Overcoming Obstacles in Drug Discovery and Development

Surmounting the Insurmountable—Case Studies for Critical Thinking

1st Edition - May 18, 2023
Editors: Kan He, Paul F. Hollenberg, Larry C. Wienkers
Language: English
Paperback ISBN:
9 7 8 - 0 - 1 2 - 8 1 7 1 3 4 - 9
eBook ISBN:
9 7 8 - 0 - 1 2 - 8 1 7 3 3 9 - 8

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 an… Read more

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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.

Cover image
Title page
Table of Contents
Copyright
Contributors
Preface
Chapter 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
Chapter 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
Chapter 3. Systems biology and data science in research and translational medicine
Brief overview of scope of systems biology and applications
Three illustrative examples
Summary and conclusions
Chapter 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
Chapter 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
Chapter 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
Chapter 7. Discovery and development of ADCs: obstacles and opportunities
Historical perspective
Learning through experience
Current critical problems for ADCs
Novel technologies
The data for ADC development: how to generate, how to use
Mathematical modeling: a quantitative approach
Emerging opportunities
Summary
Chapter 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
Chapter 9. Optimization for small volume of distribution leading to the discovery of apixaban
Milestones and pitfalls in early discovery of FXa inhibitors
Why small Vd for anti-FXa drugs
The small Vd strategy
Discovery of apixaban
Development of apixaban
Conclusion
Chapter 10. Design, conduct, and interpretation of human mass balance studies and strategies for assessing metabolites-in-safety testing (MIST) in drug development
Introduction
Review of mass balance in literature: methodology
Common issues with AME studies
Metabolites in safety testing (MIST)
Absolute bioavailability (ABA)
Novel study design: duo-tracer for ABA and mass balance in a single-period study
Conclusions
Chapter 11. Conquering low oral bioavailability issues in drug discovery and development
Introduction
Characterization of bioavailability
Design of molecules for optimizing bioavailability
Formulation strategies to optimize bioavailability
Conclusion
Chapter 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
Pharmacokinetics of statins and BMS-919373 in human subjects
Discussion
Conclusion
Chapter 13. Investigating the link between drug metabolism and toxicity
Introduction
Utility of metabolite-mediated toxicity information in discovery and development
Methods to investigate metabolite-mediated toxicology
Examples of metabolite-mediated toxicity
Conclusions
Abbreviations
Chapter 14. Overcoming nephrotoxicity in rats: the successful development and registration of the HIV-AIDS drug efavirenz (Sustiva®)
Background and introduction
Background and the problem
What was known
Hypotheses and experimental attack
Defining the rat-specific nephrotoxic metabolic pathway
Impact
Chapter 15. Disproportionate drug metabolites: challenges and solutions
Introduction
Tools for the characterization of drug metabolites
Quantitation of human metabolites
Case studies of disproportionate metabolites
Summary
Chapter 16. Disposition and metabolism of ozanimod–Surmounting the unanticipated challenge late in development
Characterizing CC112273 formation
Inhibition of MAO B by CC112273
Conclusion
Chapter 17. Application of reaction phenotyping to address pharmacokinetic variability in patient populations
Introduction
Drug metabolizing enzymes
In vitro systems to catalyze metabolic pathways
Reaction phenotyping approaches
Role of transporters in pharmacokinetic variability
In vivo assessment of elimination pathways
Case examples
Conclusion
Chapter 18. Kyprolis (carfilzomib) (approved): a covalent drug with high extrahepatic clearance via peptidase cleavage and epoxide hydrolysis
Proteasome as a drug target for the treatment of multiple myeloma
Carfilzomib irreversibly inactivates proteasome with high specificity
Carfilzomib displayed a high systemic clearance primarily mediated by peptidase and epoxide hydrolase metabolism
Despite a short half-life, carfilzomib induced rapid and sustained proteasome inhibition in preclinical species and in patients
Carfilzomib has a low potential of CYP mediated DDI and its PK is not significantly altered in patients with hepatic impairment
Evolution of carfilzomib dosing regimen
Reflection on carfilzomib discovery and development
Chapter 19. Engaging diversity in research: does your drug work in overlooked populations?
Part 1: Awareness
Part 2: Challenges and barriers to access
Part 3: Potential solutions
Part 4: Impact
Part 5: Future directions
Part 6: Conclusions
Chapter 20. PBPK modeling for early clinical study decision making
Introduction
Application of PBPK models
Challenges and future opportunities
Chapter 21. Integrated pharmacokinetic/pharmacodynamic/efficacy analysis in oncology: importance of pharmacodynamic/efficacy relationships
Introduction
PK/efficacy, biomarker PK/PD, and integrated PK/PD/efficacy models
Translational integrated PK/PD/efficacy modeling in oncology
Chapter 22. Predicting unpredictable human pharmacokinetics: case studies from the trenches of drug discovery
Introduction
General considerations in human pharmacokinetic predictions
Methodologies for human pharmacokinetic predictions
Case studies
Conclusion
Acknowledgments
Abbreviations
Chapter 23. Esmolol (soft drug design)
Introduction
Part 1. Discovery of a ‘drug wannabe’ called ‘ASL-8052’
Part 2. Development of a drug called ‘esmolol’
Part 3. Take home lessons and brief follow-ups
Index

