Antitargets and Drug Safety

by Urban, Laszlo; Patel, Vinod; Vaz, Roy J.

• ISBN13: 9783527335114
• ISBN10: 3527335110
• Edition: 1st
• Format: Hardcover
• Copyright: 2015-06-08
• Publisher: Wiley-VCH

Summary

With its focus on emerging concerns of kinase and GPCR-mediated antitarget effects, this vital reference for drug developers addresses one of the hot topics in drug safety now and in future.
Divided into three major parts, the first section deals with novel technologies and includes the utility of adverse event reports to drug discovery, the translational aspects of preclinical safety findings, broader computational prediction of drug side-effects, and a description of the serotonergic system. The main part of the book looks at some of the most common antitarget-mediated side effects, focusing on hepatotoxicity in drug safety, cardiovascular toxicity and signaling effects via kinase and GPCR anti-targets. In the final section, several case studies of recently developed drugs illustrate how to prevent anti-target effects and how big pharma deals with them if they occur. The more recent field of systems pharmacology has gained prominence and this is reflected in chapters dedicated to the utility in deciphering and modeling anti-targets. The final chapter is concerned with those compounds that inadvertently elicit CNS mediated adverse events, including a pragmatic description of ways to mitigate these types of safety risks.
Written as a companion to the successful book on antitargets by Vaz and Klabunde, this new volume focuses on recent progress and new classes, methods and case studies that were not previously covered.

Author Biography

Laszlo Urban received his MD and PhD in neurophysiology/neuropharmacology in Hungary, and was visiting professor at Duke University between 1987 and 1989. He is currently global head of Preclinical Safety Profiling at the Novartis Institutes for Biomedical Research, Cambridge, USA, and was previously the Deputy Head of the Novartis Institute for Medical Sciences in London, UK. Dr. Urban has over 130 scientific articles, book chapters and patents to his name.

Roy J. Vaz received his PhD in organic chemistry from the University of Florida, Gainesville, an MBA from the University of Illinois, and most recently an MS in molecular biology from Lehigh University, USA. He is currently a senior distinguished scientist at Sanofi Pharmaceuticals in Waltham, MA, and was previously Director of the Investigative Product Optimization department under Aventis. He has worked at Bristol-Myers Squibb as Principal Scientist as well as at Tripos, Inc, as a research scientist. Dr. Vaz has authored or co-authored around 45 publications in peer-reviewed journals, eight book chapters and several patents.

Vinod Patel gained his BSc in applied chemistry from Leicester Polytechnic, and a PhD in synthetic organic chemistry from Nottingham University, UK. He took up a post-doctoral fellowship at the University of Rochester, NY, USA, before joining Eli Lilly & Company, where he spent the next nine years as a medicinal chemist in the oncology division. He then joined Kinetix Pharmaceuticals, which was acquired by Amgen and Dr. Patel joined their new Cambridge facility as head of medicinal chemistry. In 2011, he joined Sanofi oncology research as head of medicinal chemistry where he is currently head of chemical research in lead generation candidate realization. Dr. Patel has over 50 publications and some 50 patents to his name.

Table of Contents

List of Contributors XV

Preface XXI

A Personal Foreword XXIII

Section 1 General Concept for Target-based Safety Assessment 1

1 Side Effects of Marketed Drugs: The Utility and Pitfalls of Pharmacovigilance 3
Steven Whitebread, Mateusz Maciejewski, Alexander Fekete, Eugen Lounkine, and László Urbán

1.1 Introduction 3

1.2 Postmarketing Pharmacovigilance 6

1.3 Polypharmacy and Pharmacological Promiscuity of Marketed Drugs 9

References 15

2 In Silico Prediction of Drug Side Effects 19
Michael J. Keiser

2.1 Large-Scale Prediction of Drug Activity 20

2.1.1 Networks of Known and New Target Activity 21

2.1.2 Resources for Multiscale Inquiry 25

2.2 Multiscale Models of Adverse Drug Reactions 30

2.2.1 Inferring Adverse Reactions 31

2.2.2 Forward Perturbation and Prediction of Mechanisms 33

References 36

3 Translational Value of Preclinical Safety Assessment: System Organ Class (SOC) Representation of Off-Targets 45
Mateusz Maciejewski, Eugen Lounkine, Andreas Hartmann, Steven Whitebread, and László Urbán

