{"product_id":"drug-discovery-toxicology-isbn-9781119053330","title":"Drug Discovery Toxicology","description":"\u003cp\u003eAs 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.\u003c\/p\u003e \u003cp\u003e• Guides researchers as to what drug safety experiments are both practical and useful\u003cbr\u003e• Covers a variety of key topics – safety lead optimization, in vitro-in vivo translation, organ toxicology, ADME, animal models, biomarkers, and –omics tools\u003cbr\u003e• Describes what experiments are possible and useful and offers a view into the future, indicating key areas to watch for new predictive methods\u003cbr\u003e• Features contributions from firsthand industry experience, giving readers insight into the strategy and execution of predictive toxicology practices\u003c\/p\u003e \u003cp\u003e\u003cb\u003eLIST OF CONTRIBUTORS xxi\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003eFOREWORD xxv\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePART I INTRODUCTION 1\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e1 Emerging Technologies and their Role in Regulatory Review 3\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eThomas J. Colatsky\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e1.1 Introduction 3\u003c\/p\u003e \u003cp\u003e1.2 safety assessment in Drug Development and Review 4\u003c\/p\u003e \u003cp\u003e1.3 The Role of New Technologies in Regulatory Safety Assessment 6\u003c\/p\u003e \u003cp\u003e1.4 Conclusions 8\u003c\/p\u003e \u003cp\u003eReferences 8\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePART II SAFETY LEAD OPTIMIZATION STRATEGIES 13\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e2 Small\u003c\/b\u003e\u003cb\u003e‐\u003c\/b\u003e\u003cb\u003eMolecule Safety Lead Optimization 15\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eDonna M. Dambach\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e2.1 Background and Objectives of Safety Lead Optimization Approaches 15\u003c\/p\u003e \u003cp\u003e2.2 Target Safety Assessments: Evaluation of Undesired Pharmacology and Therapeutic Area Considerations 16\u003c\/p\u003e \u003cp\u003e2.3 Implementing Lead Optimization Strategies for Small Molecules 16\u003c\/p\u003e \u003cp\u003e2.4 Conclusions 23\u003c\/p\u003e \u003cp\u003eReferences 23\u003c\/p\u003e \u003cp\u003e\u003cb\u003e3 Safety Assessment Strategies and Predictive Safety of Biopharmaceuticals and Antibody Drug Conjugates 27\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eMichelle J. Horner, Mary Jane Hinrichs and Nicholas Buss\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e3.1 Background and Objectives 27\u003c\/p\u003e \u003cp\u003e3.2 Target Safety Assessments: Strategies to Understand Target Biology and Associated Liabilities 28\u003c\/p\u003e \u003cp\u003e3.3 Strategic Approaches for Biopharmaceuticals and ADCs 29\u003c\/p\u003e \u003cp\u003e3.4 Predictive Safety Tools for Large Molecules 33\u003c\/p\u003e \u003cp\u003e3.5 Strategies for Species Selection 34\u003c\/p\u003e \u003cp\u003e3.6 Strategy for Dose‐Ranging Studies for Safety Evaluation of Biopharmaceuticals 35\u003c\/p\u003e \u003cp\u003e3.7 Conclusions 35\u003c\/p\u003e \u003cp\u003eReferences 36\u003c\/p\u003e \u003cp\u003e\u003cb\u003e4 Discovery and Development Strategies for Small Interfering Rnas 39\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eScott A. Barros and Gregory Hinkle\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e4.1 Background 39\u003c\/p\u003e \u003cp\u003e4.2 Target Assessments 40\u003c\/p\u003e \u003cp\u003e4.3 siRNA Design and Screening Strategies 41\u003c\/p\u003e \u003cp\u003e4.4 Safety Lead Optimization of siRNA 45\u003c\/p\u003e \u003cp\u003e4.5 Integration of Lead Optimization Data for Candidate Selection and Development 48\u003c\/p\u003e \u003cp\u003e4.6 Conclusions 49\u003c\/p\u003e \u003cp\u003eReferences 49\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePART III BASIS FOR \u003c\/b\u003e\u003cb\u003e\u003ci\u003eIN VITRO–IN VIVO \u003c\/i\u003e\u003c\/b\u003e\u003cb\u003ePK TRANSLATION 53\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e5 Physicochemistry and the Off\u003c\/b\u003e\u003cb\u003e‐\u003c\/b\u003e\u003cb\u003eTarget Effects of Drug Molecules 55\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eDennis A. Smith\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e5.1 Lipohilicity, Polar Surface Area, and Lipoidal Permeability 55\u003c\/p\u003e \u003cp\u003e5.2 Physicochemistry and Basic ADME Properties for High Lipoidal Permeability Drugs 56\u003c\/p\u003e \u003cp\u003e5.3 Relationship between Volume of Distribution (\u003cb\u003e\u003ci\u003eV\u003c\/i\u003e\u003c\/b\u003ed) and Target Access for Passively Distributed Drugs 58\u003c\/p\u003e \u003cp\u003e5.4 Basicity, Lipophilicity, and Volume of Distribution as a Predictor