Of TB Drug Development: What's on the Horizon (For Patients with Or Without
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Oxazolidinones for TB
Oxazolidinones for TB: Current Status and Future Prospects 12th International Workshop on Clinical Pharmacology of Tuberculosis Drugs London, UK 10 September 2019 Lawrence Geiter, PhD Disclosures • Currently contract consultant with LegoChem Biosciences, Inc., Daejeon, Korea (LCB01-0371/delpazolid) • Previously employed with Otsuka Pharmaceutical Development and Commercialization, Inc. (delamanid, OPC-167832, LAM assay) What are Oxazolidinones • A family of antimicrobials mostly targeting an early step in protein synthesis • Cycloserine technically oxazolidinone but 2-oxazolidinone different MOA and chemical properties • New generation oxazolidinones bind to both 50S subunit and 30S subunit • Linezolid (Zyvox) and Tedizolid (Sivestro) approved for drug resistant skin infections and community acquired pneumonia Cycloserine • Activity against TB demonstrated in non- clinical and clinical studies • Mitochondrial toxicity >21 days limits use in TB treatment Linezolid Developing Oxazolidinones for TB Compound Generic Brand Sponsor Development Status TB Code- Activity/Trials PNU-100766 Linezolid Zyvox Pfizer Multiple regimen Yes/Yes TR-201 Tedizolid Sivextro Merck Pre-clinical efficacy Yes/No PNU-100480 Sutezolid Pfizer Multiple regimen studies Sequella Yes/Yes (PanACEA) TB Alliance LCB01-0371 Delpazolid LegoChem Bio EBA trial recruitment completed Yes/Yes TBI-223 - Global Alliance SAD trial launched Yes/Yes AZD5847 Posizolid AstraZenica Completed EBA Yes/No RX-1741 Radezolid Melinta IND for vaginal infections ?/No RBX-7644 Ranbezolid Rabbaxy None found ?/No MRX-4/MRX-1 Contezolid MicuRx Skin infections Yes/No U-100592 Eperezolid ? No clinical trials ?/No PK of Oxazolidinones in Development for TB Steady State PK Parameters Parameter Linezolid 600 Delpazolid 800 mg QD2 mg QD3 Cmax (mg/L) 17.8 8.9 Cmin (mg/L) 2.43 0.1 Tmax (h) 0.87 0.5 T1/2 (h) 3.54 1.7 AUC0-24 (µg*h/mL) 84.5 20.1 1 MIC90 (µg/mL) 0.25 0.5 References 1. -
Efficacy and Safety of World Health Organization Group 5 Drugs for Multidrug-Resistant Tuberculosis Treatment
ERJ Express. Published on September 17, 2015 as doi: 10.1183/13993003.00649-2015 REVIEW IN PRESS | CORRECTED PROOF Efficacy and safety of World Health Organization group 5 drugs for multidrug-resistant tuberculosis treatment Nicholas Winters1,2, Guillaume Butler-Laporte1 and Dick Menzies1,2 Affiliations: 1Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute, McGill University, Montreal, PQ, Canada. 2Dept of Epidemiology and Biostatistics, McGill University, Montreal, PQ, Canada. Correspondence: Dick Menzies, Montreal Chest Institute, Room K1.24, 3650 St Urbain, Montreal, PQ, Canada, H2X 2P4. E-mail: [email protected] ABSTRACT The efficacy and toxicity of several drugs now used to treat multidrug-resistant tuberculosis (MDR-TB) have not been fully evaluated. We searched three databases for studies assessing efficacy in MDR-TB or safety during prolonged treatment of any mycobacterial infections, of drugs classified by the World Health Organization as having uncertain efficacy for MDR-TB (group 5). We included 83 out of 4002 studies identified. Evidence was inadequate for meropenem, imipenem and terizidone. For MDR-TB treatment, clarithromycin had no efficacy in two studies (risk difference (RD) −0.13, 95% CI −0.40–0.14) and amoxicillin–clavulanate had no efficacy in two other studies (RD 0.07, 95% CI −0.21–0.35). The largest number of studies described prolonged use for treatment of non- tuberculous mycobacteria. Azithromycin was not associated with excess serious adverse events (SAEs). Clarithromycin was not associated with excess SAEs in eight controlled trials in HIV-infected patients (RD 0.00, 95% CI −0.02–0.02), nor in six uncontrolled studies in HIV-uninfected patients, whereas six uncontrolled studies in HIV-infected patients clarithromycin caused substantial SAEs (proportion 0.20, 95% CI 0.12–0.27). -
Clofazimine As a Treatment for Multidrug-Resistant Tuberculosis: a Review
