENTIFIC AIM ........................................................................................................ -
Synthesis and Development of Long-Acting Abacavir Prodrug Nanoformulations
University of Nebraska Medical Center DigitalCommons@UNMC Theses & Dissertations Graduate Studies Summer 8-19-2016 Synthesis and Development of Long-Acting Abacavir Prodrug Nanoformulations Dhirender Singh University of Nebraska Medical Center Follow this and additional works at: https://digitalcommons.unmc.edu/etd Part of the Pharmaceutical Preparations Commons, and the Virus Diseases Commons Recommended Citation Singh, Dhirender, "Synthesis and Development of Long-Acting Abacavir Prodrug Nanoformulations" (2016). Theses & Dissertations. 140. https://digitalcommons.unmc.edu/etd/140 This Dissertation is brought to you for free and open access by the Graduate Studies at DigitalCommons@UNMC. It has been accepted for inclusion in Theses & Dissertations by an authorized administrator of DigitalCommons@UNMC. For more information, please contact [email protected]. SYNTHESIS AND DEVELOPMENT OF LONG-ACTING ABACAVIR PRODRUG NANOFORMULATIONS by Dhirender Singh A DISSERTATION Presented to the Faculty of the Graduate School in the University of Nebraska Medical Center in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Department of Pharmaceutical Science Under the Supervision of Dr. Howard E. Gendelman University of Nebraska Medical Center, Omaha, Nebraska August 2016 Supervisory Committee: Howard E. Gendelman, M.D. Ram Mahato, Ph.D JoEllyn M. McMillan, Ph.D. David Oupicky, Ph.D SYNTHESIS AND DEVELOPMENT OF LONG-ACTING ABACAVIR PRODRUG NANOFORMULATIONS Dhirender Singh, Ph.D. University of Nebraska Medical Center, 2016 Supervisor: Howard E Gendelman, M.D. Over the past decade, work from our laboratory has demonstrated the potential of targeted nanoformulated antiretroviral therapy (nanoART) to produce sustained high plasma and tissue drug concentrations for weeks following a single intramuscular (IM) administration that can suppress ongoing viral replication and mitigate dose associated viral resistance. -
What Lessons Can We Learn from 20 Years of Chemokine T D Di ? Receptor
What lessons can we learn from 20 years of chemokine receptdtor drug discovery? John G. Cumming, PhD 5th RSC / SCI symposium on GPCRs in Medicinal Chemistry 15th-17th September 2014, Actelion, Allschwil, Basel, Switzerland Outline Background: chemokines and their receptors Chemokine receptor drug discovery and development Emerging opportunities for chemokine drug discovery Conclusions and learning Chemokines and chemokine receptors CXC(α) • Chemokines (chemoattractant cytokines) are 70-120 aa proteins • 44 chemokines in 4 major families and 22 chemokine receptors in human genome • ‘Cell positioning system’ in the body • Many receptors bind multiple ligands • Many ligands bind multiple receptors Chemotaxis Human monocytes + CCL2 (red) Volpe et al. PLoS ONE 2012, 7(5), e37208 CCR2 antagonists inhibit chemotaxis and infiltration Vasculature CCL2 release Spinal or Peripheral Tissue Recruited monocyte Site of CCL2 release CCR2 antagonists inhibit chemotaxis and infiltration CCR2 antagonist Circulating monocyte CCL2 release CCL2 release from peripheral injury site or central PAF terminals Role of chemokine system in pathophysiology • Potential role in inflammatory and autoimmune diseases: Multiple sclerosis, Rheumatoid arthritis, COPD, allergic asthma, IBD, psoriasis - Expression levels of chemokines and receptors in relevant tissues and organs of patients and animal disease models - Mouse knockout ppyphenotype in disease models • Established role in HIV infection Katschke et al., 2001 Arthritis Rheum, 44, 1022 - CCR5 and CXCR4 act as HIV-1 -
A Novel Small Molecule CCR5 Inhibitor Active Against R5-Tropic HIV-1S
www.nature.com/scientificreports OPEN Activity and structural analysis of GRL-117C: a novel small molecule CCR5 inhibitor active against R5- Received: 24 September 2018 Accepted: 1 March 2019 tropic HIV-1s Published: xx xx xxxx Hirotomo Nakata1,2, Kenji Maeda 3, Debananda Das 1, Simon B. Chang1, Kouki Matsuda3, Kalapala Venkateswara Rao4, Shigeyoshi Harada5, Kazuhisa Yoshimura5, Arun K. Ghosh4 & Hiroaki Mitsuya1,2,3 CCR5 is a member of the G-protein coupled receptor family that serves as an essential co-receptor for cellular entry of R5-tropic HIV-1, and is a validated target for therapeutics against HIV-1 infections. In the present study, we designed and synthesized a series of novel small CCR5 inhibitors and evaluated their antiviral activity. GRL-117C inhibited the replication of wild-type R5-HIV-1 with a sub-nanomolar IC50 value. These derivatives retained activity against vicriviroc-resistant HIV-1s, but did not show activity against maraviroc (MVC)-resistant HIV-1. Structural modeling indicated that the binding of compounds to CCR5 occurs in the hydrophobic cavity of CCR5 under the second extracellular loop, and amino acids critical for their binding were almost similar with those of MVC, which explains viral cross- resistance with MVC. On the other hand, one derivative, GRL-10018C, less potent against HIV-1, but more potent in inhibiting CC-chemokine binding, occupied the upper region of the binding cavity with its bis-THF moiety, presumably causing greater steric hindrance with CC-chemokines. Recent studies have shown additional unique features of certain CCR5 inhibitors such as immunomodulating properties and HIV-1 latency reversal properties, and thus, continuous eforts in developing new CCR5 inhibitors with unique binding profles is necessary. -