of Toxicity (T): Adding The T to ADMET 59\u003c\/p\u003e \u003cp\u003e5.5 Basicity and Lipophilicity as a Predictor of Toxicity (T): Separating the D from T in ADMET 60\u003c\/p\u003e \u003cp\u003e5.6 Lipophilicity and PSA as a Predictor of Toxicity (T): Adding the T to ADMET 60\u003c\/p\u003e \u003cp\u003e5.7 Metabolism and Physicochemical Properties 61\u003c\/p\u003e \u003cp\u003e5.8 Concentration of Compounds by Transporters 61\u003c\/p\u003e \u003cp\u003e5.9 Inhibition of Excretion Pumps 63\u003c\/p\u003e \u003cp\u003e5.10 Conclusions 64\u003c\/p\u003e \u003cp\u003eReferences 65\u003c\/p\u003e \u003cp\u003e\u003cb\u003e6 The Need for Human Exposure Projection in the Interpretation of Preclinical \u003c\/b\u003e\u003cb\u003e\u003ci\u003eIn Vitro \u003c\/i\u003e\u003c\/b\u003e\u003cb\u003eand \u003c\/b\u003e\u003cb\u003e\u003ci\u003eIn Vivo \u003c\/i\u003e\u003c\/b\u003e\u003cb\u003eADME Tox Data 67\u003cbr\u003e \u003c\/b\u003e\u003ci\u003ePatrick Poulin\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e6.1 Introduction 67\u003c\/p\u003e \u003cp\u003e6.2 Methodology Used for Human PK Projection in Drug Discovery 67\u003c\/p\u003e \u003cp\u003e6.3 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\u003c\/p\u003e \u003cp\u003eAbbreviations 77\u003c\/p\u003e \u003cp\u003eReferences 77\u003c\/p\u003e \u003cp\u003e\u003cb\u003e7 A DME Properties Leading to Toxicity 82\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eKatya Tsaioun\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e7.1 Introduction 82\u003c\/p\u003e \u003cp\u003e7.2 The Science of ADME 83\u003c\/p\u003e \u003cp\u003e7.3 The ADME Optimization Strategy 83\u003c\/p\u003e \u003cp\u003e7.4 Conclusions and Future Directions 89\u003c\/p\u003e \u003cp\u003eReferences 90\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePART IV Predicting Organ Toxicity 93\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e8 Liver 95\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eJ. Gerry Kenna, Mikael Persson, Scott Q. Siler, Ke Yu, Chuchu Hu, Minjun Chen, Joshua Xu, Weida Tong, Yvonne Will and Michael D. Aleo\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e8.1 Introduction 95\u003c\/p\u003e \u003cp\u003e8.2 DILI Mechanisms and Susceptibility 96\u003c\/p\u003e \u003cp\u003e8.3 Common Mechanisms that Contribute to DILI 98\u003c\/p\u003e \u003cp\u003e8.4 Models Systems Used to Study DILI 108\u003c\/p\u003e \u003cp\u003e8.5 \u003ci\u003eIn Silico \u003c\/i\u003eModels 114\u003c\/p\u003e \u003cp\u003e8.6 Systems Pharmacology and DILI 118\u003c\/p\u003e \u003cp\u003e8.7 Summary 119\u003c\/p\u003e \u003cp\u003eReferences 121\u003c\/p\u003e \u003cp\u003e\u003cb\u003e9 Cardiac 130\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eDavid J. Gallacher, Gary Gintant, Najah Abi\u003c\/i\u003e\u003ci\u003e‐\u003c\/i\u003e\u003ci\u003eGerges, Mark R. Davies, Hua Rong Lu, Kimberley M. Hoagland, Georg Rast, Brian D. Guth, Hugo M. Vargas and Robert L. Hamlin\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e9.1 General Introduction 130\u003c\/p\u003e \u003cp\u003e9.2 Classical \u003ci\u003eIn Vitro\/Ex Vivo \u003c\/i\u003eAssessment of Cardiac Electrophysiologic Effects 133\u003c\/p\u003e \u003cp\u003e9.3 Cardiac Ion Channels and \u003ci\u003eIn Silico \u003c\/i\u003ePrediction 137\u003c\/p\u003e \u003cp\u003e9.4 From Animal \u003ci\u003eEx Vivo\/In Vitro \u003c\/i\u003eModels to Human Stem Cell‐Derived Cms for Cardiac Safety Testing 140\u003c\/p\u003e \u003cp\u003e9.5 \u003ci\u003eIn Vivo \u003c\/i\u003eTelemetry Capabilities and Preclinical Drug Development 141\u003c\/p\u003e \u003cp\u003e9.6 Assessment of Myocardial Contractility in Preclinical Models 144\u003c\/p\u003e \u003cp\u003e9.7 Assessment of Large Versus Small Molecules in CV SP 147\u003c\/p\u003e \u003cp\u003e9.8 Patients do not Necessarily Respond to Drugs and Devices as do Genetically Identical, Young Mature, Healthy Mice! 148\u003c\/p\u003e \u003cp\u003eReferences 152\u003c\/p\u003e \u003cp\u003e\u003cb\u003e10 Predictive \u003c\/b\u003e\u003cb\u003e\u003ci\u003eIn Vitro \u003c\/i\u003e\u003c\/b\u003e\u003cb\u003eModels for Assessment of Nephrotoxicity and Drug–Drug Interactions \u003c\/b\u003e\u003cb\u003e\u003ci\u003eIn Vitro \u003c\/i\u003e\u003c\/b\u003e160\u003cbr\u003e \u003ci\u003eLawrence H. Lash\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e10.1 Introduction 160\u003c\/p\u003e \u003cp\u003e10.2 Biological Processes and Toxic Responses of the Kidneys that are Normally Measured in Toxicology Research and Drug Development Studies 163\u003c\/p\u003e \u003cp\u003e10.3 Primary Cultures of hPT Cells 164\u003c\/p\u003e \u003cp\u003e10.4 Toxicology Studies in hPT Primary Cell Cultures 166\u003c\/p\u003e \u003cp\u003e10.5 Critical Studies for Drug Discovery in hpt Primary Cell Cultures 168\u003c\/p\u003e \u003cp\u003e10.6 