Drug Discovery and Development, Third Edition

James J. O'Donnell, John Somberg, Vincent Idemyor, James T. O'Donnell, James J. O'Donnell, John Somberg, Vincent Idemyor, James T. O'Donnell

• Publisher: CRC Press
• Year: 2019
• Print ISBN: 9781032084244
• eBook ISBN: 9781351625135
• Edition: 3
• Topic: Medicine
• Subtopic: Clinical Medicine

Drug Discovery and Development, Third Edition presents up-to-date scientific information for maximizing the ability of a multidisciplinary research team to discover and bring new drugs to the marketplace. It explores many scientific advances in new drug discovery and development for areas such as screening technologies, biotechnology approaches, and evaluation of efficacy and safety of drug candidates through preclinical testing. This book also greatly expands the focus on the clinical pharmacology, regulatory, and business aspects of bringing new drugs to the market and offers coverage of essential topics for companies involved in drug development. Historical perspectives and predicted trends are also provided.

Features:

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• Highlights emerging scientific fields relevant to drug discovery such as the microbiome, nanotechnology, and cancer immunotherapy; and novel research tools such as CRISPR and DNA-encoded libraries

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• Case study detailing the discovery of the anti-cancer drug, lorlatinib

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• Venture capitalist commentary on trends and best practices in drug discovery and development

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• Comprehensive review of regulations and their impact on drug development, highlighting special populations, orphan drugs, and pharmaceutical compounding

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• Multidiscipline functioning of an Academic Research Enterprise, plus a chapter on Ethical Concerns in Research
• Contributions by 70+ experts from industry and academia specialists who developed and are practitioners of the science and business

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1 Introduction to Drug Discovery and Development

James J. O’Donnell III

Rosalind Franklin University of Medicine and Science

John C. Somberg and James T. O’Donnell

Rush University Medical Center

CONTENTS

Section I. Overview

Chapter 2. Current Opinions on the Trajectory of the Pharmaceutical Development

J. Somberg

Chapter 3. Innovation in Drug Development: Perspectives of a Venture Capitalist

K. Yeshwant

Section II. Drug Discovery

Chapter 4. High-Throughput Screening

T. Spicer

Chapter 5. DNA-Encoded Compound Libraries: An Emerging Paradigm in Drug Hit Discovery

R. Franzini

Chapter 6. Bio-targeted Nanomaterials for Theranostic Applications

S. Maiti and K.K. Sen

Chapter 7. The Development of Adoptive T Cell Immunotherapies for Cancer: Challenges and Prospects

D. Dow, S.J. Howe, M.K. Talekar, and L.A. Johnson

Chapter 8. CRISPR in Drug Discovery

C. Lee and J. Luo

Chapter 9. Probiotics in the World: “Bugs as Drugs.”

T. Kuntz, M. Kim, E. Hill, M.C. Salas Garcia, and J.A. Gilbert

Chapter 10. Discovery and Early Development of the Next-Generation ALK Inhibitor, Lorlatinib (18): Agent for Non–Small Cell Lung Cancer

P.F. Richardson

Section III. Drug Development

Chapter 11. Integrated Drug Product Development: From Lead Candidate Selection to Life-Cycle Management

A. Serajuddin, M. Pudipeddi, A. Shah, and D. Mufson

Chapter 12. New Trends in Pharmacological and Pharmaceutical Profiling

J.P. Valentin, D. Armstrong, L.R. Ribeiro, and T. Jean

Chapter 13. Pharmacokinetics–Pharmacodynamics in New Drug Development

S. Niazi

Chapter 14. The Evolving Role of the Caco-2 Cell Model to Estimate Intestinal Absorption Potential and Elucidate Transport Mechanisms

J. Li and I.J. Hidalgo

Chapter 15. Preclinical Toxicology

D. Parran

Chapter 16. Safety Pharmacology: Past, Present, and Future

J.P. Valentin, A. Delaunois, M.L. Rosseels, and T.G. Hammond

Chapter 17. Ethics in Clinical Research

J. Young and L. Nesbitt

Chapter 18. Clinical Trials Methodology

J. Somberg

Chapter 19. Academic Research Enterprise

C. Brawley, M.J. Welch, J. Oswald, E. Kampschmidt, J. Garcia, A. Harley, S. Vijayan, J. McClatchy, S. Guzik, and S. Tedford

