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Metabolite Safety in Drug Development
ISBN-13: 9781118949658 / Angielski / Twarda / 2016 / 352 str.
Metabolite Safety in Drug Development
ISBN-13: 9781118949658 / Angielski / Twarda / 2016 / 352 str.
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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 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
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.
"Written by individuals who collectively possess hundreds of years of experience within the drug metabolism field, the wealth of information and insight contained is amazing. The purpose of the tome is to provide the reader with, ‘... a comprehensive overview of why and how metabolites are studied during drug development in the pharmaceutical industry’ (page 13). This objective is certainly achieved in a lucid, scholarly and engaging manner. I would not hesitate to recommend this book to anyone interested in this subject and also for those who may wish to delve into this area." (ISSX Newsletter, April 2017)
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
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 Hougaard Sunesen
7.1 Introduction, 177
7.2 Skin Structure and Function of the Epidermal Layer, 178
7.3 Skin Models, 180
7.3.1 In Vivo Studies, 181
7.3.2 Ex Vivo Skin, 182
7.3.3 In Vitro Skin Models, 182
7.4 Metabolic Capacity of Human Skin, 186
7.4.1 Phase 1 Enzymes, 186
7.4.2 Non–CYP Phase 1 Enzymes, 190
7.4.3 Phase 2 Enzymes, 193
7.5 Species Differences in Metabolic Capacity of the Skin, 196
7.6 Metabolic Capacity of Diseased Skin, 197
7.7 Soft Drug Approach, 198
7.7.1 Soft Corticosteroids, 199
7.7.2 PDE4 Inhibitors, 200
7.8 Exposure to Metabolites and Risk of Adverse Events, 202
7.8.1 Drug Interaction Potential, 204
7.8.2 Toxicities and Safety Concerns, 205
References, 206
8 In Silico Modeling of Metabolite Kinetics 213
Lu Gaohua, Howard Burt, Helen Humphries, Amin Rostami–Hodjegan, and Masoud Jamei
8.1 Introduction, 213
8.1.1 Why Do We Need to Model Metabolite PK?, 213
8.1.2 Brief Review of Existing PBPK Models of Metabolites, 214
8.2 Simcyp Approach to Modeling Metabolite PBPK, 215
8.2.1 Parent/Metabolite PBPK Model Structure, 215
8.2.2 Formation/Absorption of the Metabolite, 217
8.2.3 Distribution of Metabolite, 219
8.2.4 Elimination of Metabolite, 222
8.2.5 Interaction of Metabolite, 222
8.3 Model Verifications, 223
8.3.1 Comparison of Prediction versus Observation, 223
8.3.2 What–If Simulation Examples, 223
8.4 Discussion, 230
8.4.1 Role of M&S in Handling Metabolites, 230
8.4.2 How to Deal with Multiple Metabolites, 231
8.4.3 Role of M&S of Metabolites in Regulatory Submissions, 232
8.5 Concluding Remarks, 232
8.5.1 What has been Achieved?, 232
8.5.2 Future Works, 232
Glossary, 233
Superscription, 233
Subscription, 234
References, 234
9 Introduction to Case Studies 239
Suzanne L. Iverson
References, 242
10 A Mass Balance and Metabolite Profiling Study of Sonidegib in Healthy Male Subjects Using Microtrace Approach 243
Piet Swart, Frederic Lozac h, and Markus Zollinger
10.1 Introduction to the Study, 243
10.2 Radioactive Dose Limitations, 245
10.3 Results, 246
10.4 Metabolite Profiling and Identification, 249
Acknowledgments, 258
References, 258
11 Dealing with Reality: When is it Necessary to Qualify and Quantify Metabolites? Some Case Studies 261
Deepak K. Dalvie, R. Scott Obach, and Amit S. Kalgutkar
11.1 Introduction, 261
11.2 Case Study 1, 261
11.3 Case Study 2, 265
11.4 Case Study 3, 268
References, 271
12 The Value of Metabolite Identification and Quantification in Clinical Studies. Some Case Studies Enabling Early Assessment of Safety in Humans: GlaxoSmithKline 275
Jackie Bloomer, Claire Beaumont, Gordon J. Dear, Stephanie North, and Graeme Young
12.1 GW644784: Species–Specific Metabolites, 276
12.2 Danirixin: Assessment of Victim Drug Interaction Risk Using Bile Sampling, 279
12.3 Sitamaquine: Unique, Active, and Possible Genotoxic Metabolites and Human Radiolabel Study Not Feasible, 280
12.4 SB–773812: Concerns Over Long Half–Life Metabolite and Early Employment of Accelerator Mass Spectrometry, 285
12.5 GW766994: Consideration of Steady–State Kinetics and Multiple Analytical Methodologies for an Accurate Assessment of Human Metabolism, 288
References, 290
13 The Importance of Dose– and Time–Dependent Pharmacokinetics During Early Metabolite Safety Assessment in Humans 293
Laurent Leclercq, Marc Bockx, Hilde Bohets, Hans Stieltjes, Vikash Sinah, and Ellen Scheers
References, 303
14 Mist and the Future 305
B. Kevin Park and Dennis A. Smith
14.1 Introduction, 305
14.2 Mist and Pharmacology, 306
14.3 Reactive Metabolites, Pharmacology, and Mist, 309
14.4 Implications of Drug Bioactivation and Covalent Binding for Mist, 309
14.5 Drug Bioactivation and Drug Hepatotoxicity, 311
14.6 Drug–Conjugate Formation and Drug Hypersensitivity, 313
14.7 Drug Bioactivation, Conjugate Formation, and Drug Hypersensitivity, 315
14.8 Toward a Mist Strategy for Reactive Metabolites, 317
References, 318
Index 323
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).
Metabolism is the primary method to clear a drug from the body, but the normal process can generate metabolites that have intrinsic chemical reactivity towards cellular molecules and these metabolites remain free to circulate and exert both pharmacological and toxicological effects. Therefore, the study of drug metabolism occurs at all stages in the drug discovery and drug development process.
Targeting practitioners in all areas of nonclinical toxicology and clinical development,
Metabolite Safety in Drug Development focuses on the characterization of metabolites once a drug candidate is selected, featuring case studies to illustrate lessons learned and a perspective on future directions. The book reviews the analytical techniques and experimental designs critical for metabolite studies, emphasizing stable and circulating metabolites, and deals with (on and off) target pharmacology, in vitro systems aligned with toxicity tests, and drug drug interactions.
Deigned to provide a comprehensive resource that offers clear guidance on one of the most critical issues of drug development, this book has a number of key benefits:
Description of analytical methods like chirality, species differences, mass spectrometry, radiolabels, and in vitro/in vivo correlation
Presentation and assessment of regulatory requirements from the US FDA and EMA
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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