S ummary and Conclusions 168\u003c\/p\u003e \u003cp\u003eReferences 170\u003c\/p\u003e \u003cp\u003e\u003cb\u003e11 Predicting Organ Toxicity \u003c\/b\u003e\u003cb\u003e\u003ci\u003eIn Vitro\u003c\/i\u003e\u003c\/b\u003e\u003cb\u003e: Bone Marrow 172\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eIvan Rich and Andrew J. Olaharski\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e11.1 Introduction 172\u003c\/p\u003e \u003cp\u003e11.2 Biology of the Hematopoietic System 172\u003c\/p\u003e \u003cp\u003e11.3 Hemotoxicity 173\u003c\/p\u003e \u003cp\u003e11.4 Measuring Hemotoxicity 173\u003c\/p\u003e \u003cp\u003e11.5 The Next Generation of Assays 175\u003c\/p\u003e \u003cp\u003e11.6 Proliferation or Differentiation? 175\u003c\/p\u003e \u003cp\u003e11.7 Measuring and Predicting Hemotoxicity \u003ci\u003eIn Vitro \u003c\/i\u003e176\u003c\/p\u003e \u003cp\u003e11.8 Detecting Stem and Progenitor Cell Downstream Events 177\u003c\/p\u003e \u003cp\u003e11.9 Bone Marrow Toxicity Testing During Drug Development 177\u003c\/p\u003e \u003cp\u003e11.10 Paradigm for \u003ci\u003eIn Vitro \u003c\/i\u003eHemotoxicity Testing 178\u003c\/p\u003e \u003cp\u003e11.11 Predicting Starting Doses for Animal and Human Clinical Trials 179\u003c\/p\u003e \u003cp\u003e11.12 Future Trends 179\u003c\/p\u003e \u003cp\u003e11.13 Conclusions 180\u003c\/p\u003e \u003cp\u003eReferences 180\u003c\/p\u003e \u003cp\u003e\u003cb\u003e12 Predicting Organ Toxicity \u003c\/b\u003e\u003cb\u003e\u003ci\u003eIn Vitro\u003c\/i\u003e\u003c\/b\u003e\u003cb\u003e: Dermal Toxicity 182\u003cbr\u003e \u003c\/b\u003e\u003ci\u003ePatrick J. Hayden, Michael Bachelor, Mitchell Klausner and Helena Kandárová\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e12.1 Introduction 182\u003c\/p\u003e \u003cp\u003e12.2 Overview of Drug‐Induced Adverse Cutaneous Reactions 182\u003c\/p\u003e \u003cp\u003e12.3 Overview of \u003ci\u003eIn Vitro \u003c\/i\u003eSkin Models with Relevance to Preclinical Drug Development 183\u003c\/p\u003e \u003cp\u003e12.4 Specific Applications of \u003ci\u003eIn Vitro \u003c\/i\u003eSkin Models and Predictive \u003ci\u003eIn Vitro \u003c\/i\u003eAssays Relevant to Pharmaceutical Development 184\u003c\/p\u003e \u003cp\u003e12.5 Mechanism‐Based Cutaneous Adverse Effects 187\u003c\/p\u003e \u003cp\u003e12.6 Summary 188\u003c\/p\u003e \u003cp\u003eReferences 189\u003c\/p\u003e \u003cp\u003e\u003cb\u003e13 \u003c\/b\u003e\u003cb\u003e\u003ci\u003eIn Vitro \u003c\/i\u003e\u003c\/b\u003e\u003cb\u003eMethods in Immunotoxicity Assessment 193\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eXu Zhu and Ellen Evans\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e13.1 Introduction and Perspectives on \u003ci\u003eIn Vitro \u003c\/i\u003eImmunotoxicity Screening 193\u003c\/p\u003e \u003cp\u003e13.2 Overview of the Immune System 194\u003c\/p\u003e \u003cp\u003e13.3 Examples of \u003ci\u003eIn Vitro \u003c\/i\u003eApproaches 196\u003c\/p\u003e \u003cp\u003e13.4 Conclusions 198\u003c\/p\u003e \u003cp\u003eReferences 199\u003c\/p\u003e \u003cp\u003e\u003cb\u003e14 Strategies and Assays for Minimizing Risk of Ocular Toxicity during Early Development of Systemically Administered Drugs 201\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eChris J. Somps, Paul Butler, Jay H. Fortner, Keri E. Cannon and Wenhu Huang\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e14.1 Introduction 201\u003c\/p\u003e \u003cp\u003e14.2 \u003ci\u003eIn Silico \u003c\/i\u003eand \u003ci\u003eIn Vitro \u003c\/i\u003eTools and Strategies 201\u003c\/p\u003e \u003cp\u003e14.3 Higher‐Throughput \u003ci\u003eIn Vivo \u003c\/i\u003eTools and Strategies 202\u003c\/p\u003e \u003cp\u003e14.4 S trategies, Gaps, and Emerging Technologies 208\u003c\/p\u003e \u003cp\u003e14.5 Summary 210\u003c\/p\u003e \u003cp\u003eReferences 210\u003c\/p\u003e \u003cp\u003e\u003cb\u003e15 Predicting Organ Toxicity \u003c\/b\u003e\u003cb\u003e\u003ci\u003eIn Vivo\u003c\/i\u003e\u003c\/b\u003e\u003cb\u003e—Central Nervous System 214\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eGreet Teuns and Alison Easter\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e15.1 Introduction 214\u003c\/p\u003e \u003cp\u003e15.2 Models for Assessment of CNS ADRs 214\u003c\/p\u003e \u003cp\u003e15.3 S eizure Liability Testing 216\u003c\/p\u003e \u003cp\u003e15.4 Drug Abuse Liability Testing 218\u003c\/p\u003e \u003cp\u003e15.5 General Conclusions 222\u003c\/p\u003e \u003cp\u003e15.5.1 \u003ci\u003eIn Vitro \u003c\/i\u003e222\u003c\/p\u003e \u003cp\u003e15.5.2 \u003ci\u003eIn Vivo \u003c\/i\u003e223\u003c\/p\u003e \u003cp\u003eAbbreviations 223\u003c\/p\u003e \u003cp\u003eReferences 224\u003c\/p\u003e \u003cp\u003e\u003cb\u003e16 Biomarkers, Cell Models, and \u003c\/b\u003e\u003cb\u003e\u003ci\u003eIn Vitro \u003c\/i\u003e\u003c\/b\u003e\u003cb\u003eAssays