3.1 Introduction 45

3.2 Terminology: Medicinal Dictionary for Regulatory Activities (MedDRA) 46

3.2.1 Correct Use of MedDRA Terminology at Different Phases of Drug Discovery 48

3.2.2 Determination of Symptoms Associated with a Target 50

3.3 Data Interpretation: Modifying Factors 52

3.3.1 Access to Organs 52

3.3.2 Off-Target Promiscuity: Target Interactions (Synergies and Antagonism) 53

3.4 Conclusions 53

References 54

4 Pathological Conditions Associated with the Disturbance of the 5-HT System 57
Daniel Hoyer

4.1 Introduction 57

4.2 From “St. Anthony’s Fire” to Ergot Alkaloids, the Serotonin Syndrome, and Modern 5-HT Pharmacology 59

4.3 Appetite-Reducing Agents, Fenfluramine, and Other 5-HT Releasers 61

4.4 Gastrointestinal and Antiemetic Indications, the 5-HT3/5-HT4 Receptor Links 63

4.5 Antipsychotics and the 5-HT2/Dopamine D2 Link (and Many Other 5-HT Receptors) 65

4.6 Antimigraine Medications of Old and New and the 5-HT1B/1D Receptors 67

4.7 Antidepressants/Anxiolytics Acting at 5-HT and Other Transporters 69

4.8 Conclusions 71

References 72

Section 2 Hepatic Side Effects 81

5 Drug-Induced Liver Injury: Clinical and Diagnostic Aspects 83
John R. Senior

5.1 Introduction 83

5.1.1 Postmarketing Hepatotoxicity versus Hepatotoxicity in Development 84

5.1.2 Isoniazid – If It Were Newly Discovered, Would It Be Approved Today? 85

5.2 Special Problems of Postmarketing Hepatotoxicity 89

5.2.1 Voluntary Monitoring after Approval for Marketing 90

5.2.2 Prediction of Serious, Dysfunctional Liver Injury 90

5.2.3 Severity of Liver Injury Is Not Measured by Aminotransferase Elevations 91

5.2.4 Attempts to Standardize Terminology 91

5.2.5 What Is the “Normal” Range, or the “Upper Limit of Normal”? 92

5.2.6 Diagnostic Test Evaluation 93

5.2.7 Determination of the Likely Cause of Liver Abnormalities 94

5.2.8 Treatment and Management of DILI in Practice 95

5.3 Special Problems for New Drug Development 95

5.3.1 How Many? 95

5.3.2 How Much? 96

5.3.3 How Soon? 97

5.3.4 How Likely? 97

5.3.5 Compared with What? 97

5.3.6 ROC Curves 98

5.3.7 eDISH: Especially for Controlled Trials 99

5.3.8 Test Validation and Qualification 100

5.4 Closing Considerations 101

5.4.1 A Handful of “Do Nots” 101

5.4.2 Need to Standardize ALT Measurement and Interpretation of Normal Ranges 102

5.4.3 Research Opportunities 102

References 103

6 Mechanistic Safety Biomarkers for Drug-Induced Liver Injury 107
Daniel J. Antoine

6.1 Introduction 107

6.2 Drug-Induced Toxicity and the Liver 110

6.3 Current Status of Biomarkers for the Assessment of DILI 111

6.4 Novel Investigational Biomarkers for DILI 113

6.4.1 Glutamate Dehydrogenase (GLDH) 114

6.4.2 Acylcarnitines 115

6.4.3 High-Mobility Group Box-1 (HMGB1) 116

6.4.4 Keratin 18 (K18) 116

6.4.5 MicroRNA-122 (miR-122) 117

6.5 Conclusions and Future Perspectives 118

References 120

7 In Vitro Models for the Prediction of Drug-Induced Liver Injury in Lead Discovery 125
Frederic Moulin and Oliver Flint

7.1 Introduction 125

7.2 Simple Systems for the Detection and Investigation of Hepatic Toxicants 130

7.2.1 Primary Hepatocytes 130

7.2.2 Liver-Derived Cell Lines 135

7.2.3 Differentiated Pluripotent Stem Cells 137

7.3 Models to Mitigate Hepatocyte Dedifferentiation 140

7.3.1 Liver Slices 140

7.3.2 Selective Engineering of Metabolism 141

7.4 Understanding Immune-Mediated Hepatotoxicity 144

7.4.1 Use of Inflammatory Cofactors 145

7.4.2 Innate Immune System and Inflammasome 147

7.5 Conclusions 148

References 149

8 Transporters in the Liver 159
Bruno Stieger and Gerd A. Kullak-Ublick

8.1 Introduction 159

8.2 Role of Organic Anion Transporters for Drug Uptake 159

8.3 Drug Interaction with the Bile Salt Export Pump 160

8.4 Susceptibility Factors for Drug–BSEP Interactions 161

8.5 Role of BSEP in Drug Development 162

References 163

9 Mechanistic Modeling of Drug-Induced Liver Injury (DILI) 173
Kyunghee Yang, Jeffrey L. Woodhead, Lisl K. Shoda, Yuching Yang, Paul B. Watkins, Kim L.R. Brouwer, Brett A. Howell, and Scott Q. Siler