Current Status and Prospects of HIV Treatment
Available online at www.sciencedirect.com ScienceDirect Current status and prospects of HIV treatment 1 2 Tomas Cihlar and Marshall Fordyce Current antiviral treatments can reduce HIV-associated at suppressing plasma viremia, and significant progress morbidity, prolong survival, and prevent HIV transmission. has been made toward regimen simplification through the Combination antiretroviral therapy (cART) containing preferably combination of three active drugs into single-tablet regi- three active drugs from two or more classes is required for mens (STRs) (Figure 1) and optimization of drug profiles durable virologic suppression. Regimen selection is based on that maximize long-term tolerability and safety. Lifelong, virologic efficacy, potential for adverse effects, pill burden and chronic therapy without treatment interruption is the dosing frequency, drug–drug interaction potential, resistance standard of care, and the availability of multiple effective test results, comorbid conditions, social status, and cost. With drugs in several classes with differing resistance, safety, prolonged virologic suppression, improved clinical outcomes, and tolerability profiles provides choices after failure of and longer survival, patients will be exposed to antiretroviral first-line treatment. agents for decades. Therefore, maximizing the safety and tolerability of cART is a high priority. Emergence of resistance Herein, we review the current status of antiretroviral and/or lack of tolerability in individual patients require therapy and guidelines for HIV-infected adults, as well availability of a range of treatment options. Development of new as prospects for further innovation in HIV treatment to drugs is focused on improving safety (e.g. tenofovir benefit patients and optimize their long-term health. alafenamide) and/or resistance profile (e.g. -
HIV - Cancer ®
Leronlimab (PRO 140) ® HIV - Cancer ® INVESTOR PRESENTATION January 2019 Professor Richard G. Pestell M.D., Ph.D., MB., B.S., F.A.C.P., F.R.A.C.P., F.A.A.A.S., M.B.A. Vice Chairman and Chief Medical Officer Nader Pourhassan Ph.D., President & CEO OTCQB: CYDY www.cytodyn.com Forward-Looking Statements This presentation contains certain forward-looking statements that involve risks, uncertainties and assumptions that are difficult to predict, including statements regarding leronlimab’s efficacy in certain cancer indications, the predictive value or benefit from the Company’s prostate cancer prognostic test, the Company’s clinical focus, and the Company’s current and proposed trials. Words and expressions reflecting optimism, satisfaction or disappointment with current prospects, as well as words such as “believes,” “hopes,” “intends,” “estimates,” “expects,” “projects,” “plans,” “anticipates” and variations thereof, or the use of future tense, identify forward-looking statements, but their absence does not mean that a statement is not forward-looking. The Company’s forward- looking statements are not guarantees of performance and actual results could differ materially from those contained in or expressed by such statements. In evaluating all such statements, the Company urges investors to specifically consider the various risk factors identified in the Company’s Form 10-K for the fiscal year ended May 31, 2018 in the section titled “Risk Factors” in Part I, Item 1A, and in our Form 10-Q for the quarterly period ended August 31, 2018 in the section titled “Risk Factors” in Part II, Item 1A, any of which could cause actual results to differ materially from those indicated by the Company’s forward-looking statements. -
Background Paper 6.7 Human Immunodeficiency Virus (HIV)/ Acquired Immune Deficiency Syndromes (AIDS)
