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.

LIST OF CONTRIBUTORS xxi FOREWORD xxv PART I INTRODUCTION 1 1 Emerging Technologies and their Role in Regulatory Review 3Thomas 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 Small¿Molecule Safety Lead Optimization 15Donna 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 27Michelle 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 Dose¿Ranging Studies for Safety Evaluation of Biopharmaceuticals 35 3.7 Conclusions 35 References 36 4 Discovery and Development Strategies for Small Interfering Rnas 39Scott 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 VITRO-IN VIVO PK TRANSLATION 53 5 Physicochemistry and the Off¿Target Effects of Drug Molecules 55Dennis 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 67Patrick Poulin 6.1 Introduction 67 6.2 Methodology Used for Human PK Projection in Drug Discovery 67 6.3 Summary of the Take¿Home 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 82Katya 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 8 Liver 95J. Gerry Kenna, Mikael Persson, Scott Q. Siler, Ke Yu, Chuchu Hu, Minjun Chen, Joshua Xu, Weida Tong, Yvonne Will and Michael D. Aleo 8.1 Introduction 95 8.2 DILI Mechanisms and Susceptibility 96 8.3 Common Mechanisms that Contribute to DILI 98 8.4 Models Systems Used to Study DILI 108 8.5 In Silico Models 114 8.6 Systems Pharmacology and DILI 118 8.7 Summary 119 References 121 9 Cardiac 130David J. Gallacher, Gary Gintant, Najah Abi¿Gerges, Mark R. Davies, Hua Rong Lu, Kimberley M. Hoagland, Georg Rast, Brian D. Guth, Hugo M. Vargas and Robert L. Hamlin 9.1 General Introduction 130 9.2 Classical In Vitro/Ex Vivo Assessment of Cardiac Electrophysiologic Effects 133 9.3 Cardiac Ion Channels and In Silico Prediction 137 9.4 From Animal Ex Vivo/In Vitro Models to Human Stem Cell¿Derived Cms for Cardiac Safety Testing 140 9.5 In Vivo Telemetry Capabilities and Preclinical Drug Development 141 9.6 Assessment of Myocardial Contractility in Preclinical Models 144 9.7 Assessment of Large Versus Small Molecules in CV SP 147 9.8 Patients do not Necessarily Respond to Drugs and Devices as do Genetically Identical, Young Mature, Healthy Mice! 148 References 152 10 Predictive In Vitro Models for Assessment of Nephrotoxicity and Drug-Drug Interactions In Vitro 160
Lawrence H. Lash 10.1 Introduction 160 10.2 Biological Processes and Toxic Responses of the Kidneys that are Normally Measured in Toxicology Research and Drug Development Studies 163 10.3 Primary Cultures of hPT Cells 164 10.4 Toxicology Studies in hPT Primary Cell Cultures 166 10.5 Critical Studies for Drug Discovery in hpt Primary Cell Cultures 168 10.6 S ummary and Conclusions 168 References 170 11 Predicting Organ Toxicity In Vitro: Bone Marrow 172Ivan Rich and Andrew J. Olaharski 11.1 Introduction 172 11.2 Biology of the Hematopoietic System 172 11.3 Hemotoxicity 173 11.4 Measuring Hemotoxicity 173 11.5 The Next Generation of Assays 175 11.6 Proliferation or Differentiation? 175 11.7 Measuring and Predicting Hemotoxicity In Vitro 176 11.8 Detecting Stem and Progenitor Cell Downstream Events 177 11.9 Bone Marrow Toxicity Testing During Drug Development 177 11.10 Paradigm for In Vitro Hemotoxicity Testing 178 11.11 Predicting Starting Doses for Animal and Human Clinical Trials 179 11.12 Future Trends 179 11.13 Conclusions 180 References 180 12 Predicting Organ Toxicity In Vitro: Dermal Toxicity 182Patrick J. Hayden, Michael Bachelor, Mitchell Klausner and Helena Kandárová 12.1 Introduction 182 12.2 Overview of Drug¿Induced Adverse Cutaneous Reactions 182 12.3 Overview of In Vitro Skin Models with Relevance to Preclinical Drug Development 183 12.4 Specific Applications of In Vitro Skin Models and Predictive In Vitro Assays Relevant to Pharmaceutical Development 184 12.5 Mechanism¿Based Cutaneous Adverse Effects 187 12.6 Summary 188 References 189 13 In Vitro Methods in Immunotoxicity Assessment 193Xu Zhu