Description
LIST OF CONTRIBUTORS xxi FOREWORD xxv PART I INTRODUCTION 1 1 Emerging Technologies and their Role in Regulatory Review 3 Thomas J. Colatsky References 8 PART II SAFETY LEAD OPTIMIZATION STRATEGIES 13 2 Small-Molecule Safety Lead Optimization 15 Donna M. Dambach 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 References 36 4 Discovery and Development Strategies for Small Interfering Rnas 39 Scott A. Barros and Gregory Hinkle References 49 PART III BASIS FOR IN VITRO-IN VIVO PK TRANSLATION 53 5 Physicochemistry and the Off-Target Effects of Drug Molecules 55 Dennis A. Smith 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 Abbreviations 77 References 77 7 A DME Properties Leading to Toxicity 82 Katya Tsaioun References 90 PART IV Predicting Organ Toxicity 93 8 Liver 95 J. Gerry Kenna, Mikael Persson, Scott Q. Siler, Ke Yu, Chuchu Hu, Minjun Chen, Joshua Xu, Weida Tong, Yvonne Will and Michael D. Aleo References 121 9 Cardiac 130 David 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 References 152 10 Predictive In Vitro Models for Assessment of Nephrotoxicity and Drug-Drug Interactions In Vitro 160 Lawrence H. Lash References 170 11 Predicting Organ Toxicity In Vitro: Bone Marrow 172 Ivan Rich and Andrew J. Olaharski References 180 12 Predicting Organ Toxicity In Vitro: Dermal Toxicity 182 Patrick J. Hayden, Michael Bachelor, Mitchell Klausner and Helena Kandrov References 189 13 In Vitro Methods in Immunotoxicity Assessment 193 Xu Zhu and Ellen Evans References 199 14 Strategies and Assays for Minimizing Risk of Ocular Toxicity during Early Development of Systemically Administered Drugs 201 Chris J. Somps, Paul Butler, Jay H. Fortner, Keri E. Cannon and Wenhu Huang References 210 15 Predicting Organ Toxicity In Vivo–Central Nervous System 214 Greet Teuns and Alison Easter Abbreviations 223 References 224 16 Biomarkers, Cell Models, and In Vitro Assays for Gastrointestinal Toxicology 227 Allison Vitsky and Gina M. Yanochko References 236 17 Preclinical Safety Assessment of Drug Candidate-Induced Pancreatic Toxicity: From an Applied Perspective 242 Karrie A. Brenneman, Shashi K. Ramaiah and Lauren M. Gauthier Acknowledgments 258 References 258 PART V A DDRESSING THE FALSE NEGATIVE SPACE–INCREASING PREDICTIVITY 261 18 Animal Models of Disease for Future Toxicity Predictions 263 Sherry J. Morgan and Chandikumar S. Elangbam References 287 19 The Use of Genetically Modified Animals in Discovery Toxicology 298 Dolores Diaz and Jonathan M. Maher References 309 20 Mouse Population-Based Toxicology for Personalized Medicine and Improved Safety Prediction 314 Alison H. Harrill References 326 PART VI STEM CELLS IN TOXICOLOGY 331 21 Application of Pluripotent Stem Cells in Drug-Induced Liver Injury Safety Assessment 333 Christopher S. Pridgeon, Fang Zhang, James A. Heslop, Charlotte M.L. Nugues, Neil R. Kitteringham, B. Kevin Park and Christopher E.P. Goldring References 342 22 Human Pluripotent Stem Cell-Derived Cardiomyocytes: A New Paradigm in Predictive Pharmacology and Toxicology 346 Praveen Shukla, Priyanka Garg and Joseph C. Wu Acknowledgments 360 References 360 23 Stem Cell-Derived Renal Cells and Predictive Renal In Vitro Models 365 Jacqueline Kai Chin Chuah, Yue Ning Lam, Peng Huang and Daniele Zink Acknowledgments 379 Notes 379 References 379 PART VII CURRENT STATUS OF PRECLINICAL IN VIVO TOXICITY BIOMARKERS 385 24 Predictive Cardiac Hypertrophy Biomarkers in Nonclinical Studies 387 Steven K. Engle References 393 25 Vascular Injury Biomarkers 397 Tanja S. Zabka and Kadre Bendjama References 403 26 Novel Translational Biomarkers of Skeletal Muscle Injury 407 Peter M. Burch and Warren E. Glaab References 412 27 Translational Mechanistic Biomarkers and Models for Predicting Drug-Induced Liver Injury : Clinical to In Vitro Perspectives 416 Daniel J. Antoine References 424 PART VIII Kidney Injury Biomarkers 429 28 Assessing and Predicting Drug-Induced Kidney Injury, Functional Change, and Safety in Preclinical Studies in Rats 431 Yafei Chen References 439 29 Canine Kidney Safety Protein Biomarkers 443 Manisha Sonee References 445 30 Traditional Kidney Safety Protein Biomarkers and Next-Generation Drug-Induced Kidney Injury Biomarkers in Nonhuman Primates 446 Jean-Charles Gautier and Xiaobing Zhou References 447 31 Rat Kidney MicroRNA Atlas 448 Aaron T. Smith References 449 32 MicroRNAs as Next-Generation Kidney Tubular Injury Biomarkers in Rats 450 Heidrun Ellinger-Ziegelbauer and Rounak Nassirpour References 451 33 MicroRNAs as Novel Glomerular Injury Biomarkers in Rats 452 Rachel Church References 453 34 Integrating Novel Imaging Technologies to Investigate Drug-Induced Kidney Toxicity 454 Bettina Wilm and Neal C. Burton References 456 35 In Vitro to In Vivo Relationships with Respect to Kidney Safety Biomarkers 458 Paul Jennings References 460 36 Case Study: Fully Automated Image Analysis of Podocyte Injury Biomarker Expression in Rats 462 Jing Ying Ma References 465 37 Case Study: Novel Renal Biomarkers Translation to Humans 466 Deborah A. Burt References 467 38 Case Study: Microrn as as Novel Kidney Injury Biomarkers in Canines 468 Craig Fisher, Erik Koenig and Patrick Kirby References 470 39 Novel Testicular Injury Biomarkers 471 Hank Lin References 473 PART IX Best Practices in Biomarker Evaluations 475 40 Best Practices in Preclinical Biomarker Sample Collections 477 Jaqueline Tarrant References 480 41 Best Practices in Novel Biomarker Assay Fit-for-Purpose Testing 481 Karen M. Lynch References 487 42 Best Practices in Evaluating Novel Biomarker Fit for Purpose and Translatability 489 Amanda F. Baker References 493 43 Best Practices in Translational Biomarker Data Analysis 495 Robin Mogg and Daniel Holder References 498 44 Translatable Biomarkers in Drug Development: Regulatory Acceptance and Qualification 500 John-Michael Sauer, Elizabeth G. Walker and Amy C. Porter References 506 PART X Conclusions 509 45 Toxicogenomics in Drug Discovery Toxicology: History, Methods, Case Studies, and Future Directions 511 Brandon D. Jeffy, Joseph Milano and Richard J. Brennan References 525 46 Issue Investigation and Practices in Discovery Toxicology 530 Dolores Diaz, Dylan P. Hartley and Raymond Kemper References 538 ABBREVIATIONS 540 CONCLUDING REMARKS 542 INDEX 543