Scientia Pharmaceutica Review Clofazimine as a Treatment for Multidrug-Resistant Tuberculosis: A Review Rhea Veda Nugraha 1 , Vycke Yunivita 2 , Prayudi Santoso 3, Rob E. Aarnoutse 4 and Rovina Ruslami 2,* 1 Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung 40161, Indonesia; [email protected] 2 Division of Pharmacology and Therapy, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung 40161, Indonesia; [email protected] 3 Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran—Hasan Sadikin Hospital, Bandung 40161, Indonesia; [email protected] 4 Department of Pharmacy, Radboud University Medical Center, Radboud Institute for Health Sciences, 6255HB Nijmegen, The Netherlands; [email protected] * Correspondence: [email protected] Abstract: Multidrug-resistant tuberculosis (MDR-TB) is an infectious disease caused by Mycobac- terium tuberculosis which is resistant to at least isoniazid and rifampicin. This disease is a worldwide threat and complicates the control of tuberculosis (TB). Long treatment duration, a combination of several drugs, and the adverse effects of these drugs are the factors that play a role in the poor outcomes of MDR-TB patients. There have been many studies with repurposed drugs to improve MDR-TB outcomes, including clofazimine. Clofazimine recently moved from group 5 to group B of drugs that are used to treat MDR-TB. This drug belongs to the riminophenazine class, which has lipophilic characteristics and was previously discovered to treat TB and approved for leprosy. This review discusses the role of clofazimine as a treatment component in patients with MDR-TB, and Citation: Nugraha, R.V.; Yunivita, V.; the drug’s properties. -
Clinical Pharmacology 1: Phase 1 Studies and Early Drug Development
Clinical Pharmacology 1: Phase 1 Studies and Early Drug Development Gerlie Gieser, Ph.D. Office of Clinical Pharmacology, Div. IV Objectives • Outline the Phase 1 studies conducted to characterize the Clinical Pharmacology of a drug; describe important design elements of and the information gained from these studies. • List the Clinical Pharmacology characteristics of an Ideal Drug • Describe how the Clinical Pharmacology information from Phase 1 can help design Phase 2/3 trials • Discuss the timing of Clinical Pharmacology studies during drug development, and provide examples of how the information generated could impact the overall clinical development plan and product labeling. Phase 1 of Drug Development CLINICAL DEVELOPMENT RESEARCH PRE POST AND CLINICAL APPROVAL 1 DISCOVERY DEVELOPMENT 2 3 PHASE e e e s s s a a a h h h P P P Clinical Pharmacology Studies Initial IND (first in human) NDA/BLA SUBMISSION Phase 1 – studies designed mainly to investigate the safety/tolerability (if possible, identify MTD), pharmacokinetics and pharmacodynamics of an investigational drug in humans Clinical Pharmacology • Study of the Pharmacokinetics (PK) and Pharmacodynamics (PD) of the drug in humans – PK: what the body does to the drug (Absorption, Distribution, Metabolism, Excretion) – PD: what the drug does to the body • PK and PD profiles of the drug are influenced by physicochemical properties of the drug, product/formulation, administration route, patient’s intrinsic and extrinsic factors (e.g., organ dysfunction, diseases, concomitant medications, -
Analysis of Mutations Leading to Para-Aminosalicylic Acid Resistance in Mycobacterium Tuberculosis
www.nature.com/scientificreports OPEN Analysis of mutations leading to para-aminosalicylic acid resistance in Mycobacterium tuberculosis Received: 9 April 2019 Bharati Pandey1, Sonam Grover2, Jagdeep Kaur1 & Abhinav Grover3 Accepted: 31 July 2019 Thymidylate synthase A (ThyA) is the key enzyme involved in the folate pathway in Mycobacterium Published: xx xx xxxx tuberculosis. Mutation of key residues of ThyA enzyme which are involved in interaction with substrate 2′-deoxyuridine-5′-monophosphate (dUMP), cofactor 5,10-methylenetetrahydrofolate (MTHF), and catalytic site have caused para-aminosalicylic acid (PAS) resistance in TB patients. Focusing on R127L, L143P, C146R, L172P, A182P, and V261G mutations, including wild-type, we performed long molecular dynamics (MD) simulations in explicit solvent to investigate the molecular principles underlying PAS resistance due to missense mutations. We found