Drug Discovery Toxicology
John Wiley & Sons Inc (Verlag)
978-1-119-05333-0 (ISBN)
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
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 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 Small‐Molecule 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 Dose‐Ranging 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 VITRO–IN VIVO PK TRANSLATION 53
5 Physicochemistry and the Off‐Target 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 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 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
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
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 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
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 172
Ivan 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 182
Patrick 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 193
Xu 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 201
Chris 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 214
Greet 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 227
Allison 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 242
Karrie 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 263
Sherry 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 298
Dolores 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 314
Alison 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 333
Christopher 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 346
Praveen 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 Traditional Target‐Centric Drug Discovery Paradigm 354
22.5 iPSC‐Based Drug Discovery Paradigm 354
22.6 Limitations and Challenges 358
22.7 Conclusions and Future Perspective 359
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
23.1 Introduction 365
23.2 Protocols for the Differentiation of Pluripotent Stem Cells into Cells of the Renal Lineage 367
23.3 Renal In Vitro Models for Drug Safety Screening 376
23.4 Achievements and Future Directions 378
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
24.1 Introduction to Biomarkers 387
24.2 Cardiovascular Toxicity 387
24.3 Cardiac Hypertrophy 388
24.4 Diagnosis of Cardiac Hypertrophy 389
24.5 Biomarkers of Cardiac Hypertrophy 389
24.6 Case Studies 392
24.7 Conclusion 392
References 393
25 Vascular Injury Biomarkers 397
Tanja S. Zabka and Kaïdre Bendjama
25.1 Historical Context of Drug‐Induced Vascular Injury and Drug Development 397
25.2 Current State of Divi Biomarkers 398
25.3 Current Status and Future of In Vitro Systems to Investigate Divi 402
25.4 Incorporation of In Vitro and In Vivo Tools in Preclinical Drug Development 403
25.5 Divi Case Study 403
References 403
26 Novel Translational Biomarkers of Skeletal Muscle Injury 407
Peter M. Burch and Warren E. Glaab
26.1 Introduction 407
26.2 Overview of Drug‐Induced Skeletal Muscle Injury 407
26.3 Novel Biomarkers of Drug‐Induced Skeletal Muscle Injury 409
26.4 Regulatory Endorsement 411
26.5 Gaps and Future Directions 411
26.6 Conclusions 412
References 412
27 Translational Mechanistic Biomarkers and Models for Predicting Drug‐Induced Liver Injury : Clinical to In Vitro Perspectives 416
Daniel J. Antoine
27.1 Introduction 416
27.2 Drug‐Induced Toxicity and the Liver 417
27.3 Current Status of Biomarkers for the Assessment of DILI 418
27.4 Novel Investigational Biomarkers for DILI 419
27.5 In Vitro Models and the Prediction of Human Dili 422
27.6 Conclusions and Future Perspectives 423
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
28.1 Introduction 431
28.2 Kidney Functional Biomarkers (Glomerular Filtration and Tubular Reabsorption) 433
28.3 Novel Kidney Tissue Injury Biomarkers 435
28.4 Novel Biomarkers of Kidney Tissue Stress Response 436
28.5 Application of an Integrated Rat Platform (Automated Blood Sampling and Telemetry, Abst) for Kidney Function and Injury Assessment 437
References 439
29 Canine Kidney Safety Protein Biomarkers 443
Manisha Sonee
29.1 Introduction 443
29.2 Novel Canine Renal Protein Biomarkers 443
29.3 Evaluations of Novel Canine Renal Protein Biomarker Performance 444
29.4 Conclusion 444
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
30.1 Introduction 446
30.2 Evaluations of Novel Nhp Renal Protein Biomarker Performance 447
30.3 New Horizons: Urinary MicroRNAs and Nephrotoxicity in Nhps 447
References 447
31 Rat Kidney MicroRNA Atlas 448
Aaron T. Smith
31.1 Introduction 448
31.2 Key Findings 448
References 449
32 MicroRNAs as Next‐Generation Kidney Tubular Injury Biomarkers in Rats 450
Heidrun Ellinger‐Ziegelbauer and Rounak Nassirpour
32.1 Introduction 450
32.2 Rat Tubular miRNAs 450
32.3 Conclusions 451
References 451
33 MicroRNAs as Novel Glomerular Injury Biomarkers in Rats 452
Rachel Church
33.1 Introduction 452
33.2 Rat Glomerular miRNAs 452
References 453
