Antitargets and Drug Safety

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.

• List of Contributors XVPreface XXIA Personal Foreword XXIIISection 1 General Concept for Target-based Safety Assessment 11 Side Effects of Marketed Drugs: The Utility and Pitfalls of Pharmacovigilance 3Steven Whitebread, Mateusz Maciejewski, Alexander Fekete, Eugen Lounkine, and László Urbán1.1 Introduction 31.2 Postmarketing Pharmacovigilance 61.3 Polypharmacy and Pharmacological Promiscuity of Marketed Drugs 9References 152 In Silico Prediction of Drug Side Effects 19Michael J. Keiser2.1 Large-Scale Prediction of Drug Activity 202.1.1 Networks of Known and New Target Activity 212.1.2 Resources for Multiscale Inquiry 252.2 Multiscale Models of Adverse Drug Reactions 302.2.1 Inferring Adverse Reactions 312.2.2 Forward Perturbation and Prediction of Mechanisms 33References 363 Translational Value of Preclinical Safety Assessment: System Organ Class (SOC) Representation of Off-Targets 45Mateusz Maciejewski, Eugen Lounkine, Andreas Hartmann, Steven Whitebread, and László Urbán3.1 Introduction 453.2 Terminology: Medicinal Dictionary for Regulatory Activities (MedDRA) 463.2.1 Correct Use of MedDRA Terminology at Different Phases of Drug Discovery 483.2.2 Determination of Symptoms Associated with a Target 503.3 Data Interpretation: Modifying Factors 523.3.1 Access to Organs 523.3.2 Off-Target Promiscuity: Target Interactions (Synergies and Antagonism) 533.4 Conclusions 53References 544 Pathological Conditions Associated with the Disturbance of the 5-HT System 57Daniel Hoyer4.1 Introduction 574.2 From “St. Anthony’s Fire” to Ergot Alkaloids, the Serotonin Syndrome, and Modern 5-HT Pharmacology 594.3 Appetite-Reducing Agents, Fenfluramine, and Other 5-HT Releasers 614.4 Gastrointestinal and Antiemetic Indications, the 5-HT3/5-HT4 Receptor Links 634.5 Antipsychotics and the 5-HT2/Dopamine D2 Link (and Many Other 5-HT Receptors) 654.6 Antimigraine Medications of Old and New and the 5-HT1B/1D Receptors 674.7 Antidepressants/Anxiolytics Acting at 5-HT and Other Transporters 694.8 Conclusions 71References 72Section 2 Hepatic Side Effects 815 Drug-Induced Liver Injury: Clinical and Diagnostic Aspects 83John R. Senior5.1 Introduction 835.1.1 Postmarketing Hepatotoxicity versus Hepatotoxicity in Development 845.1.2 Isoniazid – If It Were Newly Discovered, Would It Be Approved Today? 855.2 Special Problems of Postmarketing Hepatotoxicity 895.2.1 Voluntary Monitoring after Approval for Marketing 905.2.2 Prediction of Serious, Dysfunctional Liver Injury 905.2.3 Severity of Liver Injury Is Not Measured by Aminotransferase Elevations 915.2.4 Attempts to Standardize Terminology 915.2.5 What Is the “Normal” Range, or the “Upper Limit of Normal”? 925.2.6 Diagnostic Test Evaluation 935.2.7 Determination of the Likely Cause of Liver Abnormalities 945.2.8 Treatment and Management of DILI in Practice 955.3 Special Problems for New Drug Development 955.3.1 How Many? 955.3.2 How Much? 965.3.3 How Soon? 975.3.4 How Likely? 975.3.5 Compared with What? 975.3.6 ROC Curves 985.3.7 eDISH: Especially for Controlled Trials 995.3.8 Test Validation and Qualification 1005.4 Closing Considerations 1015.4.1 A Handful of “Do Nots” 1015.4.2 Need to Standardize ALT Measurement and Interpretation of Normal Ranges 1025.4.3 Research Opportunities 102References 1036 Mechanistic Safety Biomarkers for Drug-Induced Liver Injury 107Daniel J. Antoine6.1 Introduction 1076.2 Drug-Induced Toxicity and the Liver 1106.3 Current Status of Biomarkers for the Assessment of DILI 1116.4 Novel Investigational Biomarkers for DILI 1136.4.1 Glutamate Dehydrogenase (GLDH) 1146.4.2 Acylcarnitines 1156.4.3 High-Mobility Group Box-1 (HMGB1) 1166.4.4 Keratin 18 (K18) 1166.4.5 MicroRNA-122 (miR-122) 1176.5 Conclusions and Future Perspectives 118References 1207 In Vitro Models for the Prediction of Drug-Induced Liver Injury in Lead Discovery 125Frederic Moulin and Oliver Flint7.1 Introduction 1257.2 Simple Systems for the Detection and Investigation of Hepatic Toxicants 1307.2.1 Primary Hepatocytes 1307.2.2 Liver-Derived Cell Lines 1357.2.3 Differentiated Pluripotent Stem Cells 1377.3 Models to Mitigate Hepatocyte