Metabolite safety in drug development

Content: Machine generated contents note: PREFACE LIST OF CONTRIBUTORS 1. Introduction: History of Metabolite Safety in Drug Development Dennis A. Smith and Suzanne L. Iverson 1.1. People, events and reaction 1.2. The rise of industrial drug metabolism 1.3. The appearance of MIST 1.4. The journey triggered by thalidomide- would present science have made a difference? 1.5. Key events from thalidomide to MIST 1.6. The purpose of this book 1.7. References 2. "MIST" and other metabolite guidelines in the context of industrial drug metabolism Gordon J. Dear and Angus N. R. Nedderman 2.1. A historical perspective 2.2. The emergence of the regulatory guidance documents 2.3. Impact of the guidelines 2.4. Future directions? 2.5. References 3. Metabolite technology --
qualitative and quantitative Gordon J. Dear and Andrew McEwen 3.1. Introduction 3.2. Clinical Samples 3.3. Pre-Clinical Samples 3.4. Radiolabelled test compounds 3.5. Mass Spectrometry 3.6. Nuclear magnetic resonance Spectroscopy 3.7. Accelerator mass spectrometry (AMS) 3.8. Further Reading 3.9. References 4. In Vitro methods for evaluation of drug metabolism: Identification of active and inactive metabolites and the enzymes that generate them R. Scott Obach, Amit S. Kalgutkar, and Deepak K. Dalvie 4.1. Introduction 4.2. The in vitro methods for metabolite profiling and identification 4.3. Application of in vitro methods for metabolite profiling in drug discovery and development 4.4. How well do in vitro metabolite profiles present in vivo metabolite profiles? 4.5 Pharmacologically active metabolites and their identification 4.6 Conclusion 5. Integrated reactive metabolite strategies J. Gerry Kenna and Richard A. Thompson 5.1 Introduction 5.2 Role of RMs in toxicity 5.3. Strategies for predicting, assessing and de-risking RM mediated toxicity 5.4. References 6. Understanding drug metabolism in humans --
in vivo Lars Weidolf and Ian D. Wilson 6.1. Abstract 6.2. Introduction 6.3. Preclinical Animal Studies 6.4. Early human in vivo metabolism studies 6.5. Sources of Variability in in vivo Biotransformation Studies: Species, Strain, Age and Sex differences 6.6. Extra-hepatic drug metabolism (animals and man) 6.7. Non-human metabolism in humans 6.8. Non-human models of human in vivo metabolism 6.9. Alternatives to Radiolabels 6.10. Conclusions 6.11. References 7. Topical administration and safety testing of metabolites Vibeke Hougaard Sunesen 7.1. Introduction 7.2. Skin structure and function of the epidermal layer 7.3. Skin models 7.4. Metabolic capacity of human skin 7.5. Species differences in metabolic capacity of the skin 7.6. Metabolic capacity of diseased skin 7.7. Soft drug approach 7.8. Exposure to metabolites and risk of adverse events 7.9. References 8. In Silico Modelling of Metabolite Kinetics Lu Gaohua, Howard Burt, Helen Humphries, Amin Rostami-Hodjegan, Masoud Jamei 8.1. In Silico Modelling of Metabolite Kinetics 8.2. Simcyp approach to modelling metabolite PBPK 8.3. Model verifications 8.4. Discussion 8.5. Concluding Remarks 8.6. Glossary 8.7. References 9. Introduction to Case Studies Suzanne L. Iverson References 10. A mass balance and metabolite profiling study of sonidegib in healthy male subjects using microtrace approach Piet Swart, Frederic Lozac'h, and Markus Zollinger 10.1. Introduction to the study 10.2. Radioactive dose limitations 10.3. Results 10.4. Metabolite profiling and identification 10.5. References 11. Dealing With Reality --
When is it necessary to qualify and quantify metabolites? Some Case Studies Deepak K. Dalvie, R. Scott Obach and Amit S. Kalgutkar 11.1. Introduction 11.2. Case study 1 11.3. Case study 2 11.4. Case study 3 11.5. References 12. CASE STUDIES GlaxoSmithKline Jackie Bloomer, Claire Beaumont, Gordon Dear, Stephanie North and Graeme Young 12.1. GW644784: Species Specific Metabolites 12.2. Danirixin: Assessment of Victim Drug Interaction Risk Using Bile Sampling 12.3. Sitamaquine: Unique, Active and Possible Genotoxic Metabolites and Human Radiolabel Study Not Feasible 12.4. SB-773812: Concerns Over Long Half-life Metabolite and Early Employment of Accelerator Mass Spectrometry 12.5. GW766994: Consideration of Steady State Kinetics and Multiple Analytical Methodologies for an Accurate Assessment of Human Metabolism 12.6. References 13. The importance of dose- and time- dependent pharmacokinetics during early metabolite safety assessment in humans Laurent Leclercq, Marc Bockx, Hilde Bohets, Hans Stieltjes, Vikash Sinah and Ellen Scheers 13.1. References 14. MIST and the future B. Kevin Park and Dennis A. Smith 14.1. Introduction 14.2. MIST and Pharmacology 14.3. Reactive metabolites, pharmacology and MIST 14.4. Implications of drug bioactivation and covalent binding for MIST 14.5. Implications of drug bioactivation and covalent binding for MIST 14.6. Drug-conjugate formation and Drug Hypersensitivity 14.7. Drug bioactivation, conjugate formation and drug hypersensitivity 14.8. Towards a MIST strategy for reactive metabolites 14.9. References.