Overcoming Obstacles in Drug Discovery and Development 1st Edition by Kan He, Paul F Hollenberg, Larry C Wienkers ISBN 9780128171349 0128171340

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ISBN 10: 0128171340
ISBN 13: 9780128171349
Author: Kan He, Paul F Hollenberg, Larry C Wienkers

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.

Overcoming Obstacles in Drug Discovery and Development 1st Edition Table of contents:

Chapter 1. Learning to think critically

Abstract

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

References

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

Abstract

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

References

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

Abstract

Brief overview of scope of systems biology and applications

Three illustrative examples

Summary and conclusions

References

Chapter 4. ADME considerations for siRNA-based therapeutics

Abstract

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

References

Chapter 5. Drug development of covalent inhibitors

Abstract

Acknowledgment

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

References

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

Abstract

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

References

Chapter 7. Discovery and development of ADCs: obstacles and opportunities

Abstract

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

References

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

Abstract

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

References

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

Abstract

Acknowledgment

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

References

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

Abstract

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

References

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

Abstract

Introduction

Characterization of bioavailability

Design of molecules for optimizing bioavailability

Formulation strategies to optimize bioavailability

Conclusion

References

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

Abstract

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

References

Chapter 13. Investigating the link between drug metabolism and toxicity

Abstract

Introduction

Utility of metabolite-mediated toxicity information in discovery and development

Methods to investigate metabolite-mediated toxicology

Examples of metabolite-mediated toxicity

Conclusions

Abbreviations

References

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

Abstract

Acknowledgments

Background and introduction

Background and the problem

What was known

Hypotheses and experimental attack

Defining the rat-specific nephrotoxic metabolic pathway

Impact

References

Chapter 15. Disproportionate drug metabolites: challenges and solutions

Abstract

Acknowledgments

Introduction

Tools for the characterization of drug metabolites

Quantitation of human metabolites

Case studies of disproportionate metabolites

Summary

References

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

Abstract

Characterizing CC112273 formation

Inhibition of MAO B by CC112273

Conclusion

References

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

Abstract

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

References

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

Abstract

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

References

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

Abstract

Part 1: Awareness

Part 2: Challenges and barriers to access

Part 3: Potential solutions

Part 4: Impact

Part 5: Future directions

Part 6: Conclusions

References

Chapter 20. PBPK modeling for early clinical study decision making

Abstract

Introduction

Application of PBPK models

Challenges and future opportunities

References

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

Abstract

Introduction

PK/efficacy, biomarker PK/PD, and integrated PK/PD/efficacy models

Translational integrated PK/PD/efficacy modeling in oncology

References

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

Abstract

Introduction

General considerations in human pharmacokinetic predictions

Methodologies for human pharmacokinetic predictions

Case studies

Conclusion

Acknowledgments

Abbreviations

References

Chapter 23. Esmolol (soft drug design)

Abstract

Acknowledgments

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

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Tags: Kan He, Paul F Hollenberg, Larry C Wienkers, Overcoming Obstacles, Drug Discovery