Dedifferentiation 1407.3.1 Liver Slices 1407.3.2 Selective Engineering of Metabolism 1417.4 Understanding Immune-Mediated Hepatotoxicity 1447.4.1 Use of Inflammatory Cofactors 1457.4.2 Innate Immune System and Inflammasome 1477.5 Conclusions 148References 1498 Transporters in the Liver 159Bruno Stieger and Gerd A. Kullak-Ublick8.1 Introduction 1598.2 Role of Organic Anion Transporters for Drug Uptake 1598.3 Drug Interaction with the Bile Salt Export Pump 1608.4 Susceptibility Factors for Drug–BSEP Interactions 1618.5 Role of BSEP in Drug Development 162References 1639 Mechanistic Modeling of Drug-Induced Liver Injury (DILI) 173Kyunghee Yang, Jeffrey L. Woodhead, Lisl K. Shoda, Yuching Yang, Paul B. Watkins, Kim L.R. Brouwer, Brett A. Howell, and Scott Q. Siler9.1 Introduction 1739.2 Mechanistic Modules in DILIsymðD version 3A 1759.2.1 Oxidative Stress-Mediated Toxicity 1759.2.2 Innate Immune Responses 1789.2.3 Mitochondrial Toxicity 1799.2.4 Bile Acid-Mediated Toxicity 1819.3 Examples of Bile Acid-Mediated Toxicity Module 1849.3.1 Troglitazone and Pioglitazone 1849.3.2 Bosentan and Telmisartan 1879.4 Conclusions and Future Directions 190References 191Section 3 Cardiovascular Side Effects 19910 Functional Cardiac Safety Evaluation of Novel Therapeutics 201Jean-Pierre Valentin, Brian Guth, Robert L. Hamlin, Pierre Lainée, Dusty Sarazan, and Matt Skinner10.1 Introduction: What Is the Issue? 20110.2 Cardiac Function: Definitions and General Principles 20310.2.1 Definition and Importance of Inotropy and Difference from Ventricular Function 20310.2.2 Definition and Importance of Lusitropy 20710.2.3 Components and Importance of the Systemic Arterial Pressure 21110.3 Methods Available to Assess Cardiac Function 21310.4 What Do We Know About the Translation of the Nonclinical Findings to Humans? 21710.5 Risk Assessment 21910.5.1 Hazard Identification 21910.5.2 Risk Assessment 22110.5.3 Risk Management 22410.5.4 Risk Mitigation 22510.6 Summary, Recommendations, and Conclusions 227References 22811 Safety Aspects of the Cav1.2 Channel 235Berengere Dumotier and Martin Traebert11.1 Introduction 23511.2 Structure of Cav1.2 Channels 23511.2.1 α-Subunit of Cav1.2 Channel 23611.2.2 β-Subunit of Cav1.2 Channel 23611.3 Function of Cav1.2 Channels in Cardiac Tissue 23711.3.1 Role in Conduction and Contractility 23911.3.2 Modulation of Cav1.2 Channels 24011.3.3 Cav1.2 and Cardiac Diseases 24411.4 Pharmacology of Cav1.2 Channels: Translation to the Clinic 24511.4.1 Cav1.2 Antagonists: Impact on Electromechanical Functions 24511.5 Prediction of Cav1.2 Off-Target Liability 24611.5.1 Cav1.2 in Cardiomyocytes Derived from iPS Cells 246References 24712 Cardiac Sodium Current (Nav1.5) 253Gary Gintant12.1 Background and Scope 25312.2 Structure and Function 25512.2.1 Molecular Biology 25512.2.2 SCN5A Mutations Related to Congenital Long QT Syndromes 25612.2.3 Evidence for Multiple Functional Types of Cardiac Sodium Channels and Heterogeneous Distribution 25712.3 Physiological Role and Drug Actions 25812.3.1 Fast Sodium Current (INaF): Conduction and Refractoriness 25812.3.2 Late (or Residual or Slow) Sodium Current (INaL) 25912.3.3 Drug Effects on INaF 26112.3.4 Indirect Modulation of INaF 26412.4 Methodology 26512.4.1 Use of Human Stem Cell-Derived Cardiomyocytes 26612.5 Translation of Effects on INaF: Relation to Conduction Velocity and Proarrhythmia 26812.6 Conclusions 269References 27013 Circulating Biomarkers for Drug-Induced Cardiotoxicity: Reverse Translation from Patients to Nonclinical Species 279Gül Erdemli, Haisong Ju, and Sarita Pereira13.1 Introduction 27913.2 Cardiac Troponins 28013.3 Natriuretic Peptides 28213.4 Novel/Exploratory Biomarkers: H-FABP, miRNA, and Genomic Biomarkers 28513.5 Regulatory Perspective 28613.6 Conclusions and Future Perspectives 288References 28914 The Mechanistic Basis of hERG Blockade and the Proarrhythmic Effects Thereof 295Robert A. Pearlstein, K. Andrew MacCannell, Qi-Ying Hu, Ramy Farid, and José S. Duca14.1 Introduction 29514.1.1 The Role of hERG Dysfunction/Blockade in Promoting Early After Depolarizations 29614.1.2 The Dynamics of hERG Blockade 30114.1.3 Simulations of the Human Cardiac AP in the