IX Updating Course of Antimicrobials and Infectious Diseases
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Predictive QSAR Tools to Aid in Early Process Development of Monoclonal Antibodies
Predictive QSAR tools to aid in early process development of monoclonal antibodies John Micael Andreas Karlberg Published work submitted to Newcastle University for the degree of Doctor of Philosophy in the School of Engineering November 2019 Abstract Monoclonal antibodies (mAbs) have become one of the fastest growing markets for diagnostic and therapeutic treatments over the last 30 years with a global sales revenue around $89 billion reported in 2017. A popular framework widely used in pharmaceutical industries for designing manufacturing processes for mAbs is Quality by Design (QbD) due to providing a structured and systematic approach in investigation and screening process parameters that might influence the product quality. However, due to the large number of product quality attributes (CQAs) and process parameters that exist in an mAb process platform, extensive investigation is needed to characterise their impact on the product quality which makes the process development costly and time consuming. There is thus an urgent need for methods and tools that can be used for early risk-based selection of critical product properties and process factors to reduce the number of potential factors that have to be investigated, thereby aiding in speeding up the process development and reduce costs. In this study, a framework for predictive model development based on Quantitative Structure- Activity Relationship (QSAR) modelling was developed to link structural features and properties of mAbs to Hydrophobic Interaction Chromatography (HIC) retention times and expressed mAb yield from HEK cells. Model development was based on a structured approach for incremental model refinement and evaluation that aided in increasing model performance until becoming acceptable in accordance to the OECD guidelines for QSAR models. -
Where Do Novel Drugs of 2016 Fit In?
FORMULARY JEOPARDY: WHERE DO NOVEL DRUGS OF 2016 FIT IN? Maabo Kludze, PharmD, MBA, CDE, BCPS, Associate Director Elizabeth A. Shlom, PharmD, BCPS, SVP & Director Clinical Pharmacy Program Acurity, Inc. Privileged and Confidential August 15, 2017 Privileged and Confidential Program Objectives By the end of the presentation, the pharmacist or pharmacy technician participant will be able to: ◆ Identify orphan drugs and first-in-class medications approved by the FDA in 2016. ◆ Describe the role of new agents approved for use in oncology patients. ◆ Identify and discuss the role of novel monoclonal antibodies. ◆ Discuss at least two new medications that address public health concerns. Neither Dr. Kludze nor Dr. Shlom have any conflicts of interest in regards to this presentation. Privileged and Confidential 2016 NDA Approvals (NMEs/BLAs) ◆ Nuplazid (primavanserin) P ◆ Adlyxin (lixisenatide) ◆ Ocaliva (obeticholic acid) P, O ◆ Anthim (obitoxaximab) O ◆ Rubraca (rucaparib camsylate) P, O ◆ Axumin (fluciclovive F18) P ◆ Spinraza (nusinersen sodium) P, O ◆ Briviact (brivaracetam) ◆ Taltz (ixekizumab) ◆ Cinqair (reslizumab) ◆ Tecentriq (atezolizumab) P ◆ Defitelio (defibrotide sodium) P, O ◆ Venclexta (venetoclax) P, O ◆ Epclusa (sofosburvir and velpatasvir) P ◆ Xiidra (lifitigrast) P ◆ Eucrisa (crisaborole) ◆ Zepatier (elbasvir and grazoprevir) P ◆ Exondys 51 (eteplirsen) P, O ◆ Zinbyrta (daclizumab) ◆ Lartruvo (olaratumab) P, O ◆ Zinplava (bezlotoxumab) P ◆ NETSTPOT (gallium Ga 68 dotatate) P, O O = Orphan; P = Priority Review; Red = BLA Privileged and Confidential History of FDA Approvals Privileged and Confidential Orphan Drugs ◆FDA Office of Orphan Products Development • Orphan Drug Act (1983) – drugs and biologics . “intended for safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S. -
Antimicrobial Resistance in Companion Animal Pathogens in Australia and Assessment of Pradofloxacin on the Gut Microbiota