for Gastrointestinal Toxicology 227\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eAllison Vitsky and Gina M. Yanochko\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e16.1 Introduction 227\u003c\/p\u003e \u003cp\u003e16.2 A natomic and Physiologic Considerations 228\u003c\/p\u003e \u003cp\u003e16.3 GI Biomarkers 229\u003c\/p\u003e \u003cp\u003e16.4 Cell Models of the GI Tract 231\u003c\/p\u003e \u003cp\u003e16.5 Cell‐Based \u003ci\u003eIn Vitro \u003c\/i\u003eAssays for Screening and Mechanistic Investigations to Gi Toxicity 235\u003c\/p\u003e \u003cp\u003e16.6 Summary\/Conclusions\/Challenges 236\u003c\/p\u003e \u003cp\u003eReferences 236\u003c\/p\u003e \u003cp\u003e\u003cb\u003e17 Preclinical Safety Assessment of Drug Candidate\u003c\/b\u003e\u003cb\u003e‐\u003c\/b\u003e\u003cb\u003eInduced Pancreatic Toxicity: From an Applied Perspective 242\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eKarrie A. Brenneman, Shashi K. Ramaiah and Lauren M. Gauthier\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e17.1 Drug‐Induced Pancreatic Toxicity 242\u003c\/p\u003e \u003cp\u003e17.2 Preclinical Evaluation of Pancreatic Toxicity 245\u003c\/p\u003e \u003cp\u003e17.3 Preclinical Pancreatic Toxicity Assessment: \u003ci\u003eIn Vivo \u003c\/i\u003e247\u003c\/p\u003e \u003cp\u003e17.4 Pancreatic Biomarkers 249\u003c\/p\u003e \u003cp\u003e17.5 Preclinical Pancreatic Toxicity Assessment: \u003ci\u003eIn Vitro \u003c\/i\u003e253\u003c\/p\u003e \u003cp\u003e17.6 Summary and Conclusions 257\u003c\/p\u003e \u003cp\u003eAcknowledgments 258\u003c\/p\u003e \u003cp\u003eReferences 258\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePART V A DDRESSING THE FALSE NEGATIVE SPACE—INCREASING\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePREDICTIVITY 261\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e18 Animal Models of Disease for Future Toxicity Predictions 263\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eSherry J. Morgan and Chandikumar S. Elangbam\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e18.1 Introduction 263\u003c\/p\u003e \u003cp\u003e18.2 Hepatic Disease Models 264\u003c\/p\u003e \u003cp\u003e18.3 Cardiovascular Disease Models 268\u003c\/p\u003e \u003cp\u003e18.4 Nervous System Disease Models 270\u003c\/p\u003e \u003cp\u003e18.5 Gastrointestinal Injury Models 273\u003c\/p\u003e \u003cp\u003e18.6 Renal Injury Models 279\u003c\/p\u003e \u003cp\u003e18.7 Respiratory Disease Models 282\u003c\/p\u003e \u003cp\u003e18.8 Conclusion 285\u003c\/p\u003e \u003cp\u003eReferences 287\u003c\/p\u003e \u003cp\u003e\u003cb\u003e19 The Use of Genetically Modified Animals in Discovery Toxicology 298\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eDolores Diaz and Jonathan M. Maher\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e19.1 Introduction 298\u003c\/p\u003e \u003cp\u003e19.2 Large‐Scale Gene Targeting and Phenotyping Efforts 299\u003c\/p\u003e \u003cp\u003e19.3 Use of Genetically Modified Animal Models in Discovery Toxicology 300\u003c\/p\u003e \u003cp\u003e19.4 The Use of Genetically Modified Animals in Pharmacokinetic and Metabolism Studies 303\u003c\/p\u003e \u003cp\u003e19.5 Conclusions 309\u003c\/p\u003e \u003cp\u003eReferences 309\u003c\/p\u003e \u003cp\u003e\u003cb\u003e20 Mouse Population-Based Toxicology for Personalized Medicine and Improved Safety Prediction 314\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eAlison H. Harrill\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e20.1 Introduction 314\u003c\/p\u003e \u003cp\u003e20.2 Pharmacogenetics and Population Variability 314\u003c\/p\u003e \u003cp\u003e20.3 Rodent Populations Enable a Population‐Based Approaches to Toxicology 316\u003c\/p\u003e \u003cp\u003e20.4 Applications for Pharmaceutical Safety Science 320\u003c\/p\u003e \u003cp\u003e20.5 Study Design Considerations for Genomic Mapping 322\u003c\/p\u003e \u003cp\u003e20.6 Summary 326\u003c\/p\u003e \u003cp\u003eReferences 326\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePART VI STEM CELLS IN TOXICOLOGY 331\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e21 Application of Pluripotent Stem Cells in Drug\u003c\/b\u003e\u003cb\u003e‐\u003c\/b\u003e\u003cb\u003eInduced Liver Injury Safety Assessment 333\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eChristopher S. Pridgeon, Fang Zhang, James A. Heslop, Charlotte M.L. Nugues, Neil R. Kitteringham, B. Kevin Park and Christopher E.P. Goldring\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e21.1 The Liver, Hepatocytes, and Drug‐Induced Liver Injury 333\u003c\/p\u003e \u003cp\u003e21.2 Current Models of Dili 334\u003c\/p\u003e \u003cp\u003e21.3 Uses of iPSC HLCs 338\u003c\/p\u003e \u003cp\u003e21.4 Challenges of Using ipscs and New Directions for Improvement 339\u003c\/p\u003e \u003cp\u003e21.5 Alternate