Kan He

Dr. Kan He holds more than 10 U.S. and international patents on new chemical entities and biotechnologies and is the author of more than 60 published scientific papers. In addition to contributing to the discovery and development of numerous successful prescription drugs currently on the market, as well as multiple preclinical and clinical development candidates, Dr. He made significant contributions to the discovery and development of the oral anticoagulant Eliquis® (Apixaban). Dr. He cofounded and currently serves as the General Manager of the innovative biotech service company Biotranex, now a wholly owned subsidiary of Frontage Laboratories, Inc. Dr. He has also held numerous scientific and managerial positions at Bristol-Myers Squib, Dupont Pharmaceuticals, and Pfizer, and cofounded and served as President of Princeton Drug Discovery Inc, Eternity Bioscience, and UniTris Biopharma.

Affiliations and expertise

President of Biotranex LLC, New Jersey, USA

Paul F. Hollenberg

Dr. Paul Hollenberg is a Professor Emeritus of Pharmacology at the University of Michigan Medical School. He was on the faculty at Northwestern University Medical School, Wayne State University School of Medicine (Chair of Pharmacology), and then at the University of Michigan Medical School where he was Chair for more than 20 years. He cofounded Chemical Research in Toxicology in 1988 and has served as an Associate Editor and then Review Editor since that time. He was elected a Fellow of the American Chemical Society (2010), the American Association for the Advancement of Science (2012), and the American Society of Pharmacology and Therapeutics (2019). He has received several awards including the Scientific Achievement Award from the International Society for the Study of Xenobiotics in 2011 and the Founders Award from the Division of Chemical Toxicology of the American Chemical Society in 2014. He has published more than 200 peer-reviewed papers and received more than $29 million in NIH funding as a PI or Co-PI.

Affiliations and expertise

Professor Emeritus of Pharmacology, University of Michigan Medical School, MI, USA

Larry C. Wienkers

Dr. Wienkers is currently the Principal Scientist of Wienkers Consulting, LLC. Prior to this, Larry was Vice President and Global Head of the department of Pharmacokinetics and Drug Metabolism at Amgen retiring in 2018. Before moving to Amgen, Dr. Wienkers held scientific and leadership positions in several companies (Upjohn, Pharmacia, and Pfizer) and worked across multiple drug modalities, resulting in clinical and preclinical candidates, with 30+ IND submissions and 10+ NDA submissions. He is an American Association of Pharmaceutical Scientists (AAPS) Fellow (2012), was the recipient of the University of Washington, School of Pharmacy Distinguished Alumni Award in Pharmaceutical Science and Research Award (2014), and served as Chair of American Society of Pharmacology and Experimental Therapeutics Division of Drug Metabolism (2015). In addition to consulting, he serves as an Affiliate Faculty in the Department of Medicinal Chemistry at the University of Washington and to date has published over 100 peer-reviewed manuscripts and book chapters.

Affiliations and expertise

Principal Scientist, Wienkers Consulting, LLC, Bainbridge Island, WA, USA