Antitargets and Drug Safety -- Contents -- List of Contributors -- Preface -- A Personal Foreword -- Section 1: General Concept for Target-based Safety Assessment -- 1: Side Effects of Marketed Drugs: The Utility and Pitfalls of Pharmacovigilance -- 1.1 Introduction -- 1.2 Postmarketing Pharmacovigilance -- 1.3 Polypharmacy and Pharmacological Promiscuity of Marketed Drugs -- References -- 2: In Silico Prediction of Drug Side Effects -- 2.1 Large-Scale Prediction of Drug Activity -- 2.1.1 Networks of Known and New Target Activity -- 2.1.1.1 Predicting Drug Off-Targets by Statistical Chemical Similarity -- 2.1.1.2 Representing Drugs Computationally for Rapid Comparison -- 2.1.2 Resources for Multiscale Inquiry -- 2.1.2.1 Ligands to Targets -- 2.1.2.2 Perturbing Biological Systems (Phenotypes) -- 2.1.2.3 Functional and Biological Annotations (Diseases) -- 2.1.2.4 Adverse Reactions as Drug-Induced Diseases -- 2.2 Multiscale Models of Adverse Drug Reactions -- 2.2.1 Inferring Adverse Reactions -- 2.2.1.1 From Off-Targets to Antitargets -- 2.2.1.2 Systematic Antitarget Prediction and Testing -- 2.2.1.3 Finding Side Effects sans Targets -- 2.2.2 Forward Perturbation and Prediction of Mechanisms -- 2.2.2.1 Forward Synthetic Behavior in Cell and Whole-Organism Model Systems -- 2.2.2.2 The Road Ahead -- References -- 3: Translational Value of Preclinical Safety Assessment: System Organ Class (SOC) Representation of Off-Targets -- 3.1 Introduction -- 3.2 Terminology: Medicinal Dictionary for Regulatory Activities (MedDRA) -- 3.2.1 Correct Use of MedDRA Terminology at Different Phases of Drug Discovery -- 3.2.2 Determination of Symptoms Associated with a Target -- 3.3 Data Interpretation: Modifying Factors -- 3.3.1 Access to Organs -- 3.3.2 Off-Target Promiscuity: Target Interactions (Synergies and Antagonism) -- 3.4 Conclusions -- References.

4: Pathological Conditions Associated with the Disturbance of the 5-HT System -- 4.1 Introduction -- 4.2 From "St. Anthony's Fire" to Ergot Alkaloids, the Serotonin Syndrome, and Modern 5-HT Pharmacology -- 4.3 Appetite-Reducing Agents, Fenfluramine, and Other 5-HT Releasers -- 4.4 Gastrointestinal and Antiemetic Indications, the 5-HT3/5-HT4 Receptor Links -- 4.5 Antipsychotics and the 5-HT2/Dopamine D2 Link (and Many Other 5-HT Receptors) -- 4.6 Antimigraine Medications of Old and New and the 5-HT1B/1D Receptors -- 4.7 Antidepressants/Anxiolytics Acting at 5-HT and Other Transporters -- 4.8 Conclusions -- References -- Section 2: Hepatic Side Effects -- 5: Drug-Induced Liver Injury: Clinical and Diagnostic Aspects -- 5.1 Introduction -- 5.1.1 Postmarketing Hepatotoxicity versus Hepatotoxicity in Development -- 5.1.2 Isoniazid - If It Were Newly Discovered, Would It Be Approved Today? -- 5.2 Special Problems of Postmarketing Hepatotoxicity -- 5.2.1 Voluntary Monitoring after Approval for Marketing -- 5.2.2 Prediction of Serious, Dysfunctional Liver Injury -- 5.2.3 Severity of Liver Injury Is Not Measured by Aminotransferase Elevations -- 5.2.4 Attempts to Standardize Terminology -- 5.2.5 What Is the "Normal" Range, or the "Upper Limit of Normal"? -- 5.2.6 Diagnostic Test Evaluation -- 5.2.7 Determination of the Likely Cause of Liver Abnormalities -- 5.2.8 Treatment and Management of DILI in Practice -- 5.3 Special Problems for New Drug Development -- 5.3.1 How Many? -- 5.3.2 How Much? -- 5.3.3 How Soon? -- 5.3.4 How Likely? -- 5.3.5 Compared with What? -- 5.3.6 ROC Curves -- 5.3.7 eDISH: Especially for Controlled Trials -- 5.3.8 Test Validation and Qualification -- 5.4 Closing Considerations -- 5.4.1 A Handful of "Do Nots" -- 5.4.2 Need to Standardize ALT Measurement and Interpretation of Normal Ranges -- 5.4.3 Research Opportunities -- References.