Antimicrobial resistance in companion animal pathogens in Australia and assessment of pradofloxacin on the gut microbiota Sugiyono Saputra A thesis submitted in fulfilment of the requirements of the degree of Doctor of Philosophy School of Animal and Veterinary Sciences The University of Adelaide February 2018 Table of Contents Thesis Declaration ...................................................................................................................... iii Dedication ................................................................................................................................. iv Acknowledgement ...................................................................................................................... v Preamble .................................................................................................................................... vi List of Publications ..................................................................................................................... vii Abstract .......................................................................................................................................ix Chapter 1 General Introduction ................................................................................................. 1 1.1. Antimicrobials and their consequences ............................................................................ 2 1.2. The emergence and monitoring AMR................................................................................ 2 -
Classification Decisions Taken by the Harmonized System Committee from the 47Th to 60Th Sessions (2011
CLASSIFICATION DECISIONS TAKEN BY THE HARMONIZED SYSTEM COMMITTEE FROM THE 47TH TO 60TH SESSIONS (2011 - 2018) WORLD CUSTOMS ORGANIZATION Rue du Marché 30 B-1210 Brussels Belgium November 2011 Copyright © 2011 World Customs Organization. All rights reserved. Requests and inquiries concerning translation, reproduction and adaptation rights should be addressed to [email protected]. D/2011/0448/25 The following list contains the classification decisions (other than those subject to a reservation) taken by the Harmonized System Committee ( 47th Session – March 2011) on specific products, together with their related Harmonized System code numbers and, in certain cases, the classification rationale. Advice Parties seeking to import or export merchandise covered by a decision are advised to verify the implementation of the decision by the importing or exporting country, as the case may be. HS codes Classification No Product description Classification considered rationale 1. Preparation, in the form of a powder, consisting of 92 % sugar, 6 % 2106.90 GRIs 1 and 6 black currant powder, anticaking agent, citric acid and black currant flavouring, put up for retail sale in 32-gram sachets, intended to be consumed as a beverage after mixing with hot water. 2. Vanutide cridificar (INN List 100). 3002.20 3. Certain INN products. Chapters 28, 29 (See “INN List 101” at the end of this publication.) and 30 4. Certain INN products. Chapters 13, 29 (See “INN List 102” at the end of this publication.) and 30 5. Certain INN products. Chapters 28, 29, (See “INN List 103” at the end of this publication.) 30, 35 and 39 6. Re-classification of INN products. -
Jonathan Butcher, Polyphor, Switzerland
1 BIO 2016 Global Workshop for Novel Anti-Infectives by Jonathan J. Butcher PhD, Polyphor Ltd, Hegenheimermattweg 125, CH-4123, Allschwil, Switzerland Discovery and Development of Novel Macrocycle Antibiotics BIO 2016 Global Workshop for Novel Anti-Infectives – June 6, 2016 2 Murepavadin (POL7080) A once in a generation discovery POL7080, antibiotic against Pseudomonas with a new mode of action POL0067 POL6137 POL7001 POL7080 CCS Protegrin I (1ZY6) Pseudomonas specific! PK/ADMET optimization Srinivas, S., et al. (2010) Science, 327: 1010 – 1012 Very potent and narrow MIC distribution Efficacy of POL7080 in a murine pneumonia (400 recent Pseudomonas strains) model against Pseudomonas aeruginosa (clinical isolate PAX11045, MIC = 0.125 mg/mL) EUCAST Antimicrobial MIC MIC Range 7 50 90 %S / %R Murepavadin 0.12 0.25 0.06 - 1 - / - 6 300 Meropenem 0.5 16 <0.03 - >64 73 / 13 MIC50 Ciprofloxacin 0.12 16 <0.06 - >32 73 / 22 Colistin 1 1 0.25 - 2 100 / - 5 200 CFU/lung 10 4 Log 3 MIC90 100 Number of isolates Numberof 2 Number of isolates of Number MIC99 0 Vehicle 0.06 0.125 0.25 0.5 11 0.5 0.06 0.25 0.125MIC (μg/mL) MIC (µg/mL) MIC (g/ml) Start of treatment POL7080POL7080 5.5 mg/kgPOL7080 11 mg/kgPOL7080 15 mg/kg 22 mg/kg POL7080 2.75 mg/kg Very potent anti-Pseudomonas activity, rapidly bactericidal at 2-4 times the MIC, with a narrow WT distribution. Excellent in vivo efficacy and safety in broad range of systemic infection models, allowed for FIM studies BIO 2016 Global Workshop for Novel Anti-Infectives – June 6, 2016 3 Murepavadin (POL7080) New class of anti-Pseudomonal antibiotics with novel mode of action PK snapshot and summary of clinical studies ongoing or completed AUC and C increase linearly with dose, t is approx. -