Uses of HLCs in Toxicity Assessment 341\u003c\/p\u003e \u003cp\u003eReferences 342\u003c\/p\u003e \u003cp\u003e\u003cb\u003e22 Human Pluripotent Stem Cell\u003c\/b\u003e\u003cb\u003e‐\u003c\/b\u003e\u003cb\u003eDerived Cardiomyocytes: A New Paradigm in Predictive Pharmacology and Toxicology 346\u003cbr\u003e \u003c\/b\u003e\u003ci\u003ePraveen Shukla, Priyanka Garg and Joseph C. Wu\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e22.1 Introduction 346\u003c\/p\u003e \u003cp\u003e22.2 A dvent of hPSCs: Reprogramming and Cardiac Differentiation 347\u003c\/p\u003e \u003cp\u003e22.3 iPSC‐Based Disease Modeling and Drug Testing 349\u003c\/p\u003e \u003cp\u003e22.4 Traditional Target‐Centric Drug Discovery Paradigm 354\u003c\/p\u003e \u003cp\u003e22.5 iPSC‐Based Drug Discovery Paradigm 354\u003c\/p\u003e \u003cp\u003e22.6 Limitations and Challenges 358\u003c\/p\u003e \u003cp\u003e22.7 Conclusions and Future Perspective 359\u003c\/p\u003e \u003cp\u003eAcknowledgments 360\u003c\/p\u003e \u003cp\u003eReferences 360\u003c\/p\u003e \u003cp\u003e\u003cb\u003e23 Stem Cell\u003c\/b\u003e\u003cb\u003e‐\u003c\/b\u003e\u003cb\u003eDerived Renal Cells and Predictive Renal \u003c\/b\u003e\u003cb\u003e\u003ci\u003eIn Vitro \u003c\/i\u003e\u003c\/b\u003e\u003cb\u003eModels 365\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eJacqueline Kai Chin Chuah, Yue Ning Lam, Peng Huang and Daniele Zink\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e23.1 Introduction 365\u003c\/p\u003e \u003cp\u003e23.2 Protocols for the Differentiation of Pluripotent Stem Cells into Cells of the Renal Lineage 367\u003c\/p\u003e \u003cp\u003e23.3 Renal \u003ci\u003eIn Vitro \u003c\/i\u003eModels for Drug Safety Screening 376\u003c\/p\u003e \u003cp\u003e23.4 Achievements and Future Directions 378\u003c\/p\u003e \u003cp\u003eAcknowledgments 379\u003c\/p\u003e \u003cp\u003eNotes 379\u003c\/p\u003e \u003cp\u003eReferences 379\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePART VII CURRENT STATUS OF PRECLINICAL \u003c\/b\u003e\u003cb\u003e\u003ci\u003eIN VIVO \u003c\/i\u003e\u003c\/b\u003e\u003cb\u003eTOXICITY BIOMARKERS 385\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e24 Predictive Cardiac Hypertrophy Biomarkers in Nonclinical Studies 387\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eSteven K. Engle\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e24.1 Introduction to Biomarkers 387\u003c\/p\u003e \u003cp\u003e24.2 Cardiovascular Toxicity 387\u003c\/p\u003e \u003cp\u003e24.3 Cardiac Hypertrophy 388\u003c\/p\u003e \u003cp\u003e24.4 Diagnosis of Cardiac Hypertrophy 389\u003c\/p\u003e \u003cp\u003e24.5 Biomarkers of Cardiac Hypertrophy 389\u003c\/p\u003e \u003cp\u003e24.6 Case Studies 392\u003c\/p\u003e \u003cp\u003e24.7 Conclusion 392\u003c\/p\u003e \u003cp\u003eReferences 393\u003c\/p\u003e \u003cp\u003e\u003cb\u003e25 Vascular Injury Biomarkers 397\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eTanja S. Zabka and Kaïdre Bendjama\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e25.1 Historical Context of Drug‐Induced Vascular Injury and Drug Development 397\u003c\/p\u003e \u003cp\u003e25.2 Current State of Divi Biomarkers 398\u003c\/p\u003e \u003cp\u003e25.3 Current Status and Future of \u003ci\u003eIn Vitro \u003c\/i\u003eSystems to Investigate Divi 402\u003c\/p\u003e \u003cp\u003e25.4 Incorporation of \u003ci\u003eIn Vitro \u003c\/i\u003eand \u003ci\u003eIn Vivo \u003c\/i\u003eTools in Preclinical Drug Development 403\u003c\/p\u003e \u003cp\u003e25.5 Divi Case Study 403\u003c\/p\u003e \u003cp\u003eReferences 403\u003c\/p\u003e \u003cp\u003e\u003cb\u003e26 Novel Translational Biomarkers of Skeletal Muscle Injury 407\u003cbr\u003e \u003c\/b\u003e\u003ci\u003ePeter M. Burch and Warren E. Glaab\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e26.1 Introduction 407\u003c\/p\u003e \u003cp\u003e26.2 Overview of Drug‐Induced Skeletal Muscle Injury 407\u003c\/p\u003e \u003cp\u003e26.3 Novel Biomarkers of Drug‐Induced Skeletal Muscle Injury 409\u003c\/p\u003e \u003cp\u003e26.4 Regulatory Endorsement 411\u003c\/p\u003e \u003cp\u003e26.5 Gaps and Future Directions 411\u003c\/p\u003e \u003cp\u003e26.6 Conclusions 412\u003c\/p\u003e \u003cp\u003eReferences 412\u003c\/p\u003e \u003cp\u003e\u003cb\u003e27 Translational Mechanistic Biomarkers and Models for Predicting Drug\u003c\/b\u003e\u003cb\u003e‐\u003c\/b\u003e\u003cb\u003eInduced Liver Injury : Clinical to \u003c\/b\u003e\u003cb\u003e\u003ci\u003eIn Vitro \u003c\/i\u003e\u003c\/b\u003e\u003cb\u003ePerspectives 416\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eDaniel J. Antoine\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e27.1 Introduction 416\u003c\/p\u003e \u003cp\u003e27.2 Drug‐Induced Toxicity and the Liver 417\u003c\/p\u003e \u003cp\u003e27.3 Current Status of Biomarkers for the Assessment