and Ellen Evans 13.1 Introduction and Perspectives on In Vitro Immunotoxicity Screening 193 13.2 Overview of the Immune System 194 13.3 Examples of In Vitro Approaches 196 13.4 Conclusions 198 References 199 14 Strategies and Assays for Minimizing Risk of Ocular Toxicity during Early Development of Systemically Administered Drugs 201Chris J. Somps, Paul Butler, Jay H. Fortner, Keri E. Cannon and Wenhu Huang 14.1 Introduction 201 14.2 In Silico and In Vitro Tools and Strategies 201 14.3 Higher¿Throughput In Vivo Tools and Strategies 202 14.4 S trategies, Gaps, and Emerging Technologies 208 14.5 Summary 210 References 210 15 Predicting Organ Toxicity In Vivo-Central Nervous System 214Greet Teuns and Alison Easter 15.1 Introduction 214 15.2 Models for Assessment of CNS ADRs 214 15.3 S eizure Liability Testing 216 15.4 Drug Abuse Liability Testing 218 15.5 General Conclusions 222 15.5.1 In Vitro 222 15.5.2 In Vivo 223 Abbreviations 223 References 224 16 Biomarkers, Cell Models, and In Vitro Assays for Gastrointestinal Toxicology 227Allison Vitsky and Gina M. Yanochko 16.1 Introduction 227 16.2 A natomic and Physiologic Considerations 228 16.3 GI Biomarkers 229 16.4 Cell Models of the GI Tract 231 16.5 Cell¿Based In Vitro Assays for Screening and Mechanistic Investigations to Gi Toxicity 235 16.6 Summary/Conclusions/Challenges 236 References 236 17 Preclinical Safety Assessment of Drug Candidate¿Induced Pancreatic Toxicity: From an Applied Perspective 242Karrie A. Brenneman, Shashi K. Ramaiah and Lauren M. Gauthier 17.1 Drug¿Induced Pancreatic Toxicity 242 17.2 Preclinical Evaluation of Pancreatic Toxicity 245 17.3 Preclinical Pancreatic Toxicity Assessment: In Vivo 247 17.4 Pancreatic Biomarkers 249 17.5 Preclinical Pancreatic Toxicity Assessment: In Vitro 253 17.6 Summary and Conclusions 257 Acknowledgments 258 References 258 PART V A DDRESSING THE FALSE NEGATIVE SPACE-INCREASING PREDICTIVITY 261 18 Animal Models of Disease for Future Toxicity Predictions 263Sherry J. Morgan and Chandikumar S. Elangbam 18.1 Introduction 263 18.2 Hepatic Disease Models 264 18.3 Cardiovascular Disease Models 268 18.4 Nervous System Disease Models 270 18.5 Gastrointestinal Injury Models 273 18.6 Renal Injury Models 279 18.7 Respiratory Disease Models 282 18.8 Conclusion 285 References 287 19 The Use of Genetically Modified Animals in Discovery Toxicology 298Dolores Diaz and Jonathan M. Maher 19.1 Introduction 298 19.2 Large¿Scale Gene Targeting and Phenotyping Efforts 299 19.3 Use of Genetically Modified Animal Models in Discovery Toxicology 300 19.4 The Use of Genetically Modified Animals in Pharmacokinetic and Metabolism Studies 303 19.5 Conclusions 309 References 309 20 Mouse Population-Based Toxicology for Personalized Medicine and Improved Safety Prediction 314Alison H. Harrill 20.1 Introduction 314 20.2 Pharmacogenetics and Population Variability 314 20.3 Rodent Populations Enable a Population¿Based Approaches to Toxicology 316 20.4 Applications for Pharmaceutical Safety Science 320 20.5 Study Design Considerations for Genomic Mapping 322 20.6 Summary 326 References 326 PART VI STEM CELLS IN TOXICOLOGY 331 21 Application of Pluripotent Stem Cells in Drug¿Induced Liver Injury Safety Assessment 333Christopher S. Pridgeon, Fang Zhang, James A. Heslop, Charlotte M.L. Nugues, Neil R. Kitteringham, B. Kevin Park and Christopher E.P. Goldring 21.1 The Liver, Hepatocytes, and Drug¿Induced Liver Injury 333 21.2 Current Models of Dili 334 21.3 Uses of iPSC HLCs 338 21.4 Challenges of Using ipscs and New Directions for Improvement 339 21.5 Alternate Uses of HLCs in Toxicity Assessment 341 References 342 22 Human Pluripotent Stem Cell¿Derived Cardiomyocytes: A New Paradigm in Predictive Pharmacology and Toxicology 346Praveen Shukla, Priyanka Garg and Joseph C. Wu 22.1 Introduction 346 22.2 A dvent of hPSCs: Reprogramming and Cardiac Differentiation 347 22.3 iPSC¿Based Disease Modeling and Drug Testing 349 22.4...