that these mutations lead to (i) extensive changes in the dUMP and MTHF binding sites, (ii) weak interaction of ThyA enzyme with dUMP and MTHF by inducing conformational changes in the structure, (iii) loss of the hydrogen bond and other atomic interactions and (iv) enhanced movement of protein atoms indicated by principal component analysis (PCA). In this study, MD simulations framework has provided considerable insight into mutation induced conformational changes in the ThyA enzyme of Mycobacterium. Antimicrobial resistance (AMR) threatens the efective treatment of tuberculosis (TB) caused by the bacteria Mycobacterium tuberculosis (Mtb) and has become a serious threat to global public health1. In 2017, there were reports of 5,58000 new TB cases with resistance to rifampicin (frst line drug), of which 82% have developed multidrug-resistant tuberculosis (MDR-TB)2. AMR has been reported to be one of the top health threats globally, so there is an urgent need to proactively address the problem by identifying new drug targets and understanding the drug resistance mechanism3,4. -
Terizidone.Pdf
Essential Medicines List (EML) 2015 Application for the inclusion of terizidone in the WHO Model List of Essential Medicines, as reserve second‐line drugs for the treatment of multidrug‐resistant tuberculosis (complementary lists of anti‐tuberculosis drugs for use in adults and children) General items 1. Summary statement of the proposal for inclusion, change or deletion This application concerns the updating of section 6.2.4 Antituberculosis medicines in the 2013 editions of both the WHO Model List of Essential Medicines (18th list) and the WHO Model List of Essential Medicines for Children (4th list)(1),(2). The proposal is to add terizidone to both the complementary list of anti‐tuberculosis medicines for adults and in children. Terizidone is not on the EML, but its sister medication, cycloserine, is on the complementary list in section 6.2.4 Antituberculosis medicines The applicant considers that terizidone should be viewed as an essential medicine for patients with multidrug‐resistant (MDR‐TB) and extensively drug‐resistant (XDR‐TB) disease. In many low resource settings, patients with these forms of tuberculosis are inadequately treated and often die because not enough medications are available to compose a suitable regimen (3). Second‐line drugs for the treatment of M/XDR‐TB are frequently not available; and global stock outs occur regularly. Terizidone should become more widely available to specialized care centres of national TB programmes and other health care providers treating M/XDR‐TB patients. The inclusion of terizidone as an anti‐tuberculosis agent on the EML will encourage pharmaceutical manufacturers to invest more in its production and will facilitate its inclusion in the national EML and its registration in countries where MDR and XDR‐TB are a health threat. -
Tuberculosis Report
global TUBERCULOSIS REPORT 2018 GLOBAL TUBERCULOSIS REPORT 2018 Global Tuberculosis Report 2018 ISBN 978-92-4-156564-6 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY- NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. Global tuberculosis report 2018. Geneva: World Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. -
Drugs and Drug Development: Making a Drug
Drugs and drug development: Making a drug Developing a novel drug Drug development is a long and expensive process A drug can be developed in a whole host of different ways. Constant improvement in technology has transformed drug design over the past few decades. Now, many laboratories in both universities and pharmaceutical companies make use of computers, robotics and artificial intelligence to aid in drug design. These techniques coupled with more traditional methods are becoming increasingly successful in designing novel drugs. One commonality between all the methods of drug design is that they are fraught with challenges. A pharmaceutical company may start with thousands of chemical compounds as potential drug candidates. Rigorous testing will whittle this down to a single chemical compound that can then be licensed to treat patients. Developing drugs is a risky and expensive business, but the