of DILI 418\u003c\/p\u003e \u003cp\u003e27.4 Novel Investigational Biomarkers for DILI 419\u003c\/p\u003e \u003cp\u003e27.5 \u003ci\u003eIn Vitro \u003c\/i\u003eModels and the Prediction of Human Dili 422\u003c\/p\u003e \u003cp\u003e27.6 Conclusions and Future Perspectives 423\u003c\/p\u003e \u003cp\u003eReferences 424\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePART VIII Kidney Injury Biomarkers 429\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e28 Assessing and Predicting Drug\u003c\/b\u003e\u003cb\u003e‐\u003c\/b\u003e\u003cb\u003eInduced Kidney Injury, Functional Change, and Safety in Preclinical Studies in Rats 431\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eYafei Chen\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e28.1 Introduction 431\u003c\/p\u003e \u003cp\u003e28.2 Kidney Functional Biomarkers (Glomerular Filtration and Tubular Reabsorption) 433\u003c\/p\u003e \u003cp\u003e28.3 Novel Kidney Tissue Injury Biomarkers 435\u003c\/p\u003e \u003cp\u003e28.4 Novel Biomarkers of Kidney Tissue Stress Response 436\u003c\/p\u003e \u003cp\u003e28.5 Application of an Integrated Rat Platform (Automated Blood Sampling and Telemetry, Abst) for Kidney Function and Injury Assessment 437\u003c\/p\u003e \u003cp\u003eReferences 439\u003c\/p\u003e \u003cp\u003e\u003cb\u003e29 Canine Kidney Safety Protein Biomarkers 443\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eManisha Sonee\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e29.1 Introduction 443\u003c\/p\u003e \u003cp\u003e29.2 Novel Canine Renal Protein Biomarkers 443\u003c\/p\u003e \u003cp\u003e29.3 Evaluations of Novel Canine Renal Protein Biomarker Performance 444\u003c\/p\u003e \u003cp\u003e29.4 Conclusion 444\u003c\/p\u003e \u003cp\u003eReferences 445\u003c\/p\u003e \u003cp\u003e\u003cb\u003e30 Traditional Kidney Safety Protein Biomarkers and Next\u003c\/b\u003e\u003cb\u003e‐\u003c\/b\u003e\u003cb\u003eGeneration Drug\u003c\/b\u003e\u003cb\u003e‐\u003c\/b\u003e\u003cb\u003eInduced Kidney Injury Biomarkers in Nonhuman Primates 446\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eJean\u003c\/i\u003e\u003ci\u003e‐\u003c\/i\u003e\u003ci\u003eCharles Gautier and Xiaobing Zhou\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e30.1 Introduction 446\u003c\/p\u003e \u003cp\u003e30.2 Evaluations of Novel Nhp Renal Protein Biomarker Performance 447\u003c\/p\u003e \u003cp\u003e30.3 New Horizons: Urinary MicroRNAs and Nephrotoxicity in Nhps 447\u003c\/p\u003e \u003cp\u003eReferences 447\u003c\/p\u003e \u003cp\u003e\u003cb\u003e31 Rat Kidney MicroRNA Atlas 448\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eAaron T. Smith\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e31.1 Introduction 448\u003c\/p\u003e \u003cp\u003e31.2 Key Findings 448\u003c\/p\u003e \u003cp\u003eReferences 449\u003c\/p\u003e \u003cp\u003e\u003cb\u003e32 MicroRNAs as Next\u003c\/b\u003e\u003cb\u003e‐\u003c\/b\u003e\u003cb\u003eGeneration Kidney Tubular Injury Biomarkers in Rats 450\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eHeidrun Ellinger\u003c\/i\u003e\u003ci\u003e‐\u003c\/i\u003e\u003ci\u003eZiegelbauer and Rounak Nassirpour\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e32.1 Introduction 450\u003c\/p\u003e \u003cp\u003e32.2 Rat Tubular miRNAs 450\u003c\/p\u003e \u003cp\u003e32.3 Conclusions 451\u003c\/p\u003e \u003cp\u003eReferences 451\u003c\/p\u003e \u003cp\u003e\u003cb\u003e33 MicroRNAs as Novel Glomerular Injury Biomarkers in Rats 452\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eRachel Church\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e33.1 Introduction 452\u003c\/p\u003e \u003cp\u003e33.2 Rat Glomerular miRNAs 452\u003c\/p\u003e \u003cp\u003eReferences 453\u003c\/p\u003e \u003cp\u003e\u003cb\u003e34 Integrating Novel Imaging Technologies to Investigate Drug\u003c\/b\u003e\u003cb\u003e‐\u003c\/b\u003e\u003cb\u003eInduced Kidney Toxicity 454\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eBettina Wilm and Neal C. Burton\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e34.1 Introduction 454\u003c\/p\u003e \u003cp\u003e34.2 Overviews 455\u003c\/p\u003e \u003cp\u003e34.3 Summary 456\u003c\/p\u003e \u003cp\u003eReferences 456\u003c\/p\u003e \u003cp\u003e\u003cb\u003e35 \u003c\/b\u003e\u003cb\u003e\u003ci\u003eIn Vitro \u003c\/i\u003e\u003c\/b\u003e\u003cb\u003eto \u003c\/b\u003e\u003cb\u003e\u003ci\u003eIn Vivo \u003c\/i\u003e\u003c\/b\u003e\u003cb\u003eRelationships with Respect to Kidney Safety Biomarkers 458\u003cbr\u003e \u003c\/b\u003e\u003ci\u003ePaul Jennings\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e35.1 Renal Cell Lines as Tools for Toxicological Investigations 458\u003c\/p\u003e \u003cp\u003e35.2 Mechanistic Approaches and \u003ci\u003eIn Vitro \u003c\/i\u003eto \u003ci\u003eIn Vivo \u003c\/i\u003eTranslation 