6: Mechanistic Safety Biomarkers for Drug-Induced Liver Injury -- 6.1 Introduction -- 6.2 Drug-Induced Toxicity and the Liver -- 6.3 Current Status of Biomarkers for the Assessment of DILI -- 6.4 Novel Investigational Biomarkers for DILI -- 6.4.1 Glutamate Dehydrogenase (GLDH) -- 6.4.2 Acylcarnitines -- 6.4.3 High-Mobility Group Box-1 (HMGB1) -- 6.4.4 Keratin 18 (K18) -- 6.4.5 MicroRNA-122 (miR-122) -- 6.5 Conclusions and Future Perspectives -- References -- 7: In Vitro Models for the Prediction of Drug-Induced Liver Injury in Lead Discovery -- 7.1 Introduction -- 7.2 Simple Systems for the Detection and Investigation of Hepatic Toxicants -- 7.2.1 Primary Hepatocytes -- 7.2.1.1 Cells -- 7.2.1.2 Cell Culture Conditions -- 7.2.1.3 Toxicity Endpoints -- 7.2.1.4 Limitations of Hepatocyte Cultures -- 7.2.2 Liver-Derived Cell Lines -- 7.2.2.1 HepG2 -- 7.2.2.2 HepaRG -- 7.2.3 Differentiated Pluripotent Stem Cells -- 7.2.3.1 Embryonic Stem Cells -- 7.2.3.2 Induced Pluripotent Stem Cells -- 7.3 Models to Mitigate Hepatocyte Dedifferentiation -- 7.3.1 Liver Slices -- 7.3.2 Selective Engineering of Metabolism -- 7.4 Understanding Immune-Mediated Hepatotoxicity -- 7.4.1 Use of Inflammatory Cofactors -- 7.4.2 Innate Immune System and Inflammasome -- 7.5 Conclusions -- References -- 8: Transporters in the Liver -- 8.1 Introduction -- 8.2 Role of Organic Anion Transporters for Drug Uptake -- 8.3 Drug Interaction with the Bile Salt Export Pump -- 8.4 Susceptibility Factors for Drug-BSEP Interactions -- 8.5 Role of BSEP in Drug Development -- References -- 9: Mechanistic Modeling of Drug-Induced Liver Injury (DILI) -- 9.1 Introduction -- 9.2 Mechanistic Modules in DILIsym version 3A -- 9.2.1 Oxidative Stress-Mediated Toxicity -- 9.2.2 Innate Immune Responses -- 9.2.3 Mitochondrial Toxicity -- 9.2.4 Bile Acid-Mediated Toxicity.

