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.
1. Title of Book - p. i 2. Cover image - p. i 3. Title page - p. ii 4. Table of Contents - p. iii 5. Copyright - p. iii 6. Contributors - p. xi 7. Preface - p. xiii 8. Chapter 1. Learning to think critically - p. 1 9. Chapter 2. Leveraging ADME/PK information to enable knowledge-driven decisions in drug discovery and development - p. 7 10. Chapter 3. Systems biology and data science in research and translational medicine - p. 25 11. Chapter 4. ADME considerations for siRNA-based therapeutics - p. 41 12. Chapter 5. Drug development of covalent inhibitors - p. 51 13. Chapter 6. Denosumab: dosing and drug interaction challenges on the path to approval - p. 63 14. Chapter 7. Discovery and development of ADCs: obstacles and opportunities - p. 75 15. Chapter 8. How to reduce risk of drug induced liver toxicity from the beginning - p. 107 16. Chapter 9. Optimization for small volume of distribution leading to the discovery of apixaban - p. 123 17. Chapter 10. Design, conduct, and interpretation of human mass balance studies and strategies for assessing metabolites-in-safety testing (MIST) in drug development - p. 137 18. Chapter 11. Conquering low oral bioavailability issues in drug discovery and development - p. 175 19. Chapter 12. Case study of OATP1B DDI assessment and challenges in drug discovery and development—real-life examples - p. 189 20. Chapter 13. Investigating the link between drug metabolism and toxicity - p. 201 21. Chapter 14. Overcoming nephrotoxicity in rats: the successful development and registration of the HIV-AIDS drug efavirenz (Sustiva®) - p. 215 22. Chapter 15. Disproportionate drug metabolites: challenges and solutions - p. 223 23. Chapter 16. Disposition and metabolism of ozanimod–Surmounting the unanticipated challenge late in development - p. 239 24. Chapter 17. Application of reaction phenotyping to address pharmacokinetic variability in patient populations - p. 249 25. Chapter 18. Kyprolis (carfilzomib) (approved): a covalent drug with high extrahepatic clearance via peptidase cleavage and epoxide hydrolysis - p. 269 26. Chapter 19. Engaging diversity in research: does your drug work in overlooked populations? - p. 283 27. Chapter 20. PBPK modeling for early clinical study decision making - p. 293 28. Chapter 21. Integrated pharmacokinetic/pharmacodynamic/efficacy analysis in oncology: importance of pharmacodynamic/efficacy relationships - p. 305 29. Chapter 22. Predicting unpredictable human pharmacokinetics: case studies from the trenches of drug discovery - p. 317 30. Chapter 23. Esmolol (soft drug design) - p. 351 31. Index - p. 427
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.
1. Title of Book - p. i 2. Cover image - p. i 3. Title page - p. ii 4. Table of Contents - p. iii 5. Copyright - p. iii 6. Contributors - p. xi 7. Preface - p. xiii 8. Chapter 1. Learning to think critically - p. 1 9. Chapter 2. Leveraging ADME/PK information to enable knowledge-driven decisions in drug discovery and development - p. 7 10. Chapter 3. Systems biology and data science in research and translational medicine - p. 25 11. Chapter 4. ADME considerations for siRNA-based therapeutics - p. 41 12. Chapter 5. Drug development of covalent inhibitors - p. 51 13. Chapter 6. Denosumab: dosing and drug interaction challenges on the path to approval - p. 63 14. Chapter 7. Discovery and development of ADCs: obstacles and opportunities - p. 75 15. Chapter 8. How to reduce risk of drug induced liver toxicity from the beginning - p. 107 16. Chapter 9. Optimization for small volume of distribution leading to the discovery of apixaban - p. 123 17. Chapter 10. Design, conduct, and interpretation of human mass balance studies and strategies for assessing metabolites-in-safety testing (MIST) in drug development - p. 137 18. Chapter 11. Conquering low oral bioavailability issues in drug discovery and development - p. 175 19. Chapter 12. Case study of OATP1B DDI assessment and challenges in drug discovery and development—real-life examples - p. 189 20. Chapter 13. Investigating the link between drug metabolism and toxicity - p. 201 21. Chapter 14. Overcoming nephrotoxicity in rats: the successful development and registration of the HIV-AIDS drug efavirenz (Sustiva®) - p. 215 22. Chapter 15. Disproportionate drug metabolites: challenges and solutions - p. 223 23. Chapter 16. Disposition and metabolism of ozanimod–Surmounting the unanticipated challenge late in development - p. 239 24. Chapter 17. Application of reaction phenotyping to address pharmacokinetic variability in patient populations - p. 249 25. Chapter 18. Kyprolis (carfilzomib) (approved): a covalent drug with high extrahepatic clearance via peptidase cleavage and epoxide hydrolysis - p. 269 26. Chapter 19. Engaging diversity in research: does your drug work in overlooked populations? - p. 283 27. Chapter 20. PBPK modeling for early clinical study decision making - p. 293 28. Chapter 21. Integrated pharmacokinetic/pharmacodynamic/efficacy analysis in oncology: importance of pharmacodynamic/efficacy relationships - p. 305 29. Chapter 22. Predicting unpredictable human pharmacokinetics: case studies from the trenches of drug discovery - p. 317 30. Chapter 23. Esmolol (soft drug design) - p. 351 31. Index - p. 427