459\u003c\/p\u003e \u003cp\u003e35.3 Closing Remarks 460\u003c\/p\u003e \u003cp\u003eReferences 460\u003c\/p\u003e \u003cp\u003e\u003cb\u003e36 Case Study: Fully Automated Image Analysis of Podocyte Injury Biomarker Expression in Rats 462\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eJing Ying Ma\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e36.1 Introduction 462\u003c\/p\u003e \u003cp\u003e36.2 Material and Methods 462\u003c\/p\u003e \u003cp\u003e36.3 Results 463\u003c\/p\u003e \u003cp\u003e36.4 Conclusions 465\u003c\/p\u003e \u003cp\u003eReferences 465\u003c\/p\u003e \u003cp\u003e\u003cb\u003e37 Case Study: Novel Renal Biomarkers Translation to Humans 466\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eDeborah A. Burt\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e37.1 Introduction 466\u003c\/p\u003e \u003cp\u003e37.2 Implementation of Translational Renal Biomarkers in Drug Development 466\u003c\/p\u003e \u003cp\u003e37.3 Conclusion 467\u003c\/p\u003e \u003cp\u003eReferences 467\u003c\/p\u003e \u003cp\u003e\u003cb\u003e38 Case Study: Microrn as as Novel Kidney Injury Biomarkers in Canines 468\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eCraig Fisher, Erik Koenig and Patrick Kirby\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e38.1 Introduction 468\u003c\/p\u003e \u003cp\u003e38.2 Material and Methods 468\u003c\/p\u003e \u003cp\u003e38.3 Results 468\u003c\/p\u003e \u003cp\u003e38.4 Conclusions 470\u003c\/p\u003e \u003cp\u003eReferences 470\u003c\/p\u003e \u003cp\u003e\u003cb\u003e39 Novel Testicular Injury Biomarkers 471\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eHank Lin\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e39.1 Introduction 471\u003c\/p\u003e \u003cp\u003e39.2 The Testis 471\u003c\/p\u003e \u003cp\u003e39.3 Potential Biomarkers for Testicular Toxicity 472\u003c\/p\u003e \u003cp\u003e39.4 Conclusions 473\u003c\/p\u003e \u003cp\u003eReferences 473\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePART IX Best Practices in Biomarker Evaluations 475\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e40 Best Practices in Preclinical Biomarker Sample Collections 477\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eJaqueline Tarrant\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e40.1 Considerations for Reducing Preanalytical Variability in Biomarker Testing 477\u003c\/p\u003e \u003cp\u003e40.2 Biological Sample Matrix Variables 477\u003c\/p\u003e \u003cp\u003e40.3 Collection Variables 480\u003c\/p\u003e \u003cp\u003e40.4 Sample Processing and Storage Variables 480\u003c\/p\u003e \u003cp\u003eReferences 480\u003c\/p\u003e \u003cp\u003e\u003cb\u003e41 Best Practices in Novel Biomarker Assay Fit\u003c\/b\u003e\u003cb\u003e‐\u003c\/b\u003e\u003cb\u003efor\u003c\/b\u003e\u003cb\u003e‐\u003c\/b\u003e\u003cb\u003ePurpose Testing 481\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eKaren M. Lynch\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e41.1 Introduction 481\u003c\/p\u003e \u003cp\u003e41.2 Why Use a Fit‐for‐Purpose Assay? 481\u003c\/p\u003e \u003cp\u003e41.3 Overview of Fit‐for‐Purpose Assay Method Validations 482\u003c\/p\u003e \u003cp\u003e41.4 Assay Method Suitability in Preclinical Studies 482\u003c\/p\u003e \u003cp\u003e41.5 Best Practices for Analytical Methods Validation 482\u003c\/p\u003e \u003cp\u003e41.6 Species‐ and Gender‐Specific Reference Ranges 486\u003c\/p\u003e \u003cp\u003e41.7 Analyte Stability 487\u003c\/p\u003e \u003cp\u003e41.8 Additional Method Performance Evaluations 487\u003c\/p\u003e \u003cp\u003eReferences 487\u003c\/p\u003e \u003cp\u003e\u003cb\u003e42 Best Practices in Evaluating Novel Biomarker Fit for Purpose and Translatability 489\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eAmanda F. Baker\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e42.1 Introduction 489\u003c\/p\u003e \u003cp\u003e42.2 Protocol Development 489\u003c\/p\u003e \u003cp\u003e42.3 Assembling an Operations Team 489\u003c\/p\u003e \u003cp\u003e42.4 Translatable Biomarker Use 490\u003c\/p\u003e \u003cp\u003e42.5 Assay Selection 490\u003c\/p\u003e \u003cp\u003e42.6 Biological Matrix Selection 490\u003c\/p\u003e \u003cp\u003e42.7 Documentation of Patient Factors 491\u003c\/p\u003e \u003cp\u003e42.8 Human Sample Collection Procedures 491\u003c\/p\u003e \u003cp\u003e42.9 Choice of Collection Device 491\u003c\/p\u003e \u003cp\u003e42.10 Schedule of Collections 492\u003c\/p\u003e \u003cp\u003e42.11 Human Sample Quality Assurance 492\u003c\/p\u003e \u003cp\u003e42.12 Logistics Plan 493\u003c\/p\u003e \u003cp\u003e42.13 Database Considerations 493\u003c\/p\u003e \u003cp\u003e42.14 Conclusive Remarks 493\u003c\/p\u003e \u003cp\u003eReferences 493\u003c\/p\u003e \u003cp\u003e\u003cb\u003e43 Best Practices in Translational Biomarker Data Analysis 