9.3 Examples of Bile Acid-Mediated Toxicity Module -- 9.3.1 Troglitazone and Pioglitazone -- 9.3.2 Bosentan and Telmisartan -- 9.4 Conclusions and Future Directions -- References -- Section 3: Cardiovascular Side Effects -- 10: Functional Cardiac Safety Evaluation of Novel Therapeutics -- 10.1 Introduction: What Is the Issue? -- 10.2 Cardiac Function: Definitions and General Principles -- 10.2.1 Definition and Importance of Inotropy and Difference from Ventricular Function -- 10.2.2 Definition and Importance of Lusitropy -- 10.2.3 Components and Importance of the Systemic Arterial Pressure -- 10.2.3.1 Afterload -- 10.3 Methods Available to Assess Cardiac Function -- 10.4 What Do We Know About the Translation of the Nonclinical Findings to Humans? -- 10.5 Risk Assessment -- 10.5.1 Hazard Identification -- 10.5.2 Risk Assessment -- 10.5.3 Risk Management -- 10.5.4 Risk Mitigation -- 10.6 Summary, Recommendations, and Conclusions -- References -- 11: Safety Aspects of the Cav1.2 Channel -- 11.1 Introduction -- 11.2 Structure of Cav1.2 Channels -- 11.2.1 α-Subunit of Cav1.2 Channel -- 11.2.2 β-Subunit of Cav1.2 Channel -- 11.3 Function of Cav1.2 Channels in Cardiac Tissue -- 11.3.1 Role in Conduction and Contractility -- 11.3.2 Modulation of Cav1.2 Channels -- 11.3.2.1 Voltage- and Calcium-Dependent Facilitation -- 11.3.2.2 Sympathetic Stimulation and Kinase Regulation -- 11.3.2.3 Inactivation -- 11.3.2.4 Regulation by Calmodulin -- 11.3.2.5 Indirect Regulation of Cav1.2 Channels -- 11.3.3 Cav1.2 and Cardiac Diseases -- 11.4 Pharmacology of Cav1.2 Channels: Translation to the Clinic -- 11.4.1 Cav1.2 Antagonists: Impact on Electromechanical Functions -- 11.5 Prediction of Cav1.2 Off-Target Liability -- 11.5.1 Cav1.2 in Cardiomyocytes Derived from iPS Cells -- References -- 12: Cardiac Sodium Current (Nav1.5) -- 12.1 Background and Scope.

12.2 Structure and Function -- 12.2.1 Molecular Biology -- 12.2.2 SCN5A Mutations Related to Congenital Long QT Syndromes -- 12.2.3 Evidence for Multiple Functional Types of Cardiac Sodium Channels and Heterogeneous Distribution -- 12.3 Physiological Role and Drug Actions -- 12.3.1 Fast Sodium Current (INaF): Conduction and Refractoriness -- 12.3.2 Late (or Residual or Slow) Sodium Current (INaL) -- 12.3.3 Drug Effects on INaF -- 12.3.3.1 Voltage-Dependent Block -- 12.3.3.2 Use-Dependent Block (and Tonic Block) -- 12.3.3.3 Models of Block and Classification Schemes Based on Antiarrhythmic Drug Effects -- 12.3.4 Indirect Modulation of INaF -- 12.4 Methodology -- 12.4.1 Use of Human Stem Cell-Derived Cardiomyocytes -- 12.5 Translation of Effects on INaF: Relation to Conduction Velocity and Proarrhythmia -- 12.6 Conclusions -- References -- 13: Circulating Biomarkers for Drug-Induced Cardiotoxicity: Reverse Translation from Patients to Nonclinical Species -- 13.1 Introduction -- 13.2 Cardiac Troponins -- 13.3 Natriuretic Peptides -- 13.4 Novel/Exploratory Biomarkers: H-FABP, miRNA, and Genomic Biomarkers -- 13.5 Regulatory Perspective -- 13.6 Conclusions and Future Perspectives -- References -- 14: The Mechanistic Basis of hERG Blockade and the Proarrhythmic Effects Thereof -- 14.1 Introduction -- 14.1.1 The Role of hERG Dysfunction/Blockade in Promoting Early After Depolarizations -- 14.1.2 The Dynamics of hERG Blockade -- 14.1.3 Simulations of the Human Cardiac AP in the Presence of hERG Blockade -- 14.1.4 Estimation of Proarrhythmic hERG Occupancy Levels Based on AP Simulations -- 14.1.5 Novel Insights about the Causes of Inadvertent hERG Binding Function -- 14.1.6 Implications of Our Findings for hERG Safety Assessment -- 14.1.7 Conclusion and Future Directions -- References -- Section 4: Kinase Antitargets -- 15: Introduction to Kinase Antitargets.

References.