34 Integrating Novel Imaging Technologies to Investigate Drug‐Induced Kidney Toxicity 454
Bettina Wilm and Neal C. Burton
34.1 Introduction 454
34.2 Overviews 455
34.3 Summary 456
References 456
35 In Vitro to In Vivo Relationships with Respect to Kidney Safety Biomarkers 458
Paul Jennings
35.1 Renal Cell Lines as Tools for Toxicological Investigations 458
35.2 Mechanistic Approaches and In Vitro to In Vivo Translation 459
35.3 Closing Remarks 460
References 460
36 Case Study: Fully Automated Image Analysis of Podocyte Injury Biomarker Expression in Rats 462
Jing Ying Ma
36.1 Introduction 462
36.2 Material and Methods 462
36.3 Results 463
36.4 Conclusions 465
References 465
37 Case Study: Novel Renal Biomarkers Translation to Humans 466
Deborah A. Burt
37.1 Introduction 466
37.2 Implementation of Translational Renal Biomarkers in Drug Development 466
37.3 Conclusion 467
References 467
38 Case Study: Microrn as as Novel Kidney Injury Biomarkers in Canines 468
Craig Fisher, Erik Koenig and Patrick Kirby
38.1 Introduction 468
38.2 Material and Methods 468
38.3 Results 468
38.4 Conclusions 470
References 470
39 Novel Testicular Injury Biomarkers 471
Hank Lin
39.1 Introduction 471
39.2 The Testis 471
39.3 Potential Biomarkers for Testicular Toxicity 472
39.4 Conclusions 473
References 473
PART IX Best Practices in Biomarker Evaluations 475
40 Best Practices in Preclinical Biomarker Sample Collections 477
Jaqueline Tarrant
40.1 Considerations for Reducing Preanalytical Variability in Biomarker Testing 477
40.2 Biological Sample Matrix Variables 477
40.3 Collection Variables 480
40.4 Sample Processing and Storage Variables 480
References 480
41 Best Practices in Novel Biomarker Assay Fit‐for‐Purpose Testing 481
Karen M. Lynch
41.1 Introduction 481
41.2 Why Use a Fit‐for‐Purpose Assay? 481
41.3 Overview of Fit‐for‐Purpose Assay Method Validations 482
41.4 Assay Method Suitability in Preclinical Studies 482
41.5 Best Practices for Analytical Methods Validation 482
41.6 Species‐ and Gender‐Specific Reference Ranges 486
41.7 Analyte Stability 487
41.8 Additional Method Performance Evaluations 487
References 487
42 Best Practices in Evaluating Novel Biomarker Fit for Purpose and Translatability 489
Amanda F. Baker
42.1 Introduction 489
42.2 Protocol Development 489
42.3 Assembling an Operations Team 489
42.4 Translatable Biomarker Use 490
42.5 Assay Selection 490
42.6 Biological Matrix Selection 490
42.7 Documentation of Patient Factors 491
42.8 Human Sample Collection Procedures 491
42.9 Choice of Collection Device 491
42.10 Schedule of Collections 492
42.11 Human Sample Quality Assurance 492
42.12 Logistics Plan 493
42.13 Database Considerations 493
42.14 Conclusive Remarks 493
References 493
43 Best Practices in Translational Biomarker Data Analysis 495
Robin Mogg and Daniel Holder
43.1 Introduction 495
43.2 Statistical Considerations for Preclinical Studies of Safety Biomarkers 496
43.3 Statistical Considerations for Exploratory Clinical Studies of Translational Safety Biomarkers 497
43.4 Statistical Considerations for Confirmatory Clinical Studies of Translational Safety Biomarkers 498
43.5 Summary 498
References 498
44 Translatable Biomarkers in Drug Development: Regulatory Acceptance and Qualification 500
John‐Michael Sauer, Elizabeth G. Walker and Amy C. Porter
44.1 Safety Biomarkers 500
44.2 Qualification of Safety Biomarkers 501
44.3 Letter of Support for Safety Biomarkers 502
44.4 Critical Path Institute’s Predictive Safety Testing Consortium 502
44.5 Predictive Safety Testing Consortium and its Key Collaborations 504
44.6 Advancing the Qualification Process and Defining Evidentiary Standards 505
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
45.1 A Brief History of Toxicogenomics 511
45.2 Tools and Strategies for Analyzing Toxicogenomics Data 513
45.3 Drug Discovery Toxicology Case Studies 519
References 525
46 Issue Investigation and Practices in Discovery Toxicology 530
Dolores Diaz, Dylan P. Hartley and Raymond Kemper
46.1 Introduction 530
46.2 Overview of Issue Investigation in the Discovery Space 530
46.3 Strategies to Address Toxicities in the Discovery Space 532
46.4 Cross‐Functional Collaborative Model 533
46.5 Case‐Studies of Issue Resolution in The Discovery Space 536
46.6 Data Inclusion in Regulatory Filings 538
References 538
ABBREVIATIONS 540
CONCLUDING REMARKS 542
INDEX 543
| Verlagsort | New York |
|---|---|
| Sprache | englisch |
| Maße | 218 x 282 mm |
| Gewicht | 1610 g |
| Themenwelt | Medizin / Pharmazie ► Medizinische Fachgebiete |
| Studium ► 2. Studienabschnitt (Klinik) ► Pharmakologie / Toxikologie | |
| Naturwissenschaften ► Biologie | |
| Naturwissenschaften ► Chemie | |
| Technik | |
| ISBN-10 | 1-119-05333-1 / 1119053331 |
| ISBN-13 | 978-1-119-05333-0 / 9781119053330 |
| Zustand | Neuware |
| Haben Sie eine Frage zum Produkt? |
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