Drug Discovery Toxicology

From Target Assessment to Translational Biomarkers
1. Auflage 2016
ISBN: 978-1-119-05333-0
Verlag: Turner Publishing Company

Buch, Englisch, 584 Seiten, Format (B × H): 221 mm x 282 mm, Gewicht: 1601 g

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

Autoren/Hrsg.

Will, Yvonne

McDuffie, J Eric

Olaharski, Andrew J

Jeffy, Brandon D

Fachgebiete

• Medizin | Veterinärmedizin Medizin | Public Health | Pharmazie | Zahnmedizin Medizinische Fachgebiete Pharmakologie, Toxikologie

Inhaltsverzeichnis

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 Kandárová

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 Kaïdre 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

Über Autor(innen)

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.