Drug-Drug Interactions: Scientific and Regulatory Perspectives (eBook)

Front Cover 1
Drug-Drug Interactions: Scientific and Regulatory Perspectives 4
Copyright Page 5
Contents 6
Contributors 14
Foreword 16
Preface 18
Chapter 1. Overview: Pharmacokinetic Drug–Drug Interactions 20
I. Clinical Significance of Drug–Drug Interactions 20
II. Mechanism of Pharmacokinetic Drug–Drug Interactions 22
III. Prediction of Drug–Drug Interactions 23
IV. Conclusions and Future Directions 24
References 25
Chapter 2. Role of Cytochrome P450 Enzymes in Drug–Drug Interactions 26
I. Introduction 26
II. Potential Consequences of Drug-Drug Interactions 27
III. Use of Information about Human P450s 29
IV. Mechanisms of Drug Interactions Attributable to P450s 30
V. Examples of P450-Based Interactions 35
VI. Other Issues 43
VII. Summary and Conclusions 45
References 46
Chapter 3. The Liver as a Target for Chemical–Chemical Interactions 56
I. Chemically Induced Tissue Injury 56
II. The Liver as a Target Organ for Chemically Induced Toxicity 58
III. Chemical–Chemical Interactions in the Liver 60
IV. Conclusions 77
References 79
Chapter 4. Application of Human Liver Microsomes in Metabolism–Based Drug–Drug Interactions: In Vitro–in Vivo Correlations and the Abbott Laboratories Experience 84
I. Introduction 84
II. The Utility of in Vitro Human Drug–Drug Interaction Studies in Drug Discovery and Development 87
III. In Vitro Drug–Drug Interaction Studies 88
IV. In Vitro–in Vivo Correlations 102
V. Conclusions 113
References 114
Chapter 5. Primary Hepatocyte Cultures as an in Vitro Experimental Model for the Evaluation of Pharmacokinetic Drug–Drug Interactions 122
I. Introduction 122
II. The Liver as an Important Organ for Drug–Drug Interaction Evaluation 123
III. Isolation, Culturing, and Cryopreservation of Hepatocytes 124
IV. Advantages of Primary Hepatocytes as an Experimental System: Intact Cell Properties 126
V. Validity of Primary Hepatocytes as an Experimental System for Drug Metabolism: in Vitro–in Vivo Correlation 129
VII. Application of Primary Human Hepatocytes in the Evaluation of Pharmacokinetic Drug–Drug Interactions 130
VIII. Primary Human Hepatocytes in Drug–Drug Interactions: Conclusion and Future Research Directions 143
References 146
Chapter 6. Liver Slices as a Model in Drug Metabolism 150
I. Introduction 150
II. Characteristics of Liver Slice Metabolism: Comparison with in Vivo 157
III. Metabolic Drug Stability: Pharmacokinetic Comparisons 167
IV. Prediction of Metabolic Drug–Drug Interactions 170
V. Conclusions 183
References 184
Chapter 7. Use of cDNA-Expressed Human Cytochrome P450 Enzymes to Study Potential Drug–Drug Interactions 190
I. Summary 190
II. Introduction 191
III. Methods 193
IV. Results and Discussion 195
V. Conclusions 204
References 204
Chapter 8. Pharmacokinetics of Drug Interactions 208
I. Introduction 208
II. Drug Interactions Affecting Absorption 209
III. Drug Interactions Affecting Distribution 212
IV. Drug Interactions Affecting Metabolism 213
V. Drug Interactions Affecting Excretion 219
VI. Drug Interactions during Liver Disease 219
VII. Genetic Factors in Drug Interactions 220
VIII. Beneficial Drug Interactions 220
References 221
Chapter 9. Experimental Models for Evaluating Enzyme Induction Potential of New Drug Candidates in Animals and Humans and a Strategy for Their Use 224
I. Purpose/Scope 224
II. Introduction 225
III. Rationale for Evaluating Enzyme Induction Potential during Drug Development 226
IV. Models Available for the Evaluation of Enzyme Induction in Animals and Humans 229
V. A Strategy for Evaluation of Enzyme Induction Potential of Drugs in Development 236
VI. Summary 238
References 239
Chapter 10. Metabolic Drug–Drug Interactions: Perspective from FDA Medical and Clinical Pharmacology Reviewers 250
I. Case Report 250
II. Assessment of in Vitro Drug Metabolism 251
III. In Vitro–in Vivo Correlation 254
IV. Conclusions 254
References 256
Chapter 11. Drug Interactions: Perspectives of the Canadian Drugs Directorate 258
I. Introduction 258
II. Current Regulatory Approach 261
III. New Initiatives 263
IV. Trends/Concerns 264
V. Regulatory Research in Drugs Directorate Laboratories: Case of Terfenadine–Drug Interactions 265
VI. General Comments on in Vitro Studies 268
VII. General Comments on Clinical Studies 270
VIII. Conclusion 271
References 271
Chapter 12. Overview of Experimental Approaches for Study of Drug Metabolism and Drug-Drug Interactions 274
I. Drug Metabolism and Drug Interactions 274
II. Drug-Metabolizing Enzymes 275
III. Species Differences 276
IV. Methods for Studying Drug Metabolism for Prediction of Drug Interactions 278
V. A Case Study with Taxol Metabolism 288
VI. Conclusions 289
References 290
Index 298
Contents of Previous Volumes 310