Contents:

Introduction Dr R G Hughes - Consultant in Pharmaceutical Development Chapter 1 Assessing the Commercial Implications of Cardiotoxicity Jo Pisani and Yann Bonduelle, Pharmaceutical Strategy Consultants, PricewaterhouseCoopers LLP 1.0 Introduction 1.1 The cardiotoxicity challenge 1.2 The impact on stakeholders of cardiotoxicity 1.3 Assessing the size of the cardiotoxicity problem 1.4 Assessing the commercial costs of cardiotoxicity 1.5 Reacting to a cardiotoxic event: What option? 1.6 The case of Vioxx direct costs 1.7 The case of Fen-Phen: Impact on the obesity market 1.8 The case of Celebrex: The indirect costs of cardiotoxicity 1.9 The case of Vioxx & Fen-Phen: Litigation costs 1.10 The case of Gleevec: Reformulation costs 1.11 Understanding and addressing the problem of cardiotoxicity in the future 1.12 So what? Chapter 2 Introduction to Cardiac Pharmacology Professor D Terrar - Professor of Cardiac Electrophysiology, University of Oxford 2.0 A discussion of the pharmacology of the heart and what are the key pharmacologic processes 2.1 Introduction 2.2 Drug action and the heart 2.2.1 Ion channels and what they are and do 2.2.2 Which enzymes and other proteins are important? 2.2.3 Which proteins are involved in the contractile process? Chapter 3 Introduction to electrical activity in the heart Professor D Terrar - Professor of Cardiac Electrophysiology, University of Oxford 3.0 Description of the important electrical processes 3.1 Equivalent circuit model 3.2 Electrogenic transporters and their influence on membrane potential. 3.3 Importance of gK1 and its reduction during the action potential plateau 3.4 Detailed models of electrical activity in ventricular myocytes 3.5 Genes associated with ion channels 3.5.1 Description of an electrocardiogram Chapter 4 Mechanisms of Cardiac Toxicity Professor D Terrar - Professor of Cardiac Electrophysiology, University of Oxford 4.0 QT interval prolongation 4.1 QT interval shortening 4.1.1 Torsade des Pointes 4.1.2 Short and long term functional changes 4.1.3 Gene related adverse events Chapter 5 Preclinical Determination of Cardiac Toxicity Professor D Terrar - Professor of Cardiac Electrophysiology, University of Oxford 5.0 In Vitro 5.1 hERG testing 5.1.1 Advantages of hERG assays 5.1.2 Conventional electrophysiology 5.1.3 High throughput methods 5.1.4 Disadvantages of hERG assays 5.2 Purkinje Fibres 5.2.1 Myocytes (action potentials and currents) 5.2.2 Papillary muscles 5.2.3 Langendorf Hearts 5.2.4 Cardiac Wedge 5.3 In vivo telemetry Chapter 6 Determination of Cardiac Toxicity in the Clinic Daniel B. Goodman, MD, Medical Director, Entelligent Solutions, Inc Eileen M. Daniel, Vice President of Operations, Reliance Clinical Research Services 6.0 Introduction 6.1 Early Phase Clinical Trials 6.1.1 Thorough QT/QTc Study 6.1.2 TQTS Design 6.1.3 The TQTS in Practice 6.1.4 Collection of ECG data in the Clinic 6.1.5 Completion of ECG readings 6.1.6 Clinical Study Report 6.2 Later Phase Trials 6.2.1 Oncology 6.2.2 Other Cardiac Toxicity 6.3 Conclusion Chapter 7 Regulatory Aspects of QT/QTc Interval Prolongation Thomas E. Donnelly, Ph.D., Senior Vice President of Regulatory Affairs, Quality Assurance and Compliance, Reliance Clinical Research Services 7.0 Introduction 7.1 ICH Guidance and Thorough QT (TQT) Study 7.2 Risk Management Guidance during Development 7.3 Regulatory Review of QT/QTc Protocols 7.4 Interdisciplinary Review Team for QT Studies 7.5 Risk Management Guidance Post-Marketing for Drugs that Prolong the QT/QTc Interval 7.5.1 Risk Management General 7.5.2 Risk Management with QT/QTc Interval Prolongation 7.6 Labeling Issues for Drugs that Prolong the QT/QTc Interval 7.7 Regulatory Review of Clinical Safety Data in a Marketing Application 7.8 Summary Chapter 8 Future Prospects Professor D Terrar Dr Eileen Daniel Dr D Goodman Dr T Donnelly Dr RG Hughes 8.0 Imaging: Optical probes for measuring electrical activity 8.1 Imaging: Optical probes for calcium and other ions 8.2 Tissue culture cardiac cells 8.3 Computational methods 8.4 Medium Throughput screening for cardiac toxicity 8.5 Commercial prospects 8.6 Regulatory prospects 8.7 Clinical Challenges Chapter 9 References and Useful Reading Chapter 10 Glossary & Abbreviations About the Contributors