Overcoming Obstacles in Drug Discovery and Development

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. 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. 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.

• PrefaceKan He, Paul Frederick Hollenberg and Larry C. Wienkers1. Learning to think criticallyBrian Barnes 2. Leveraging ADME/PK information to enable knowledge-driven decisions in drug discovery and developmentLarry C. Wienkers3. Systems biology and data science in research and translational medicineKarim Azer, Jeff S. Barrett, Mirjam Trame and Cynthia J. Musante4. Drug Discovery and Development of ASOBrooke Rock5. Drug development of covalent InhibitorsUpendra P. Dahal and Jan L. Wahlstrom6. Denosumab: dosing and drug interaction challenges on the path to approvalGraham Jang7. Discovery and development of ADCs: obstacles and opportunitiesHsuan Ping Chang, Yuen Kiu Cheung and Dhaval K. Shah8. How to reduce risk of drug induced liver toxicity from the beginningJinping Gan, Kan He and W. Griffith Humphreys9. Optimization for small volume of distribution leading to the discovery of apixabanKan He10. Design, conduct, and interpretation of human mass balance studies and strategies for assessing metabolites-in-safety testing (MIST) in drug developmentSimon G. Wong and Shuguang Ma11. Conquering low oral bioavailability issues in drug discovery and developmentTimothy J. Carlson12. Case study of OATP1B DDI assessment and challenges in drug discovery and development—real-life examplesHong Shen, Jinping Gan and Giridhar S. Tirucherai13. Investigating the link between drug metabolism and toxicity W. Griffith Humphreys14. Overcoming nephrotoxicity in rats: the successful development and registration of the HIV-AIDS drug efavirenz (Sustiva®)D.D. Christ15. Disproportionate drug metabolites: challenges and solutionsChandra Prakash16. Disposition and metabolism of ozanimod—Surmounting the unanticipated challenge late in the developmentDeepak Dalvie and Sekhar Surapaneni17. Application of reaction phenotyping to address pharmacokinetic variability in patient populationsRobert S. Foti, Joseph M. Roesner and Joshua T. Pearson18. Kyprolis (carfilzomib) (approved): a covalent drug with high extrahepatic clearance via peptidase cleavage and epoxide hydrolysisZhengping Wang, Jinfu Yang an Christopher Kirk 19. Engaging diversity in research: Does your drug work in overlooked populations?Karen E. Brown and Erica L. Woodahl20. PBPK modeling for Early clinical study decision makingArian Emami Riedmaier21. Integrated pharmacokinetic/pharmacodynamic/efficacy analysis in oncology: importance of pharmacodynamic/efficacy relationshipsHarvey Wong22. Predicting unpredictable human pharmacokinetics: Case studies from the trenches of drug discoveryZheng Yang23. 　Esmolol (soft drug design)Paul W. Erhardt