Priority Medicines for Europe and the World "A Public Health Approach to Innovation" Update on 2004 Background Paper Written by Warren Kaplan Background Paper 6.7 Human Immunodeficiency Virus (HIV)/ Acquired Immune Deficiency Syndromes (AIDS) By Warren Kaplan, Ph.D., JD, MPH 15 February 2013 Update on 2004 Background Paper, BP 6.7 HIV/AIDS Table of Contents What is new since 2004? ..................................................................................................................................... 4 1. Introduction ................................................................................................................................................. 7 2. What are the Epidemiological Trends for Europe and the World? ................................................... 7 2.1 Western and Central Europe ............................................................................................................. 7 2.2 Eastern Europe .................................................................................................................................... 9 2.2 The World (including Europe) ........................................................................................................ 11 3. What is the Control Strategy? Is There an Effective Package of Control Methods Assembled into a “Control Strategy” for Most Epidemiological Settings?................................................................. 13 3.1 Is there a pharmaceutical ‘gap’? .................................................................................................... -
Leronlimab, a Humanized Monoclonal Antibody to CCR5, Blocks Breast Cancer Metastasis and Enhances Cell Death Induced by DNA Dama
Leronlimab, a humanized monoclonal antibody to CCR5, blocks breast cancer metastasis and enhances cell death induced by DNA damaging chemotherapy Xuanmao Jiao1, Min Wang1, Zhiping Li1, Richard G. Pestell1, 2, 3, * 1Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA., 18902. 2CytoDyn Inc., 1111 Main St, Suite 660, Vancouver, WA, 98660. 3Lee Kong Chian School of Medicine, Nanyang Technological University, 637551, Singapore. Abstract 1.The binding of Leronlimab with CCR5 expressed in 2. The effects of PRO140 on CCL5 induced Ca2+ responses in breast cancer cells MDA-MB-231-CCR5 cells Purpose of the study. To assess binding and functional interaction of the humanized monoclonal antibody to CCR5 (Leronlimab) with A B A 20 sec before 60 sec after 240 sec after 60 sec after B C human breast cancer cell lines. The G protein coupled receptor CCR5, is adding CCL5 adding CCL5 adding CCL5 adding FBS FBS 4 CCL5 4 FBS - Leronlimab Leronlimab Leronlimab 1600 - 1600 CCL5 normally expressed on a subset of T cells and serves as a co-receptor 140 µg/ml 70 µg/ml 35 µg/ml 120 1200 1200 for HIV infection. During malignant transformation CCR5 expression is 100 800 800 80 known to increase in a number of cancers (breast cancer (BCa), Control 400 400 Mean FI of Fluo FI ofMean 60 Contro Fluo FI ofMean PRO140 prostate cancer, colon cancer, melanoma). CCR5 targeted cancer 0 l 0 40 0 200 400 600 800 1000 0 200 400 600 800 1000 clinical trials using small molecular inhibitors opened to accrual in late 20 Time Time (Sec) (Sec) binding to CCR5 (%) (%) CCR5 to binding 2018. -
Can the Further Clinical Development of Bevirimat Be Justified?
SwatiCE: Swati; QAD/201969; Total nos of Pages: 2; QAD 201969 EDITORIAL COMMENT Can the further clinical development of bevirimat be justified? Mark A. Wainberga and Jan Albertb AIDS 2010, 24:000–000 Keywords: bevirimat, protease inhibitor resistance HIV-infected patients who fail standard therapeutic Not surprisingly, however, HIV resistance against BVM regimens are in need of new drugs that will remain has been selected in tissue culture. Mutations responsible active against drug-resistant viral variants. There is a for resistance have been identified within flanking constant need to develop new compounds that will not be sequences of the p24/p2 cleavage site and have been compromised by problems of cross-resistance, as so often confirmed as possessing biological relevance by site- occurs among members of the same family of drugs, for directed mutagenesis [3]. These mutations can sometimes example, nucleoside reverse transcriptase inhibitors interfere with the ability of BVM to bind to its target, (NRTIs), nonnucleoside reverse transcriptase inhibitors although, in most cases, increased cleavage efficiency at (NNRTIs), and protease inhibitors. Indeed, successful the p24/p2 junction may also occur [3,4]. second-line and salvage regimens will commonly include members of drug classes to which a patient has not Recent results have revealed that naturally occurring previously been exposed, for example, a protease inhibi- polymorphisms located within p2, close to the p24 tor and an integrase strand transfer inhibitor (INSTI) in cleavage site, may be present in some individuals, the case of an individual who began therapy with two resulting in lower BVM anti-HIV efficacy. In addition, NRTIs and a NNRTI, as well as the use of fusion clinical investigators have long suspected that BVM might inhibitors, for example, enfuvirtide, and CCR5 antago- potentially be less effective in the treatment of patients nists, for example, maraviroc.