Chapter 20. Clinical Testing Challenges in HIV/AIDS Research

V. Idemyor

Chapter 21. The Evolving Role of the Pharmacist in Clinical, Academic, and Industry Sectors

G. Patel and S.E. Tedford

Chapter 22. Intellectual Property in the Drug Discovery Process

M. Rumore and W. Schmidt

Chapter 23. Drug Repurposing: Academic Clinician Research Endeavors

K. Heneghan and S.E. Tedford

Section IV. Regulations

Chapter 24. The Role of the Regulatory Affairs Professional in Guiding New Drug Research, Development, and Approval

S.A. Edwards

Chapter 25. Orphan Drug Development and Regulations

A.M. Lynch

Chapter 26. Development of Drug Products for Older Adults: Challenges, Solutions, and Regulatory Considerations

S.W.J. Lau, C. Sahajwalla, and D.R. Abernethy

Chapter 27. Clinical Pharmacology and Regulatory Concerns for Developing Drug Products for Pediatric Patients

J.M. Burnham and G.J. Burckart

Chapter 28. Pharmacy Compounding Regulations

L. Allen and W.C. Triplett

In the 15 years since the release of Smith and O’Donnell’s The Process of New Drug Discovery and Development, Second Edition (2005), the fields of drug discovery and development have seen tremendous changes. Advances in understanding of human biology and disease have uncovered fresh territory for drugs to target, and this progression of knowledge has been accelerated by the invention of new investigational tools. Further, new platforms to efficiently sift through the drug candidates have made it easier to find that needle in the haystack, the drug that will treat a disease safely and effectively. What’s more, the processes of drug discovery and drug development, once separated in independent silos of sorts, have become increasingly integrated. No longer is the drug candidate handed off from drug inventor to drug developer like runners in a track relay meet. These changes in the drug discovery and development processes have reverberated throughout the biotech world, significantly impacting the scientific methodology employed for drug discovery initiatives as well as the institutional platforms underlying biomedical research.

The third edition of this book builds on the information published in the earlier editions and presents a thorough up-to-date overview of the field and a review of new developments. More than 60% of the chapter topics are new, and many other chapters have new authors offering fresh perspectives. Some chapters from the second edition were removed, as their subject matter was no longer relevant to drug discovery and development today. We are fortunate to have recruited more than 70 contributors – scientists, clinicians, and a few business types – from industry, academia, and government (FDA and NIH), as well as international representatives. While highly technical, our objective is for each chapter to be useful and current to experts in that particular subfield but still accessible to someone not familiar with that aspect of drug discovery and development.

The book is divided into four sections:

• Overview
• Drug Discovery
• Drug Development
• Regulations.

As leaders in the subfield detailed in each chapter, authors are uniquely positioned not only to review the literature but also to make generalizations informed by personal experience, comment on areas under debate, and make predictions on how the subfield is likely to change in the future. In keeping with this theme, the “Overview” section contains extended editorialization from two experts, Dr. John Somberg (an author of this chapter and an editor of this book) and Dr. Krishna Yeshwant. Dr. Somberg has been a basic and clinical investigator in anti-arrhythmic pharmacology for 40 years and has served as a Principal Investigator in over 100 Phase I, Phase II, and Phase III clinical trials. Dr. Yeshwant was trained as a physician and programmer in addition to business, and he currently serves as General Partner at Google Ventures; his chapter offers the rare perspective of a venture capitalist on trends and best practices in drug discovery and development. Another unique perspective of pharmacology is shown in a chapter detailing one case study in the discovery and early development of the cancer drug, lorlatinib, which was approved by the FDA in 2018. Instead of the traditional organization of a pharmaceutical journal article with a listing of positive results only, this chapter takes a more chronological approach, showing the twists and turns of drug discovery from the point of view of one of the investigators, Dr. Paul Richardson of Pfizer. As such, this success story demonstrates how the facets of drug discovery and development fit together in real life, and how one may lead such a project and overcome the challenges that commonly emerge.

