Drug Discovery Toxicology

As a guide for pharmaceutical professionals to the issues and practices of drug discovery toxicology, this book integrates and reviews the strategy and application of tools and methods at each step of the drug discovery process. Guides researchers as to what drug safety experiments are both practical and useful Covers a variety of key topics safety lead optimization, in vitro-in vivo translation, organ toxicology, ADME, animal models, biomarkers, and omics tools Describes what experiments are possible and useful and offers a view into the future, indicating key areas to watch for new predictive methods Features contributions from firsthand industry experience, giving readers insight into the strategy and execution of predictive toxicology practices

Auteur

Yvonne Will, PhD, is a Senior Director and the Head of Science and Technology Strategy, Drug Safety Research and Development at Pfizer, Connecticut, USA. She co-edited the book Drug-Induced Mitochondrial Dysfunction, published by Wiley in 2008.

J. Eric McDuffie, PhD, is the Director of the Discovery / Investigative Toxicology and Laboratory Animal Medicine groups at Janssen Research & Development, California, USA.

Andrew J. Olaharski, PhD, is an Associate Director of Toxicology at Agios Pharmaceuticals, Massachusetts, USA.

Brandon D. Jeffy, PhD, is a Senior Principal Scientist in the Exploratory Toxicology division of Nonclinical Development at Celgene Pharmaceuticals, California, USA.

Texte du rabat

Developing novel pharmaceuticals requires nonclinical safety studies on candidate drugs to assess general toxicology (through in vivo experiments), safety pharmacology (effects on major organ systems), and genetic toxicity tests. These data provide risk assessment data that supports progression of candidate drugs from discovery phase through clinical development, to regulatory submission and registration. Traditionally, however, less emphasis was placed on the evaluation of safety issues for projects while still in the drug design phase.

In response to this costly attrition, many pharmaceutical companies invested in drug discovery toxicology or drug discovery safety to identify hazards and take steps to design out or significantly reduce undesirable safety liabilities earlier; with the ultimate aim of enhancing the probability of success in non-clinical and clinical drug development. Because of this, there is a strong need for personnel involved with toxicology and pharmacology studies need to understand the varied tools and approaches to perform early drug discovery safety analysis.

Drug Discovery Toxicology: From Target Assessment to Translational Biomarkers serves as a valuable tool for those discovery scientists. The authors, writing from firsthand industry experience, give readers insight into the strategy and execution of predictive toxicology practices, including what experiments are possible and useful. In addition, they offer a view into the future, indicating key areas to watch for new predictive methods. Broken into different sections, the book deals with the key topics Safety Lead Optimization Strategies, In Vitro-In Vivo Pharmacokinetics Translation, Predicting Organ Toxicity In Vitro, False Negative Space, --Omics in Predictive Toxicology, Translational Biomarkers, and Signal Investigation Rationale and Practices.

As a guide for pharmaceutical professionals to the issues and practices of drug discovery toxicology, this book integrates and reviews the strategy and application of tools and methods throughout the pre-clinical drug discovery development process.

Contenu

LIST OF CONTRIBUTORS xxi

FOREWORD xxv

PART I INTRODUCTION 1

1 Emerging Technologies and their Role in Regulatory Review 3
Thomas J. Colatsky

1.1 Introduction 3

1.2 safety assessment in Drug Development and Review 4

1.3 The Role of New Technologies in Regulatory Safety Assessment 6

1.4 Conclusions 8

References 8

PART II SAFETY LEAD OPTIMIZATION STRATEGIES 13

2 SmallMolecule Safety Lead Optimization 15
Donna M. Dambach

2.1 Background and Objectives of Safety Lead Optimization Approaches 15

2.2 Target Safety Assessments: Evaluation of Undesired Pharmacology and Therapeutic Area Considerations 16

2.3 Implementing Lead Optimization Strategies for Small Molecules 16

2.4 Conclusions 23

References 23

3 Safety Assessment Strategies and Predictive Safety of Biopharmaceuticals and Antibody Drug Conjugates 27
Michelle J. Horner, Mary Jane Hinrichs and Nicholas Buss

3.1 Background and Objectives 27

3.2 Target Safety Assessments: Strategies to Understand Target Biology and Associated Liabilities 28

3.3 Strategic Approaches for Biopharmaceuticals and ADCs 29

3.4 Predictive Safety Tools for Large Molecules 33

3.5 Strategies for Species Selection 34

3.6 Strategy for DoseRanging Studies for Safety Evaluation of Biopharmaceuticals 35

3.7 Conclusions 35

References 36

4 Discovery and Development Strategies for Small Interfering Rnas 39
Scott A. Barros and Gregory Hinkle

4.1 Background 39

4.2 Target Assessments 40

4.3 siRNA Design and Screening Strategies 41

4.4 Safety Lead Optimization of siRNA 45

4.5 Integration of Lead Optimization Data for Candidate Selection and Development 48

4.6 Conclusions 49

References 49

PART III BASIS FOR IN VITROIN VIVO PK TRANSLATION 53

5 Physicochemistry and the OffTarget Effects of Drug Molecules 55
Dennis A. Smith

5.1 Lipohilicity, Polar Surface Area, and Lipoidal Permeability 55

5.2 Physicochemistry and Basic ADME Properties for High Lipoidal Permeability Drugs 56

5.3 Relationship between Volume of Distribution (Vd) and Target Access for Passively Distributed Drugs 58

5.4 Basicity, Lipophilicity, and Volume of Distribution as a Predictor of Toxicity (T): Adding The T to ADMET 59

5.5 Basicity and Lipophilicity as a Predictor of Toxicity (T): Separating the D from T in ADMET 60

5.6 Lipophilicity and PSA as a Predictor of Toxicity (T): Adding the T to ADMET 60

5.7 Metabolism and Physicochemical Properties 61

5.8 Concentration of Compounds by Transporters 61

5.9 Inhibition of Excretion Pumps 63

5.10 Conclusions 64

References 65

6 The Need for Human Exposure Projection in the Interpretation of Preclinical In Vitro and *In Vivo ADME Tox Data 67
* Patrick Poulin

6.1 Introduction 67

6.2 Methodology Used for Human PK Projection in Drug Discovery 67

6.3 Summary of the TakeHome Messages from the Pharmaceutical Research and Manufacturers of America Cpcdc Initiative on Predictive Models of Human PK from 2011 72

Abbreviations 77

References 77

7 A DME Properties Leading to Toxicity 82
Katya Tsaioun

7.1 Introduction 82

7.2 The Science of ADME 83

7.3 The ADME Optimization Strategy 83

7.4 Conclusions and Future Directions 89

References 90

PART IV Predicting Organ Toxicity 93 ...