9.1 Introduction 173

9.2 Mechanistic Modules in DILIsymðD version 3A 175

9.2.1 Oxidative Stress-Mediated Toxicity 175

9.2.2 Innate Immune Responses 178

9.2.3 Mitochondrial Toxicity 179

9.2.4 Bile Acid-Mediated Toxicity 181

9.3 Examples of Bile Acid-Mediated Toxicity Module 184

9.3.1 Troglitazone and Pioglitazone 184

9.3.2 Bosentan and Telmisartan 187

9.4 Conclusions and Future Directions 190

References 191

Section 3 Cardiovascular Side Effects 199

10 Functional Cardiac Safety Evaluation of Novel Therapeutics 201
Jean-Pierre Valentin, Brian Guth, Robert L. Hamlin, Pierre Lainée, Dusty Sarazan, and Matt Skinner

10.1 Introduction: What Is the Issue? 201

10.2 Cardiac Function: Definitions and General Principles 203

10.2.1 Definition and Importance of Inotropy and Difference from Ventricular Function 203

10.2.2 Definition and Importance of Lusitropy 207

10.2.3 Components and Importance of the Systemic Arterial Pressure 211

10.3 Methods Available to Assess Cardiac Function 213

10.4 What Do We Know About the Translation of the Nonclinical Findings to Humans? 217

10.5 Risk Assessment 219

10.5.1 Hazard Identification 219

10.5.2 Risk Assessment 221

10.5.3 Risk Management 224

10.5.4 Risk Mitigation 225

10.6 Summary, Recommendations, and Conclusions 227

References 228

11 Safety Aspects of the Cav1.2 Channel 235
Berengere Dumotier and Martin Traebert

11.1 Introduction 235

11.2 Structure of Cav1.2 Channels 235

11.2.1 α-Subunit of Cav1.2 Channel 236

11.2.2 β-Subunit of Cav1.2 Channel 236

11.3 Function of Cav1.2 Channels in Cardiac Tissue 237

11.3.1 Role in Conduction and Contractility 239

11.3.2 Modulation of Cav1.2 Channels 240

11.3.3 Cav1.2 and Cardiac Diseases 244

11.4 Pharmacology of Cav1.2 Channels: Translation to the Clinic 245

11.4.1 Cav1.2 Antagonists: Impact on Electromechanical Functions 245

11.5 Prediction of Cav1.2 Off-Target Liability 246

11.5.1 Cav1.2 in Cardiomyocytes Derived from iPS Cells 246

References 247

12 Cardiac Sodium Current (Nav1.5) 253
Gary Gintant

12.1 Background and Scope 253

12.2 Structure and Function 255

12.2.1 Molecular Biology 255

12.2.2 SCN5A Mutations Related to Congenital Long QT Syndromes 256

12.2.3 Evidence for Multiple Functional Types of Cardiac Sodium Channels and Heterogeneous Distribution 257

12.3 Physiological Role and Drug Actions 258

12.3.1 Fast Sodium Current (INaF): Conduction and Refractoriness 258

12.3.2 Late (or Residual or Slow) Sodium Current (INaL) 259

12.3.3 Drug Effects on INaF 261

12.3.4 Indirect Modulation of INaF 264

12.4 Methodology 265

12.4.1 Use of Human Stem Cell-Derived Cardiomyocytes 266

12.5 Translation of Effects on INaF: Relation to Conduction Velocity and Proarrhythmia 268

12.6 Conclusions 269

References 270

13 Circulating Biomarkers for Drug-Induced Cardiotoxicity: Reverse Translation from Patients to Nonclinical Species 279
Gül Erdemli, Haisong Ju, and Sarita Pereira

13.1 Introduction 279

13.2 Cardiac Troponins 280

13.3 Natriuretic Peptides 282

13.4 Novel/Exploratory Biomarkers: H-FABP, miRNA, and Genomic Biomarkers 285

13.5 Regulatory Perspective 286

13.6 Conclusions and Future Perspectives 288

References 289

14 The Mechanistic Basis of hERG Blockade and the Proarrhythmic Effects Thereof 295
Robert A. Pearlstein, K. Andrew MacCannell, Qi-Ying Hu, Ramy Farid, and José S. Duca

14.1 Introduction 295

14.1.1 The Role of hERG Dysfunction/Blockade in Promoting Early After Depolarizations 296

14.1.2 The Dynamics of hERG Blockade 301

14.1.3 Simulations of the Human Cardiac AP in the Presence of hERG Blockade 303

14.1.4 Estimation of Proarrhythmic hERG Occupancy Levels Based on AP Simulations 304

14.1.5 Novel Insights about the Causes of Inadvertent hERG Binding Function 305

14.1.6 Implications of Our Findings for hERG Safety Assessment 313

14.1.7 Conclusion and Future Directions 324

References 324

Section 4 Kinase Antitargets 329

15 Introduction to Kinase Antitargets 331
Mark C. Munson

References 360

16 Clinical and Nonclinical Adverse Effects of Kinase Inhibitors 365
Douglas A. Keller, Richard J. Brennan, and Karen L. Leach

