Antitargets and Drug Safety

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.

Auteur
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.

Contenu

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&lt...