potential profits are huge. The following step-by-step process provides a guide to how a compound in the laboratory becomes a disease-fighting drug. Option 1 explains the process of transforming initial research in a university lab (or biotechnology company) into a potential drug – about a quarter of drugs approved by the FDA between 1998 and 2007 began in this way. The remaining three-quarters began in pharmaceutical companies, as explained in option 2. STEP 1 – OPTION 1: Origins in the research lab In universities and research institutes all over the globe, many scientists dedicate their lives to understanding the molecular details of disease – how disease works. By using animal models, usually mice, they are able to identify specific biochemical pathways that are altered by the disease. -
Early-Phase Drug Discovery
Early-Phase Drug Discovery In partnership with the North Carolina Translational & Clinical Sciences (NC TraCs) Institute, RTI International is participating in the Early-Phase Drug Discovery Service (EPDD) to help researchers navigate challenges in the drug discovery process and move technologies toward development. This new RTI-based NC TraCS service can provide researchers with biological assay development and optimization, hit or lead identification, medicinal chemistry optimization, in vitro absorption, distribution, metabolism, excretion, and toxicology (ADMET), and in vivo pharmacokinetics. Overview Early stages of the drug discovery process contain hurdles that must be cleared before more robust drug development can commence. Once a molecular target is selected, drug discovery begins with identification of a hit and progresses toward a lead candidate through a series of structural optimizations. If no hit or lead molecules exist, a researcher must have a validated biological assay that can be optimized for high-throughput screening (HTS). Screening hits typically do not possess optimal drug- like properties. Therefore, their affinity, selectivity, and pharmacokinetic (PK) properties must be improved through structural modifications by a medicinal chemist. Once acceptable drug-like properties have been achieved, efficacy is validated through proof-of-principle studies in vivo. The most promising set of optimized compounds is then slated for further development. The EPDD can assist researchers by providing target development and assay miniaturization, identification of hits through HTS in a 25,000-compound library, lead optimization, in vitro ADMET assays, and preliminary in vivo PK studies. Services will be provided on a tiered basis. Tier 1 consists of consulting services designed to inform the researcher of gaps in his or her early-phase drug discovery plan. -
Comparative Thermodynamics of Partial Agonist Binding to An
COMPARATIVE THERMODYNAMICS OF PARTIAL AGONIST BINDING TO AN AMPA RECEPTOR BINDING DOMAIN A Dissertation Presented to the Faculty of the Graduate School of Cornell University In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Madeline Martínez May 2015 © 2015 Madeline Martínez ALL RIGHTS RESERVED Comparative Thermodynamics of Partial Agonist Binding to an AMPA Receptor Binding Domain Madeline Martínez, Ph.D. Cornell University 2015 AMPA receptors, ligand-gated cation channels endogenously activated by glutamate, mediate the majority of rapid excitatory synaptic transmission in the vertebrate central nervous system and are crucial for information processing within neural networks. Their involvement in a variety of neuropathologies and injured states makes them important therapeutic targets, and understanding the forces that drive the interactions between the ligands and protein binding sites is a key element in the development and optimization of potential drug candidates. Calorimetric studies yield quantitative data on the thermodynamic forces that drive binding reactions. This information can help elucidate mechanisms of binding and characterize ligand- induced conformational changes, as well as reduce the potential unwanted effects in drug candidates. The studies presented here characterize the thermodynamics of binding of a series of 5’substituted willardiine analogues, partial agonists to the GluA2 LBD under several conditions. The moiety substitutions (F, Cl, I, H, and NO2) explore a range of electronegativity, pKa, radii, and h-bonding capability. Competitive binding of these ligands to glutamate-bound GluA2 LBD at different pH conditions demonstrates the effects of charge in the enthalpic and entropic components of the Gibb’s free energy of binding. -