Recurrent Clostridioides Difficile Infection by Disrupting the Mouth for 10 Days Followed by Rifaximin Normal Colonic Microbiota
MEDICAL GRAND ROUNDS TAKE-HOME CME MOC Constantine Tsigrelis, MD POINTS FROM Department of Infectious Disease, Cleveland Clinic; LECTURES BY Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, CLEVELAND Cleveland, OH CLINIC AND VISITING FACULTY Recurrent Clostridioides difficile infection: Recognition, management, prevention ABSTRACT LOSTRIDIOIDES (formerly Clostridium) C difficile)is an anaerobic spore-forming ba- Clostridioides difficile infection (CDI) is the cillus that colonizes the intestinal tract in pa- most common cause of diarrhea in hospi- tients whose normal gut microbiota is disrupt- talized patients and results in substantial ed by antibiotic therapy.1 C difficile produces morbidity, mortality, and costs. Its clinical 2 major toxins—toxins A and B—that cause management, primarily with antibiotics, is intestinal mucosal injury, diarrhea, and colitis, often complicated by recurrent episodes. and in some cases, fulminant infection leading These recurrent CDI episodes are thought to shock, ileus, and toxic megacolon.2 C difficile to be caused by antibiotic disruption of co- infection (CDI) recurs in up to one-quarter or lonic microbiota and usually occur within 4 more of treated patients, complicating its man- weeks of completing antibiotic therapy. The agement. risk of recurrent CDI increases after the first In the United States, C difficile is a com- episode, creating a need for management mon hospital-acquired infection, affecting strategies to diagnose, treat, and prevent about 500,000 patients annually, causing up these complications. to 30,000 deaths, and incurring inpatient costs Diagnosis of nearly $5 billion.2–4 This article reviews the KEY POINTS current standards for diagnosing and treating requires CDI and discusses strategies for managing and unexplained Diagnostic testing for CDI should be per- preventing recurrent disease. -
(12) Patent Application Publication (10) Pub. No.: US 2017/0172932 A1 Peyman (43) Pub
US 20170172932A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0172932 A1 Peyman (43) Pub. Date: Jun. 22, 2017 (54) EARLY CANCER DETECTION AND A 6LX 39/395 (2006.01) ENHANCED IMMUNOTHERAPY A61R 4I/00 (2006.01) (52) U.S. Cl. (71) Applicant: Gholam A. Peyman, Sun City, AZ CPC .......... A61K 9/50 (2013.01); A61K 39/39558 (US) (2013.01); A61K 4I/0052 (2013.01); A61 K 48/00 (2013.01); A61K 35/17 (2013.01); A61 K (72) Inventor: sham A. Peyman, Sun City, AZ 35/15 (2013.01); A61K 2035/124 (2013.01) (21) Appl. No.: 15/143,981 (57) ABSTRACT (22) Filed: May 2, 2016 A method of therapy for a tumor or other pathology by administering a combination of thermotherapy and immu Related U.S. Application Data notherapy optionally combined with gene delivery. The combination therapy beneficially treats the tumor and pre (63) Continuation-in-part of application No. 14/976,321, vents tumor recurrence, either locally or at a different site, by filed on Dec. 21, 2015. boosting the patient’s immune response both at the time or original therapy and/or for later therapy. With respect to Publication Classification gene delivery, the inventive method may be used in cancer (51) Int. Cl. therapy, but is not limited to such use; it will be appreciated A 6LX 9/50 (2006.01) that the inventive method may be used for gene delivery in A6 IK 35/5 (2006.01) general. The controlled and precise application of thermal A6 IK 4.8/00 (2006.01) energy enhances gene transfer to any cell, whether the cell A 6LX 35/7 (2006.01) is a neoplastic cell, a pre-neoplastic cell, or a normal cell. -
761046Orig1s000
CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761046Orig1s000 MICROBIOLOGY/VIROLOGY REVIEW(S) Division of Anti-Infective Products Clinical microbiology Review BLA761046 Bezlotoxumab BLA: 761046 Date Submitted: 11-22-15 Date Received by CDER: 11-23-15 Date Assigned: 12-1-15 Date Completed: 4-19-16 Reviewer: Kerian Grande Roche, Ph.D. APPLICANT: Merck Sharp and Dohme Corp., a subsidiary of Merck and Co., Inc. (Merck) DRUG PRODUCT NAMES: Proprietary: Bezlotoxumab Nonproprietary: CDB1, MK6072 Antibody Class: IgG1/kappa isotype subclass Molecular Weight: 148.2 kDa DRUG CATEGORY: Human monoclonal antibody to C. difficile Toxin B PROPOSED INDICATION: Prevention of Clostridium difficile infection (CDI) recurrence in patients 18 years or older receiving antibiotic therapy for CDI PROPOSED DOSAGE FORM, STRENGTH, ROUTE OF ADMINISTRATION AND DURATION OF TREATMENT: MK-6072 drug product is a sterile, aqueous solution. Vials contain a target deliverable dose of 40 mL of 25mg/mL MK-6072 for a total of 1000 mg per vial. MK-6072 drug product is diluted (b) (4) prior to administration. The recommended dose of bezlotoxumab is 10 mg/kg by intravenous infusion over 60 minutes in one dose. DISPENSED: Rx RELATED PRODUCTS: N/A REMARKS: This submission is for an original Biologics License Application (BLA) for bezlotoxumab injection for intravenous use. Bezlotoxumab (MK-6072) is a fully human monoclonal antibody (mAb) of the IgG1/kappa isotype subclass that binds to Clostridium difficile (C. difficile) toxin B. CONCLUSIONS AND RECOMMENDATIONS: From clinical microbiology perspective, this BLA submission is approvable pending an accepted version of the labeling. See FDA’s proposed version of the microbiology section of the labeling below (this may not be the final Agency label as discussions are still ongoing). -
Revisión Bibliográfica
Vol. 34 (1), Marzo 2017. ISSN 1409-0015 Medicina Legal de Costa Rica - Edición Virtual REVISIÓN BIBLIOGRÁFICA Antibioticoterapia y nuevas terapias no farmacológicas en infecciones por Clostridium difficile Barrientos Jiménez, Maryam1; Esquivel Zúñiga, María Rebeca2; 3 4 5 Álvarez Umaña Silvia Vanessa ; Tencio Araya, Jose ; Soto Cerdas Jahaira Resumen: La infección por Clostridium difficile es la principal causa de diarrea infecciosa en pacientes hospitalizados. Los pacientes pueden ser portadores asintomáticos o presentar desde una diarrea leve a una colitis pseudomembranosa, megacolon tóxico, sepsis y muerte. El manejo de esta infección sigue presentando puntos de controversia, tanto en la elección del mejor método diagnóstico como en el tratamiento. En los casos en los cuales la infección por este agente fue confirmada la primera y más efectiva medida es suspender la antibioticoterapia que el paciente este recibiendo, en la medida de lo posible. El tratamiento se basa en tres agentes clásicos: metronidazol, vancomicina y teicoplanina con la más reciente adición de fidaxomicina y ridinilazol. Pacientes con presentación severa muchas veces requieren resolución quirúrgica además de las medidas de soporte y monitoreo. El objetivo de esta revisión es ofrecer información actualizada sobre la patogénesis y estrategias terapéuticas sobre el manejo de la infección por este patógeno. Palabras claves: Clostridium difficile, infección por Clostridium difficile, colitis pseudomembranosa. Fuente: MeSH Abstract: Clostridium difficile infection is the leading cause of hospital acquired diarrhea. The patients can be asymptomatic carriers or present a mild diarrhea, a pseudomembranous colitis, toxic megacolon, sepsis and death. There is controversy in this infection’s including the best method of diagnosis and also regarding therapeutic regimen. -
Ridinilazole: a Novel Antimicrobial for Clostridium Difficile Infection
REVIEW ARTICLE Annals of Gastroenterology (2019) 32, 134-140 Ridinilazole: a novel antimicrobial for Clostridium difficile infection Jonathan C. Choa, Matthew P. Crottyb, Joe Pardoc The University of Texas at Tyler, Tyler, TX; Methodist Dallas Medical Center, Dallas, TX; North FL/South GA Veterans Health System, Gainesville, FL, USA Abstract Clostridium difficile (C. difficile) infection remains a global healthcare threat worldwide and the limited options available for its treatment are of particular concern. Ridinilazole is one potential future agent, as it demonstrates rapid bactericidal activity against C. difficile. Current studies show that ridinilazole has a lower propensity for collateral damage to the gut microbiome and appears to diminish the production of C. difficile toxins. Results from phase II studies demonstrate that patients receiving ridinilazole had a higher sustained clinical response compared with patients receiving