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Format: 1 online resource (xiv, 432 pages) : , illustrations

ISBN: 9780128173398 , 0128173394

Content: Overcoming Obstacles in Drug Discovery and Development uses real-world case studies to illustrate how critical thinking and problem solving skills are applied in the discovery and development of drugs. It also shows how developing critical thinking to overcome issues plays an essential role in the process. Modern drug discovery and development is a highly complex undertaking that requires scientific and professional expertise to be successful. After the identification of a molecular entity for treating a medical condition, challenges inevitably arise during the subsequent development to understand and characterize the biological profile; feedback from scientists is used to fine-tune the molecular entity to obtain an effective and safe product. In this process, the discovery team may identify unexpected safety issues and new medical disorders for treatment by the molecular entity. Invariably inherent in this complex undertaking are miscues, mistakes, and unexpected problems that can derail development and throw timetables into disarray, potentially leading to failure in the development of a medically useful drug. Addressing critical unexpected problems during development often requires scientists to utilize critical thinking and imaginative problem-solving skills. Overcoming Obstacles in Drug Discovery and Development will be essential to young scientists to help learn the skills to successfully face challenges, learn from mistakes, and further develop critical thinking skills. It will also be beneficial to experienced researchers who can learn from the case studies of successful and unsuccessful drug development.

