‏1,131.00 ₪

Drug Discovery Toxicology - From Target Assessment to Translational Biomarkers

‏1,131.00 ₪

ISBN13

9781119053330

יצא לאור ב

Hoboken

זמן אספקה

21 ימי עסקים

עמודים

584

פורמט

Hardback

תאריך יציאה לאור

1 ביולי 2016

לדלג לסוף של גלריית תמונות

לדלג להתחלה של גלריית תמונות

פרטים

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

מידע נוסף

מידע נוסף
עמודים	584
פורמט	Hardback
ISBN10	1119053331
יצא לאור ב	Hoboken
תאריך יציאה לאור	1 ביולי 2016
תוכן עניינים	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 Kandarova 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 Kaidre 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
זמן אספקה	21 ימי עסקים