Cardiac Drug Safety: A Bench To Bedside Approach

by Matthew J Killeen

Overview

Ensuring the safety of new medical products remains a major challenge for the pharmaceutical industry. Cardiac safety, particularly drug-induced heart rhythm abnormalities, remains an important cause of pipeline attrition and has resulted in countless major product recalls or label changes. The risk of encountering this major adverse event continues to shape the drug development and regulatory landscape.Extensive research over the past decade has shed light on the root causes of arrhythmias that are triggered by medications and has helped drive, and optimize, drug safety testing. However, current cardiac safety platforms have several limitations and there remains a pressing unmet need to improve the predictive power of today's drug safety tests.Fundamental to addressing the problem of drug-induced arrhythmias, and to reducing the impact of this safety signal on drug development, is a complete understanding of how these events may arise, what cardiac safety tests are currently used, and what opportunities there are to enhance patient safety and reduce the risk of detecting cardiac toxicity in later stages of product commercialization. By introducing the reader to these core concepts, this book delivers key insight into the increasingly important and dynamic field of cardiac safety.

Product Details

ISBN-13:	9789814317450
Publisher:	World Scientific Publishing Company, Incorporated
Publication date:	02/03/2012
Pages:	188
Product dimensions:	6.10(w) x 9.00(h) x 0.80(d)

Table of Contents

Foreword ix

Preface xi

Chapter 1 Challenges Facing the Pharmaceutical Industry in the 21st Century 1

Introduction 1

The Impact of Cardiac Toxicity on the Pharmaceutical Industry 4

References 10

Chapter 2 The Cellular Basis of Cardiac Electrophysiology 11

Introduction 11

The Initiation of the Heart Beat 11

The Ventricular Cardiac Action Potential 12

The Relationship Between the Cardiac Action Potential and the Electrocardiogram 15

Ion Channels Underlying the Cardiac Action Potential 15

Summary 26

References 26

Chapter 3 Clinical Arrhythmia Syndromes 31

Introduction 31

The Long QT Syndrome 31

Congenital Long QT Syndrome 32

Drug-Induced QT Prolongation 34

Summary 40

References 41

Chapter 4 The Mechanisms Underlying Cardiac Arrhythmias 43

Introduction 43

Mechanisms Underlying Cardiac Arrhythmias 43

Abnormal Automaticity 44

Early and Delayed Afterdepolarizations 44

Re-entry 45

Transmural Dispersion of Repolarization 48

How does Action Potential and QT Prolongation Generate Arrhythmias? 51

Does the M-Cell Play a Role in Arrhythmia Induction in Humans? 53

Using Mouse Models to Study Arrhythmia Mechanisms 54

Experimental Studies Exploring the Relationship Between Changes in Transmural Repolarization Gradients and Arrhythmias in Mouse Hearts 57

Arrhythmia Mechanisms and Novel Antiarrhythmic Approaches Identified Using the Hypokalemic Mouse Model 58

Summary 67

References 67

Chapter 5 The Mechanisms Underlying Drug-Induced Arrhythmias 73

Introduction 73

The Classical Model of Drug-Induced QT 73

Prolongation and Proarrhythmia: HERG Blockade Additional Mechanisms Contributing to 74

Drug-Induced Arrhythmias Drug-Induction Activation of Depolarizing Ion Channels 75

Drug-Induced Changes in Ion Channel Expression 77

Drug-Induced Sodium Channel Dysfunction 78

Summary 80

References 80

Chapter 6 Assessing Cardiac Safety in Drug Development 83

Introduction 83

Preclinical Evaluation of Cardiac Drug Safety 83

The ICH S7B Guidelines 84

Single Cell Safety Studies 87

The Purkinje Fiber Model 88

The Ventricular Wedge Model 89

Isolated Heart Models 90

In Vivo Models 92

The Impact of Species-Related Differences in Cardiac Electrophysiology on Preclinical Drug Safety Assessment 95

Methods to Provoke Arrhythmias in Preclinical Studies 97

Clinical Evaluation of Cardiac Safety 100

Additional Biomarkers to Detect Drug-Induced Proarrhythmia 104

Recent Case Studies of Drug-Induced Proarrhythmia 109

Propoxyphene-Induced Cardiac Toxicity 110

Clinical and Experimental Studies of Propoxyphene-Induced Cardiac Toxicity 110

Regulatory Assessment of Propoxyphene's Cardiac Safety Profile 113

Dolasetron-Induced Cardiac Toxicity 113

Clinical and Experimental Studies of Dolasetron-Induced Cardiac Toxicity 114

Regulatory Assessment of Dolasetron's Cardiac Safety Profile 116

Summary 117

References 118

Chapter 7 Pediatric Cardiac Safety 123

Introduction 123

Cisapride-Induced Pediatric Cardiac Toxicity 124

Potential Mechanisms Underlying Cisapride-Induced Cardiac Toxicity in Pediatric Patients 126

Drug-Induced Cardiac Toxicity in the Embryonic Heart 130

Summary 132

References 134

Chapter 8 Drug-Induced Atrial Fibrillation 137

Introduction 137

Atrial Fibrillation 137

Bisphosphonate-Induced Atrial Fibrillation 138

Adenosine-Induced Atrial Fibrillation 142

Corticosteroid-Induced Atrial Fibrillation 144

Implications for Cardiac Safety Testing During Drug Development 146

Summary 149

References 149

Chapter 9 Navigating the Future Path of Cardiac Drug Safety 153

Introduction 153

Disease-Driven Approaches to Cardiac Safety 153

Emerging Technologies for Cardiac Safety Assessment 157

New Proarrhythmic Paradigms 162

Engagement of Key Stakeholders to Advance Cardiac Safely Assessments 164

References 166

Index 169