495\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eRobin Mogg and Daniel Holder\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e43.1 Introduction 495\u003c\/p\u003e \u003cp\u003e43.2 Statistical Considerations for Preclinical Studies of Safety Biomarkers 496\u003c\/p\u003e \u003cp\u003e43.3 Statistical Considerations for Exploratory Clinical Studies of Translational Safety Biomarkers 497\u003c\/p\u003e \u003cp\u003e43.4 Statistical Considerations for Confirmatory Clinical Studies of Translational Safety Biomarkers 498\u003c\/p\u003e \u003cp\u003e43.5 Summary 498\u003c\/p\u003e \u003cp\u003eReferences 498\u003c\/p\u003e \u003cp\u003e\u003cb\u003e44 Translatable Biomarkers in Drug Development: Regulatory Acceptance and Qualification 500\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eJohn\u003c\/i\u003e\u003ci\u003e‐\u003c\/i\u003e\u003ci\u003eMichael Sauer, Elizabeth G. Walker and Amy C. Porter\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e44.1 Safety Biomarkers 500\u003c\/p\u003e \u003cp\u003e44.2 Qualification of Safety Biomarkers 501\u003c\/p\u003e \u003cp\u003e44.3 Letter of Support for Safety Biomarkers 502\u003c\/p\u003e \u003cp\u003e44.4 Critical Path Institute’s Predictive Safety Testing Consortium 502\u003c\/p\u003e \u003cp\u003e44.5 Predictive Safety Testing Consortium and its Key Collaborations 504\u003c\/p\u003e \u003cp\u003e44.6 Advancing the Qualification Process and Defining Evidentiary Standards 505\u003c\/p\u003e \u003cp\u003eReferences 506\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePART X Conclusions 509\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e45 Toxicogenomics in Drug Discovery Toxicology: History, Methods, Case Studies, and Future Directions 511\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eBrandon D. Jeffy, Joseph Milano and Richard J. Brennan\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e45.1 A Brief History of Toxicogenomics 511\u003c\/p\u003e \u003cp\u003e45.2 Tools and Strategies for Analyzing Toxicogenomics Data 513\u003c\/p\u003e \u003cp\u003e45.3 Drug Discovery Toxicology Case Studies 519\u003c\/p\u003e \u003cp\u003eReferences 525\u003c\/p\u003e \u003cp\u003e\u003cb\u003e46 Issue Investigation and Practices in Discovery Toxicology 530\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eDolores Diaz, Dylan P. Hartley and Raymond Kemper\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e46.1 Introduction 530\u003c\/p\u003e \u003cp\u003e46.2 Overview of Issue Investigation in the Discovery Space 530\u003c\/p\u003e \u003cp\u003e46.3 Strategies to Address Toxicities in the Discovery Space 532\u003c\/p\u003e \u003cp\u003e46.4 Cross‐Functional Collaborative Model 533\u003c\/p\u003e \u003cp\u003e46.5 Case‐Studies of Issue Resolution in The Discovery Space 536\u003c\/p\u003e \u003cp\u003e46.6 Data Inclusion in Regulatory Filings 538\u003c\/p\u003e \u003cp\u003eReferences 538\u003c\/p\u003e \u003cp\u003e\u003cb\u003eABBREVIATIONS 540\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003eCONCLUDING REMARKS 542\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003eINDEX 543\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003eYvonne Will, PhD,\u003c\/b\u003e 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 \u003ci\u003eDrug-Induced Mitochondrial Dysfunction\u003c\/i\u003e, published by Wiley in 2008.\u003cbr\u003e\u003cb\u003e\u003cbr\u003eJ. Eric McDuffie, PhD,\u003c\/b\u003e is the Director of the Discovery \/ Investigative Toxicology and Laboratory Animal Medicine groups at Janssen Research \u0026amp; Development, California, USA.\u003cbr\u003e\u003cb\u003e\u003cbr\u003eAndrew J. Olaharski, PhD,\u003c\/b\u003e is an Associate Director of Toxicology at Agios Pharmaceuticals, Massachusetts, USA.\u003cbr\u003e\u003cb\u003e\u003cbr\u003eBrandon D. Jeffy, PhD,\u003c\/b\u003e is a Senior Principal Scientist in the Exploratory Toxicology division of Nonclinical Development at Celgene Pharmaceuticals, California, USA.\u003c\/p\u003e \u003cp\u003eDeveloping 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.\u003c\/p\u003e \u003cp\u003eIn 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.\u003c\/p\u003e \u003cp\u003e\u003ci\u003eDrug Discovery Toxicology: From Target Assessment to Translational Biomarkers\u003c\/i\u003e 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.\u003c\/p\u003e \u003cp\u003eAs 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.\u003c\/p\u003e","brand":"Wiley","offers":[{"title":"Default Title","offer_id":47989087994085,"sku":"NP9781119053330","price":218.95,"currency_code":"USD","in_stock":false}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/1842\/7735\/files\/9781119053330.jpg?v=1761782745","url":"https:\/\/k12savings.com\/products\/drug-discovery-toxicology-isbn-9781119053330","provider":"K12savings","version":"1.0","type":"link"}