Overcoming Obstacles in Drug Discovery and Development. Surmounting the Insurmountable-Case Studies for Critical Thinking

Table of Contents

Preface

Kan He, Paul Frederick Hollenberg and Larry C. Wienkers

1. Learning to think critically

Brian Barnes

2. Leveraging ADME/PK information to enable knowledge-driven decisions in drug discovery and development

Larry C. Wienkers

3. Systems biology and data science in research and translational medicine

Karim Azer, Jeff S. Barrett, Mirjam Trame and Cynthia J. Musante

4. Drug Discovery and Development of ASO

Brooke Rock

5. Drug development of covalent Inhibitors

Upendra P. Dahal and Jan L. Wahlstrom

6. Denosumab: dosing and drug interaction challenges on the path to approval

Graham Jang

7. Discovery and development of ADCs: obstacles and opportunities

Hsuan Ping Chang, Yuen Kiu Cheung and Dhaval K. Shah

8. How to reduce risk of drug induced liver toxicity from the beginning

Jinping Gan, Kan He and W. Griffith Humphreys

9. Optimization for small volume of distribution leading to the discovery of apixaban

Kan He

10. Design, conduct, and interpretation of human mass balance studies and strategies for assessing metabolites-in-safety testing (MIST) in drug development

Simon G. Wong and Shuguang Ma

11. Conquering low oral bioavailability issues in drug discovery and development

Timothy J. Carlson

12. Case study of OATP1B DDI assessment and challenges in drug discovery and development-real-life examples

Hong Shen, Jinping Gan and Giridhar S. Tirucherai

13. Investigating the link between drug metabolism and toxicity

W. Griffith Humphreys

14. Overcoming nephrotoxicity in rats: the successful development and registration of the HIV-AIDS drug efavirenz (Sustiva?)

D.D. Christ

15. Disproportionate drug metabolites: challenges and solutions

Chandra Prakash

16. Disposition and metabolism of ozanimod-Surmounting the unanticipated challenge late in the development

Deepak Dalvie and Sekhar Surapaneni

17. Application of reaction phenotyping to address pharmacokinetic variability in patient populations

Robert S. Foti, Joseph M. Roesner and Joshua T. Pearson

18. Kyprolis (carfilzomib) (approved): a covalent drug with high extrahepatic clearance via peptidase cleavage and epoxide hydrolysis

Zhengping Wang, Jinfu Yang an Christopher Kirk

19. Engaging diversity in research: Does your drug work in overlooked populations?

Karen E. Brown and Erica L. Woodahl

20. PBPK modeling for Early clinical study decision making

Arian Emami Riedmaier

21. Integrated pharmacokinetic/pharmacodynamic/efficacy analysis in oncology: importance of pharmacodynamic/efficacy relationships

Harvey Wong

22. Predicting unpredictable human pharmacokinetics: Case studies from the trenches of drug discovery

Zheng Yang

23. Esmolol (soft drug design)

Paul W. Erhardt

Authors

Kan He President of Biotranex LLC, New Jersey, USA. 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. Paul F. Hollenberg Professor Emeritus of Pharmacology, University of Michigan Medical School, MI, USA. 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. Larry C. Wienkers Principal Scientist, Wienkers Consulting, LLC, Bainbridge Island, WA, USA. 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.