Metabolite Safety in Drug Development
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Metabolite Safety in Drug Development

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Suzanne L. Iverson
242xx mm
Preface xi
List of Contributors xiii
1 Introduction: History of Metabolite Safety in Drug Development 1
Dennis A. Smith and Suzanne L. Iverson
1.1 People, Events, and Reaction, 1
1.2 The Rise of Industrial Drug Metabolism, 2
1.3 The Appearance of Mist, 4
1.4 The Journey Triggered by Thalidomide: Would Present Science have Made a Difference?, 5
1.5 Key Events from Thalidomide to Mist, 8
1.6 The Purpose of this Book, 13
References, 14
2 "Mist" and other Metabolite Guidelines in the Context of Industrial Drug Metabolism 17
Gordon J. Dear and Angus N. R. Nedderman
2.1 A Historical Perspective, 17
2.2 The Emergence of the Regulatory Guidance Documents, 23
2.3 Impact of the Guidelines, 30
2.4 Future Directions, 32
References, 37
3 Metabolite Technology: Qualitative and Quantitative 45
Gordon J. Dear and Andrew McEwen
3.1 Introduction, 45
3.2 Clinical Samples, 46
3.3 Preclinical Samples, 48
3.4 Radiolabeled Test Compounds, 51
3.5 Mass Spectrometry, 55
3.6 NMR Spectroscopy, 65
3.7 Accelerator Mass Spectrometry, 72
References, 75
Further Reading, 85
4 In Vitro Methods for Evaluation of Drug Metabolism: Identification of Active and Inactive Metabolites and the Enzymes that Generate them 87
R. Scott Obach, Amit S. Kalgutkar, and Deepak K. Dalvie
4.1 Introduction, 874.2 In Vitro Methods for Metabolite Profiling and Identification, 88
4.2.1 In Vitro Systems We Use: Most Complex to Simplest, 88
4.2.2 Criteria for Selecting the Most Appropriate In Vitro System for In Vitro Metabolite Profiling, 92
4.3 Application of In Vitro Methods for Metabolite Profiling in Drug Discovery and Development, 96
4.3.1 In Vitro Metabolite Profiling and Identification in the Early Drug Discovery Stage, 96
4.3.2 In Vitro Metabolite Profiling and Identification in the Late Drug Discovery Stage: Selection of Candidate Compounds for Further Development, 98
4.3.3 In Vitro Metabolite Profiling and Identification in the Drug Development Stage: Support of Candidate
Compounds for New Drug Registration, 101
4.4 How Well Do In Vitro Metabolite Profiles Represent In Vivo Metabolite Profiles?, 103
4.5 Pharmacologically Active Metabolites and their Identification, 104
4.5.1 When Is a Metabolite Considered Active?, 104
4.5.2 Experimental Approaches to Reveal Active Metabolites, 106
4.6 Conclusion, 108
References, 108
5 Integrated Reactive Metabolite Strategies 111
J. Gerry Kenna and Richard A. Thompson
5.1 Introduction, 111
5.2 Role of RMs in Toxicity, 114
5.3 Strategies for Predicting, Assessing, and Derisking RM-Mediated Toxicity, 118
5.3.1 Assessing RM Hazard: Awareness/Avoidance, 118
5.3.2 Assessing RM Risk: Covalent Binding and Dose, 122
5.3.3 Integrated Risk Assessments: Integrating RM Assessment and In Vitro Safety Assay Endpoints, 127
5.3.4 Integrated RM Risk Assessments: Future Directions, 129
References, 131
6 Understanding Drug Metabolism in Humans: In Vivo 141
Lars Weidolf and Ian D. Wilson
6.1 Introduction, 141
6.2 Preclinical Animal Studies, 142
6.2.1 Whole-Body Autoradiography and Imaging, 144
6.3 Early Human In Vivo Metabolism Studies, 146
6.3.1 Pre-FTIM Data Acquisition, 147
6.3.2 The First Clinical Studies, 149
6.3.3 Metabolite Exposure Assessment, 150
6.3.4 Exceptions to Regulatory Recommendations, 153
6.3.5 Dealing with DHMs, 153
6.3.6 The Human ADME Study, 156
6.3.7 Early Metabolite Exposure Assessment and Relevance to the Target Patient Population, 159
6.3.8 Summary, 160
6.4 The "What ifs...?", 162
6.5 Sources of Variability in In Vivo Biotransformation Studies: Species, Strain, Age, and Sex Differences, 162
6.6 Extrahepatic Drug Metabolism (Animals and Man), 164
6.7 Nonhuman Metabolism in Humans, 166
6.8 Nonhuman Models of Human In Vivo Metabolism, 167
6.8.1 "Humanized" Transgenic Mice, 168
6.8.2 "Chimeric" Humanized Mice, 169
6.9 Alternatives to Radiolabels, 170
6.10 Conclusions, 171
References, 172
7 Topical Administration and Safety Testing of Metabolites 177
Vibeke Houga
A reference on drug metabolism and metabolite safety in the development phase, this book reviews the analytical techniques and experimental designs critical for metabolite studies. It features case studies of lessons learned and real world examples, along with regulatory perspectives from the US FDA and EMA.
Reviews the analytical techniques and experimental designs critical for metabolite studies
Covers methods including chirality, species differences, mass spectrometry, radiolabels, and in vitro / in vivo correlation
Discusses target pharmacology, in vitro systems aligned to toxicity tests, and drug-drug interactions
Includes perspectives from authors with firsthand involvement in industry and the study of drug metabolites, including viewpoints that have influenced regulatory guidelines