vancomycin (66.7% vs. 42.4%; P=0.0004). Adverse reactions were similar between ridinilazole and vancomycin (40% vs. 56%, respectively), with most being gastrointestinal-related. Nausea (20%) and abdominal pain (12%) were the most commonly reported adverse reactions associated with ridinilazole. Phase II study results are promising and future availability of phase III trial results will help further delineate the role and value of ridinilazole. Keywords Ridinilazole, Clostridium difficile, infectious diarrhea Ann Gastroenterol 2019; 32 (2): 134-140 Introduction aspects of managing patients with C. difficile is the pathogen’s propensity to cause recurrent infections. Recurrence rates Clostridium difficile (C. difficile) is recognized as an urgent of up to 25% have been reported following treatment with metronidazole or vancomycin [14,15]. The vicious cycle of threat to human health and represents an extremely challenging recurrence continues further, with patients who have one pathogen, given its impact on the healthcare system [1-5]. -
Ridinilazole—A Novel Antibiotic for Treatment of Clostridium Difficile Infection
120 Editorial Ridinilazole—a novel antibiotic for treatment of Clostridium difficile infection Niels Steinebrunner, Wolfgang Stremmel, Karl H. Weiss Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg, Germany Correspondence to: Prof. Karl Heinz Weiss, MD. Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg 69120, Germany. Email: [email protected]. Provenance: This is an invited Editorial commissioned by Section Editor Dr. Ming Zhong (Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China). Comment on: Vickers RJ, Tillotson GS, Nathan R, et al. Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Lancet Infect Dis 2017;17:735-44. Submitted Dec 04, 2017. Accepted for publication Dec 18, 2017. doi: 10.21037/jtd.2017.12.117 View this article at: http://dx.doi.org/10.21037/jtd.2017.12.117 Clostridium difficile (C. difficile) infection has become a major completing initial therapy. Risk factors for recurrence of health problem worldwide and is considered to be one of CDI include gastric acid suppression by proton pump the most common hospital-acquired (nosocomial) infections inhibitor therapy, gastrointestinal tract surgery, underlying with increasing incidence and severity (1). In Germany, immunosuppression (malignancy, cirrhosis, chemotherapy, the number of C. difficile infections (CDI) increased from immunosuppressive therapy), as well as older age 7 to 39 reported cases per 100,000 hospitalized patients (>65 years) of affected patients (6-11). Recurrent infections between 2000 and 2004, with yet another doubling of are associated with an increased risk of further episodes of numbers between 2004 and 2006 (2). -
AHRQ Healthcare Horizon Scanning System – Status Update
AHRQ Healthcare Horizon Scanning System – Status Update Horizon Scanning Status Update: January 2015 Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www.ahrq.gov Contract No. HHSA290-2010-00006-C Prepared by: ECRI Institute 5200 Butler Pike Plymouth Meeting, PA 19462 January 2015 Statement of Funding and Purpose This report incorporates data collected during implementation of the Agency for Healthcare Research and Quality (AHRQ) Healthcare Horizon Scanning System by ECRI Institute under contract to AHRQ, Rockville, MD (Contract No. HHSA290-2010-00006-C). The findings and conclusions in this document are those of the authors, who are responsible for its content, and do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. A novel intervention may not appear in this report simply because the System has not yet detected it. The list of novel interventions in the Horizon Scanning Status Update Report will change over time as new information is collected. This should not be construed as either endorsements or rejections of specific interventions. As topics are entered into the System, individual target technology reports are developed for those that appear to be closer to diffusion into practice in the United States. A representative from AHRQ served as a Contracting Officer’s Technical Representative and provided input during the implementation of the horizon scanning system. AHRQ did not directly participate in the horizon scanning, assessing the leads or topics, or provide opinions regarding potential impact of interventions.