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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…mehr
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
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Autorenporträt
Suzanne L. Iverson, PhD, ERT, earned her PhD studying reactive drug metabolites and idiosyncratic drug reactions (University of Toronto, Dr. Jack Uetrecht supervisor) and has worked in the pharmaceutical industry for over 14 years as principal scientist and manager of development in vitro/in vivo metabolism and distribution imaging as well as functional project leader for both DMPK and safety assessment functions. Since 2011, she has served on the management committee of the Drug Metabolism Discussion Group, UK, and the Board of the PK-Metabolism subcommittee of the Swedish Pharmaceutical Society. Dennis A. Smith, PhD, currently holds part-time advisory and academic positions and, previously, worked in the pharmaceutical industry for 32 years. He has coauthored over 150 publications, including Attrition in the Pharmaceutical Industry (Wiley, 2016), Reactive Drug Metabolites (Wiley, 2012), and three editions of the book Pharmacokinetics and Metabolism in Drug Design (Wiley, 2012).
Inhaltsangabe
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, 87
4.2 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
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, 87
4.2 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