Antibiotic Use and Abuse: a Threat to Mitochondria and Chloroplasts with Impact on Research, Health, and Environment
Insights & Perspectives Think again Antibiotic use and abuse: A threat to mitochondria and chloroplasts with impact on research, health, and environment Xu Wang1)†, Dongryeol Ryu1)†, Riekelt H. Houtkooper2)* and Johan Auwerx1)* Recently, several studies have demonstrated that tetracyclines, the antibiotics Introduction most intensively used in livestock and that are also widely applied in biomedical research, interrupt mitochondrial proteostasis and physiology in animals Mitochondria and chloroplasts are ranging from round worms, fruit flies, and mice to human cell lines. Importantly, unique and subcellular organelles that a plant chloroplasts, like their mitochondria, are also under certain conditions have evolved from endosymbiotic - proteobacteria and cyanobacteria-like vulnerable to these and other antibiotics that are leached into our environment. prokaryotes, respectively (Fig. 1A) [1, 2]. Together these endosymbiotic organelles are not only essential for cellular and This endosymbiotic origin also makes organismal homeostasis stricto sensu, but also have an important role to play in theseorganellesvulnerabletoantibiotics. the sustainability of our ecosystem as they maintain the delicate balance Mitochondria and chloroplasts retained between autotrophs and heterotrophs, which fix and utilize energy, respec- multiple copies of their own circular DNA (mtDNA and cpDNA), a vestige of the tively. Therefore, stricter policies on antibiotic usage are absolutely required as bacterial DNA, which encodes for only a their use in research confounds experimental outcomes, and their uncontrolled few polypeptides, tRNAs and rRNAs [1, 3, applications in medicine and agriculture pose a significant threat to a balanced 4]. Furthermore, both mitochondria and ecosystem and the well-being of these endosymbionts that are essential to chloroplasts have bacterial-type ribo- sustain health. -
Research and Development in the Pharmaceutical Industry
Research and Development in the Pharmaceutical Industry APRIL | 2021 At a Glance This report examines research and development (R&D) by the pharmaceutical industry. Spending on R&D and Its Results. Spending on R&D and the introduction of new drugs have both increased in the past two decades. • In 2019, the pharmaceutical industry spent $83 billion dollars on R&D. Adjusted for inflation, that amount is about 10 times what the industry spent per year in the 1980s. • Between 2010 and 2019, the number of new drugs approved for sale increased by 60 percent compared with the previous decade, with a peak of 59 new drugs approved in 2018. Factors Influencing R&D Spending. The amount of money that drug companies devote to R&D is determined by the amount of revenue they expect to earn from a new drug, the expected cost of developing that drug, and policies that influence the supply of and demand for drugs. • The expected lifetime global revenues of a new drug depends on the prices that companies expect to charge for the drug in different markets around the world, the volume of sales they anticipate at those prices, and the likelihood the drug-development effort will succeed. • The expected cost to develop a new drug—including capital costs and expenditures on drugs that fail to reach the market—has been estimated to range from less than $1 billion to more than $2 billion. • The federal government influences the amount of private spending on R&D through programs (such as Medicare) that increase the demand for prescription drugs, through policies (such as spending for basic research and regulations on what must be demonstrated in clinical trials) that affect the supply of new drugs, and through policies (such as recommendations for vaccines) that affect both supply and demand.