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

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.

List 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

About the author

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.

Product details

• Assisted by: Kan He (Editor), Kan (President of Biotranex LLC He (Editor), Paul F. Hollenberg (Editor), Paul F. (Professor Emeritus of Pharmacology Hollenberg (Editor), Paul F. Hollenberg (Editor), Larry C. Wienkers (Editor), Larry C. (Principal Scientist Wienkers (Editor), Wienkers Larry C. (Editor)
• Publisher: Elsevier
• Languages: English
• Product format: Paperback / Softback
• Released: 26.05.2023
• EAN: 9780128171349
• ISBN: 978-0-12-817134-9
• Dimensions: 216 mm x 276 mm x 24 mm
• Weight: 1250 g
• Subjects: Social sciences, law, business > Business > Individual industrial sectors, branches; MEDICAL / Pharmacology, Pharmacology, Manufacturing industries, Pharmaceutical industries