16.1 Introduction 365

16.2 Perspectives on the Clinical Safety of Kinase Inhibitor Therapy 371

16.3 Adverse Effects of Kinase Inhibitor Drugs 372

16.3.1 Hepatic Toxicity 372

16.3.2 Thyroid Toxicity 377

16.3.3 Bone and Tooth Toxicity 379

16.3.4 Cardiovascular Toxicity 380

16.3.5 Cutaneous Toxicity 380

16.3.6 Developmental and Reproductive Toxicity 383

16.3.7 Gastrointestinal Toxicity 385

16.3.8 Hematopoietic Toxicity 385

16.3.9 Ocular Toxicity 387

16.3.10 Pulmonary Toxicity 388

16.3.11 Renal Toxicity 389

16.4 Derisking Strategies for Kinase Inhibitor Toxicity 389

16.5 Concluding Remarks 391

References 391

17 Cardiac Side Effects Associated with Kinase Proteins and Their Signaling Pathways 401
Roy J. Vaz and Vinod F. Patel

17.1 A Case Study 401

17.2 Introduction 402

17.3 Cardiac-Specific Kinase Antitargets 404

17.3.1 Preclinical Findings in Genetically Modified or KI-Treated Mice 404

17.3.2 Clinical Findings of Kinase Inhibitors on the Heart and Their Mechanistic Understandings 404

17.4 Current and Future Directions 409

17.4.1 Preclinical Safety and Clinical Outcome Predictions 409

17.5 Conclusions 410

References 411

18 Case Studies: Selective Inhibitors of Protein Kinases – Exploiting Demure Features 413
Ellen R. Laird

18.1 Introduction 413

18.2 Case I: Indane Oximes as Selective B-Raf Inhibitors 414

18.3 Case II: ARRY-380 (ONT-380) – an ErbB2 Agent that Spares EGFR 420

18.4 Case III: Discovery of GDC-0068 (Ipatasertib), a Potent and Selective ATP-Competitive Inhibitor of AKT 424

18.5 Concluding Remarks 428

References 429

Section 5 Examples of Clinical Translation 435

19 Torcetrapib and Dalcetrapib Safety: Relevance of Preclinical In Vitro and In Vivo Models 437
Eric J. Niesor, Andrea Greiter-Wilke, and Lutz Müller

19.1 Introduction 437

19.2 Effect of Torcetrapib on Blood Pressure 437

19.3 In Vitro Studies 438

19.3.1 Direct Effect of Torcetrapib on Aldosterone Production In Vitro in Cultured H295R Adrenal Corticocarcinoma Cells 439

19.3.2 Molecular Mechanism of Torcetrapib Induction of Aldosterone Secretion 439

19.3.3 Development of Reproducible In Vitro Screening Models for Increase in Aldosterone and Cyp11B2 mRNA in a Human Adrenal Corticocarcinoma Cell Line 440

19.3.4 Application of In Vitro Models for the Successful Derisking of Dalcetrapib, Anacetrapib, and Evacetrapib 440

19.4 In Vivo Studies 441

19.4.1 Effect of Torcetrapib on Aldosterone and BP 441

19.4.2 Molecular Mechanisms of Torcetrapib-Induced BP Increase 444

19.5 General Safety Risk with Increased Aldosterone and BP 447

19.5.1 Inappropriate Increase in Aldosterone Secretion May Increase CV Risks 447

19.6 Relevance of BP and Aldosterone Preclinical Models to Clinical Observation with Dalcetrapib and Anacetrapib 448

19.7 Similarities between Potent CETPi and Halogenated Hydrocarbons 449

19.7.1 The Macrophage Scavenger Receptor MARCO, a Possible Antitarget for Dalcetrapib, and Its Relevance to Humans 450

19.8 Conclusions 451

References 451

20 Targets Associated with Drug-Related Suicidal Ideation and Behavior 457
Andreas Hartmann, Steven Whitebread, Jacques Hamon, Alexander Fekete, Christian Trendelenburg, Patrick Y. Müller, and László Urbán

20.1 Introduction 457

20.2 Targets Associated with Increased Suicidal Intent and Behavior 458

20.2.1 G-Protein-Coupled Receptors 458

20.2.2 Transporters 466

20.2.3 Ion Channels 469

20.3 Conclusions 472

References 473

Index 479