A significant portion of the book is devoted to coverage of “hot” scientific fields that are fertile ground for new drug candidates. Examples of this that are highlighted in the book include the microbiome and the potential of probiotics as drugs, nanotechnology for diagnostic and therapeutic applications, and the harnessing of the immune system to combat cancer. The emergence of the gene-editing tool CRISPR and its applications to drug discovery is also the subject of a chapter.

Another large section of the book details technical processes for screening compounds and evaluating promising drug candidates for efficacy and safety. High-throughput screening of compounds, a staple of drug discovery for decades which has undergone continual innovation, is the subject of one chapter. DNA-encoded libraries, the subject of another chapter, is a novel technology that has quickly become entrenched in the drug discovery process in the past decade. In this technology, many test compounds can be tested for affinity to target protein in the same well of a multi-well plate since amplification of the DNA tag reveals the identity of the binding compound after the fact. The evaluation of the safety of drugs is the specific focus of three chapters on preclinical toxicology, safety pharmacology, and in vitro pharmaceutical profiling of drug selectivity.

The viability of drugs is not limited to activity at the target site – whether the drug can reach the target site is also critical to determining “drugability.” As such, one chapter is devoted to pharmacokinetics as well as pharmacodynamics. Another chapter on the Caco-2 cell model focuses on one aspect of pharmacokinetics, absorption, which is the main determinant of bioavailability.

Also presented are extended discussions of clinical research, both inside and outside the academic research institution. In addition to broad chapters on clinical trials methodology, biomedical research in academia, and ethics in clinical trials, more specialized chapters focus on the role of the pharmacist in research as well as the special challenges associated with clinical testing of HIV drugs, respectively. Another chapter is a comprehensive treatment of drug product development as a whole, discussing the progression from lead candidate selection to life-cycle management. This chapter integrates many of the other topics that are the subject of extended discussion in other chapters in the “Drug Development” section.

Since drug development does not exist in a vacuum, the regulatory hurdles which drug development aims to surmount are also discussed. Chapters in this section include a comprehensive treatment of important regulations in drug development and chapters on regulations in special populations, regulations governing compounding and pharmaceutics, and regulations guiding orphan drug development.

Patents, the protectors of the financial renumeration which drives companies to pursue drug development, are the subject of another chapter. “Repurposing” of drugs for new indications, a valuable strategy to avoid the costs of developing a brand-new compound, is covered in another chapter. This unique contribution was provided by a nurse clinician–turned researcher who led initiatives in drug repurposing, and it includes a case study of the repurposing of loperamide as a topical anesthetic for blood sample needle sticks in neonates.

The following abstracts provide a preview of the chapters offered.

Section I. Overview

Chapter 2. Current Opinions on the Trajectory of the Pharmaceutical Development

J. Somberg

Dr. John Somberg, a uniquely experienced clinician, academician, researcher, and president of his own pharmaceutical (drug development) company, provides a good historical review as well as a look to the future. If one goes back a couple of decades reviewing the volumes of a medical journal, one will pass through a decade or so of clinical trials from large, adequately powered studies, to small trials and then retrospective clinical data reviews often with historic controls. Before the 1970s, one would see articles dealing with therapeutic approaches relating a clinicians’ experience with a therapy and recalling the results of prior therapeutic approaches. Drug development and discovery is a most exciting field. It is creative, intellectually challenging, and organizationally demanding. Those involved are to be congratulated for undertaking efforts that are usually anonymous but affect clinical therapeutics to a considerable degree. The drug discovery process has gone through the botanical phase and the synthetic chemistry phase, and is now into a most exciting era of biotechnology and gene manipulation.

Chapter 3. Innovation in Drug Developmen...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Dedication
• Contents
• Acknowledgments
• Introduction to the First Edition (1992)
• Introduction to the Second Edition (2006)
• Editors
• Contributors
• Chapter 1 Introduction to Drug Discovery and Development
• SECTION I Overview
• SECTION II Drug Discovery
• SECTION III Drug Development
• SECTION IV Regulations
• Index