Presence of hERG Blockade 30314.1.4 Estimation of Proarrhythmic hERG Occupancy Levels Based on AP Simulations 30414.1.5 Novel Insights about the Causes of Inadvertent hERG Binding Function 30514.1.6 Implications of Our Findings for hERG Safety Assessment 31314.1.7 Conclusion and Future Directions 324References 324Section 4 Kinase Antitargets 32915 Introduction to Kinase Antitargets 331Mark C. MunsonReferences 36016 Clinical and Nonclinical Adverse Effects of Kinase Inhibitors 365Douglas A. Keller, Richard J. Brennan, and Karen L. Leach16.1 Introduction 36516.2 Perspectives on the Clinical Safety of Kinase Inhibitor Therapy 37116.3 Adverse Effects of Kinase Inhibitor Drugs 37216.3.1 Hepatic Toxicity 37216.3.2 Thyroid Toxicity 37716.3.3 Bone and Tooth Toxicity 37916.3.4 Cardiovascular Toxicity 38016.3.5 Cutaneous Toxicity 38016.3.6 Developmental and Reproductive Toxicity 38316.3.7 Gastrointestinal Toxicity 38516.3.8 Hematopoietic Toxicity 38516.3.9 Ocular Toxicity 38716.3.10 Pulmonary Toxicity 38816.3.11 Renal Toxicity 38916.4 Derisking Strategies for Kinase Inhibitor Toxicity 38916.5 Concluding Remarks 391References 39117 Cardiac Side Effects Associated with Kinase Proteins and Their Signaling Pathways 401Roy J. Vaz and Vinod F. Patel17.1 A Case Study 40117.2 Introduction 40217.3 Cardiac-Specific Kinase Antitargets 40417.3.1 Preclinical Findings in Genetically Modified or KI-Treated Mice 40417.3.2 Clinical Findings of Kinase Inhibitors on the Heart and Their Mechanistic Understandings 40417.4 Current and Future Directions 40917.4.1 Preclinical Safety and Clinical Outcome Predictions 40917.5 Conclusions 410References 41118 Case Studies: Selective Inhibitors of Protein Kinases – Exploiting Demure Features 413Ellen R. Laird18.1 Introduction 41318.2 Case I: Indane Oximes as Selective B-Raf Inhibitors 41418.3 Case II: ARRY-380 (ONT-380) – an ErbB2 Agent that Spares EGFR 42018.4 Case III: Discovery of GDC-0068 (Ipatasertib), a Potent and Selective ATP-Competitive Inhibitor of AKT 42418.5 Concluding Remarks 428References 429Section 5 Examples of Clinical Translation 43519 Torcetrapib and Dalcetrapib Safety: Relevance of Preclinical In Vitro and In Vivo Models 437Eric J. Niesor, Andrea Greiter-Wilke, and Lutz Müller19.1 Introduction 43719.2 Effect of Torcetrapib on Blood Pressure 43719.3 In Vitro Studies 43819.3.1 Direct Effect of Torcetrapib on Aldosterone Production In Vitro in Cultured H295R Adrenal Corticocarcinoma Cells 43919.3.2 Molecular Mechanism of Torcetrapib Induction of Aldosterone Secretion 43919.3.3 Development of Reproducible In Vitro Screening Models for Increase in Aldosterone and Cyp11B2 mRNA in a Human Adrenal Corticocarcinoma Cell Line 44019.3.4 Application of In Vitro Models for the Successful Derisking of Dalcetrapib, Anacetrapib, and Evacetrapib 44019.4 In Vivo Studies 44119.4.1 Effect of Torcetrapib on Aldosterone and BP 44119.4.2 Molecular Mechanisms of Torcetrapib-Induced BP Increase 44419.5 General Safety Risk with Increased Aldosterone and BP 44719.5.1 Inappropriate Increase in Aldosterone Secretion May Increase CV Risks 44719.6 Relevance of BP and Aldosterone Preclinical Models to Clinical Observation with Dalcetrapib and Anacetrapib 44819.7 Similarities between Potent CETPi and Halogenated Hydrocarbons 44919.7.1 The Macrophage Scavenger Receptor MARCO, a Possible Antitarget for Dalcetrapib, and Its Relevance to Humans 45019.8 Conclusions 451References 45120 Targets Associated with Drug-Related Suicidal Ideation and Behavior 457Andreas Hartmann, Steven Whitebread, Jacques Hamon, Alexander Fekete, Christian Trendelenburg, Patrick Y. Müller, and László Urbán20.1 Introduction 45720.2 Targets Associated with Increased Suicidal Intent and Behavior 45820.2.1 G-Protein-Coupled Receptors 45820.2.2 Transporters 46620.2.3 Ion Channels 46920.3 Conclusions 472References 473Index 479

“Overall, there is plenty of information in this book making it a valuable indepth reading matter for experts working in the complex and quickly evolving scientific field of translational safety.  Academic students and new industrial recruits will also profit from selected chapters of this reference book.”  (ChemMedChem, 1 October 2015)