Note: Front Cover -- Overcoming Obstacles in Drug Discovery and Development -- Overcoming Obstacles in Drug Discovery and Development -- Copyright -- Contents -- Contributors -- Preface -- 1 - Learning to think critically -- Some concerns with drug development & -- discovery -- Critical thinking basics -- Critical thinking analysis -- Critical thinking assessment -- Critical thinking traits -- Working on critical thinking -- Biases and conclusion -- References -- 2 - Leveraging ADME/PK information to enable knowledge-driven decisions in drug discovery and development -- Introduction -- Decision-making stages across the drug discovery/development continuum -- The importance of data in decision-making -- Product differentiation: first in class versus best in class -- Developing and using a target product profile in decision-making -- Why drugs fail and the evolution of ADME/PK in drug discovery -- Conclusion -- References -- 3 - Systems biology and data science in research and translational medicine -- Brief overview of scope of systems biology and applications -- Introduction -- The origin of systems biology hypothesis -- Systems biology-the approach and scope -- Systems biology and its applications -- Obstacles in drug discovery and translational medicine, with a focus on new indications/targets-systems biology as a bridge ... -- Systems biology as the integration of discovery biology and data sciences -- Quantitative Systems Pharmacology Models-mechanistic virtualization of drug discovery and development processes -- Defining the therapeutics mechanism of action -- Systems biology and pharmacology approaches in translational medicine -- Three illustrative examples -- Rare diseases-development of gene therapies -- Global Public Health-challenges specific to public health and opportunities captured versus gaps. , Cardiovascular diseases-a look back at an area with lots of precedence and model richness-how models enabled evaluation of MOA -- Summary and conclusions -- References -- 4 - ADME considerations for siRNA-based therapeutics -- Introduction -- Deep dive on RNAi mechanism of action -- Measurement of siRNA drug exposure -- Biodistribution of siRNA -- Considerations for metabolic pathways of siRNA -- Measurement of plasma protein binding (PPB) -- siRNA and de-risking drug-drug interactions -- Immunogenicity of siRNA molecules -- Characterizing target engagement of siRNA -- Conclusions -- References -- 5 - Drug development of covalent inhibitors -- Introduction to covalent drugs -- Therapeutic areas -- Chemical considerations for TCI design -- ADME considerations -- Unique assays critical for covalent drug discovery and development -- PK/PD establishment -- Conclusion -- Acknowledgment -- References -- 6 - Denosumab: dosing and drug interaction challenges on the path to approval -- Introduction -- Justifying the dose regimen for bone loss indications -- Justifying the dose regimen for the advanced cancer indications -- Inhibition of RANKL and the potential for drug-disease interactions -- Closing perspectives -- References -- 7 - Discovery and development of ADCs: obstacles and opportunities -- Historical perspective -- Early development -- First-generation ADCs -- Second-generation ADCs -- Third-generation ADCs -- Learning through experience -- Antibodies: the ones that put it together -- Linkers: the ones that hold the ADC together -- Cleavable linkers -- Non-cleavable linkers -- Payloads: small but mighty -- Moving forward -- Current critical problems for ADCs -- The antibodies -- The linker -- Non-cleavable linkers -- Cleavable linkers -- Linker selection: cleavable or non-cleavable -- Hydrophobicity: the dilemma of DAR, payload, and hydrophobicity. , The payloads -- Bystander effect: favorable or not -- Payload resistance: efflux transporters matter -- Novel technologies -- The antibodies -- Fragment-drug conjugates (FDCs) -- The linkers -- Site-specific conjugation -- The payloads -- Novel payloads -- Non-traditional payloads -- The data for ADC development: how to generate, how to use -- In in situ, ex vivo, ex vitro etc.). As per style latin terms are followed by roman throughout the chapter. Kindly check an ... -- Cytotoxicity assay -- Bystander effect -- Antigen expression -- Intracellular trafficking of ADCs -- In vivo studies -- Bioanalysis: multiple formats -- In vivo PK data -- In vivo PD data -- Toxicity and safety -- Clinical data -- Considerations for clinical pharmacology beyond guidance -- Mathematical modeling: a quantitative approach -- Modeling of in vitro data -- Modeling of in vivo data -- Mechanistic models -- PBPK models -- Model advancement -- Emerging opportunities -- ADC combination therapy -- ADC-IO -- Other combinations -- ADC beyond oncology -- Infectious diseases -- Immunological diseases -- Summary -- References -- 8 - How to reduce risk of drug induced liver toxicity from the beginning -- Introduction -- Dose -- Reactive metabolite screening -- Screening for drug-induced dysfunction of liver transporters -- Dysfunction of BSEP and bile acid homeostasis -- Dysfunction of MDR3 and phospholipid homeostasis -- Dysfunction of other liver transporters -- Immune-mediated liver toxicity -- Thinking beyond hepatocytes -- Signal detection in preclinical species and translation to humans -- Concluding remarks -- References -- 9 - Optimization for small volume of distribution leading to the discovery of apixaban -- Milestones and pitfalls in early discovery of FXa inhibitors -- Selection of FXa over thrombin as the therapeutic target for new oral anticoagulant drugs. , Screening of the DuPont library of glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors pointed to the discovery of lead molecule ... -- Innovative biological screening approaches -- The discoveries of DPC-423 and DPC-906 (razaxaban) -- Why small Vd for anti-FXa drugs -- The small Vd strategy -- Discovery of apixaban -- Development of apixaban -- Nonclinical safety assessment -- Clinical pharmacology -- Clinical development -- Conclusion -- Acknowledgment -- References -- 10 - Design, conduct, and interpretation of human mass balance studies and strategies for assessing metabolites-in- ... -- Introduction -- Objectives of the mass balance study -- Timing of the human mass balance study -- Review of mass balance in literature: methodology -- Experimental methods and study design -- Subject selection: patients versus healthy volunteers -- Special considerations for subject selection: use of genotyped subjects for AME study -- Subject selection: gastrointestinal status -- Sample collection time and discharge criteria -- Traditional approaches to AME versus microtracer -- Human only approach-an argument against conducting preclinical 14C mass balance studies -- Common issues with AME studies -- Compounds with low recovery -- Problems with fecal recovery -- Long plasma half-life -- Recovery for irreversibly or covalently bound drugs -- Recommendations for addressing poor recovery and long half-life compounds -- Metabolites in safety testing (MIST) -- Prediction of circulating metabolites from in vitro data -- Metabolite profiling from single dose versus multiple dose studies -- Strategies for addressing MIST guidance: tiered approaches -- Semi-quantitation of drug metabolites -- Mixed matrix method (MmM) for early assessment of metabolite exposures -- Toxicology studies for assessing the safety of human unique/disproportional metabolites. , Absolute bioavailability (ABA) -- Novel study design: duo-tracer for ABA and mass balance in a single-period study -- Conclusions -- References -- 11 - Conquering low oral bioavailability issues in drug discovery and development -- Introduction -- Characterization of bioavailability -- In vivo approaches -- In vitro approaches -- Solubility and permeability -- First pass metabolism -- Design of molecules for optimizing bioavailability -- Rule-based approaches to design -- Computational modeling -- Formulation strategies to optimize bioavailability -- Conclusion -- References -- 12 - Case study of OATP1B DDI assessment and challenges in drug discovery and development-real-life examples -- Background -- BMS-919373 -- Estimation of drug interaction potential for BMS-919373 using in vitro data -- Pharmacokinetcs of rosuvastatin and BMS-919373 in cynomolgus monkeys -- (A) BMS-919373 20mg/kg -- (B) BMS-919373 1mg/kg -- Pharmacokinetics of statins and BMS-919373 in human subjects -- Safety -- Discussion -- Conclusion -- References -- 13 - Investigating the link between drug metabolism and toxicity -- Introduction -- Utility of metabolite-mediated toxicity information in discovery and development -- Discovery studies -- Development studies -- Metabolites in safety testing considerations -- Species specific metabolism-related toxicology -- Metabolism-related toxicology during clinical development -- Methods to investigate metabolite-mediated toxicology -- Exposure at site of action -- In vitro methods -- In vivo methods -- Examples of metabolite-mediated toxicity -- General -- Amgen PI3K inhibitor program -- Bristol-Myers Squibb MET kinase inhibitor -- Saxagliptin -- Empagliflozin -- SGX523 -- Conclusions -- Abbreviations -- References -- 14 - Overcoming nephrotoxicity in rats: the successful development and registration of the HIV-AIDS drug efavirenz. , Background and introduction.

Additional Edition: Print version: Overcoming obstacles in drug discovery and development ISBN 9780128171349

Language: English

Keywords: Case Reports ; Case studies.