Drug-drug Interactions in Pharmaceutical Development

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ISBN: 9780471794417 | 0471794414
Cover: Hardcover
Copyright: 11/12/2007

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Drug-Drug Interactions in Pharmaceutical Development comprehensively reviews the relevant science, industrial practice, and regulatory agency positions on drug-drug interactions. It focuses on the evaluation of potential drug-drug interactions, allowing researchers to address risk factors before a drug is put to market. The book covers both clinical and nonclinical aspects for understanding drug-drug interactions as well as in vitro and in vivo studies for use in studying interactions at the drug discovery stage.

Preface	p. xi
Contributors	p. xiii
In Vitro Evaluation of Metabolic Drug-Drug Interactions: Concepts and Practice	p. 1
Introduction	p. 2
Mechanisms of Adverse Drug-Drug Interactions	p. 4
Pharmacological Interactions	p. 4
Pharmacokinetic Interactions	p. 5
Drug Metabolism	p. 5
Phase I Oxidation	p. 5
Phase II Conjugation	p. 5
CYP Isoforms	p. 7
Human In Vitro Experimental Systems for Drug Metabolism	p. 7
Hepatocytes	p. 8
Liver Postmitochondrial Supernatant (PMS)	p. 9
Human Liver Microsomes	p. 9
Recombinant P450 Isoforms (rCYP)	p. 9
Cytosol	p. 9
Mechanisms of Metabolic Drug-Drug Interactions	p. 9
Mechanism-Based Approach for Evaluation of Drug-Drug Interaction Potential	p. 10
Metabolic Phenotyping	p. 11
Evaluation of Inhibitory Potential for Drug-Metabolizing Enzymes	p. 11
Induction Potential for Drug-Metabolizing Enzymes	p. 11
Experimental Approaches for In Vitro Evaluation of Drug-Drug Interaction Potential	p. 11
Study 1: Metabolic Phenotyping 1-Metabolite Identification	p. 11
Study 2: Metabolic Phenotyping 2-Identification of Major Metabolic Pathways	p. 12
Study 3: Metabolic Phenotyping 3-Identification of P450 Isoform Pathways (P450 Phenotyping)	p. 13
Study 4: CYP Inhibitory Potential	p. 16
Study 5: Enzyme Induction Potential	p. 19
Study 6: In Vitro Empirical Drug-Drug Interactions	p. 22
Data Interpretation	p. 22
Pathway Evaluation	p. 22
P450 Inhibition	p. 23
P450 Induction	p. 24
Conclusion	p. 25
References	p. 26
In Vitro Approaches to Anticipating Clinical Drug Interactions	p. 31
In Vitro Systems for Human CYP450 Metabolism	p. 32
Incubation Buffer (pH and Ionic Strength)	p. 33
MgCl[subscript 2] and Cytochrome b[subscript 5]	p. 34
Nonspecific Binding	p. 34
Organic Solvents and Excipients	p. 35
Analysis of Data from In Vitro Systems	p. 36
Linear Transformation of Michaelis-Menten Equation (Lineweaver-Burk and Eadie-Hofstee)	p. 36
Nonlinear Regression Analysis of Hyperbolic Kinetic Data	p. 37
Consideration of Non-Michaelis-Menten Kinetics	p. 37
Use of In Vitro Kinetic Data to Predict In Vivo Clearance	p. 39
Calculation of In Vitro (Predicted) Hepatic Clearance	p. 40
Comparison of In Vitro (Predicted) with In Vivo Hepatic Clearance	p. 41
Use of In Vitro Kinetic Data to Predict Drug-Drug Interactions	p. 43
Choice of Probe Substrates for Inhibition Studies	p. 43
Determining the Mechanism of CYP450 Inhibition	p. 46
Prediction of In Vivo Drug-Drug Inhibition Interactions from In Vitro Data	p. 53
Consideration of Non-CYP Enzymatic Systems	p. 58
Flavin-Containing Monooxygenase (FMO)	p. 58
UDP-glucuronosyltransferase (UGT)	p. 59
Sulfotransferase (SULT)	p. 61
N-Acetyltransferase (NAT)	p. 61
Methyltransferase	p. 62
Epoxidase Hydrolase	p. 62
Aldehyde Oxidase and Dehydrogenase	p. 63
Glutathione-S-transferase (GST)	p. 63
Summary	p. 63
Acknowledgments	p. 64
References	p. 64
Inhibition of Drug-Metabolizing Enzymes and Drug-Drug Interactions in Drug Discovery and Development	p. 75
Introduction	p. 76
Laboratory Approaches Inhibiting Drug-Metabolizing Enzymes	p. 76
Analytical Method	p. 77
Determination of Linearity of Velocity	p. 77
Substrate Saturation Experiment	p. 80
Reversible Inhibition Experiments: K[subscript i]	p. 81
Reversible Inhibition Experiments: IC[subscript 50]	p. 84
Selection of Substrates for Inhibition Experiments in Drug Metabolism	p. 85
Inhibition of Drug-Metabolizing Enzymes in Drug Discovery and Development	p. 87
Inhibition Experiments in Early Drug Discovery	p. 87
Inhibition Experiments in Late Drug Discovery	p. 89
Inhibition Experiments During Drug Development	p. 90
Summary	p. 90
References	p. 91
Mechanism-Based CYP Inhibition: Enzyme Kinetics, Assays, and Prediction of Human Drug-Drug Interactions	p. 95
Kinetic Model for Mechanism-Based Inhibition	p. 97
Methodological Measurements of Kinetic Parameters	p. 99
Incubation	p. 100
CYP Isoform-Specific Assays	p. 100
General Incubation Procedure and Sample Preparation	p. 100
LC-MS-MS Analysis	p. 100
Data Analysis	p. 102
Prediction of Human DDIs from In Vitro MBI Data	p. 103
Acknowledgments	p. 108
References	p. 108
Genomic Approaches To Drug-Drug Interactions	p. 113
Introduction	p. 113
DNA Microarrays	p. 114
Array Platforms	p. 115
Gene Expression Profiling Using Microarray	p. 115
Genotyping Using Microarray	p. 117
Genomic Application Toward the Prediction of DDIs	p. 117
Gene Expression Profiling of Compound Mixtures	p. 118
Expression Profiling of DMEs and Transporters	p. 118
Identification of Gene Expression Patterns Indicative of DDIs	p. 120
Genomics Approach to Decipher the Molecular Basis of DDI: Nuclear Receptors	p. 121
Genomic Approaches to Address the Genetic Variability in DDIs	p. 122
Conclusion	p. 124
References	p. 124
Transporters and Drug Interactions	p. 131
Introduction	p. 131
Interactions Involving Liver Transporters	p. 132
Role of Transporters in the Biliary Excretion of Drugs	p. 132
Transporter-Mediated DDIs in the Process of Hepatobilary Excretion	p. 137
Transporters as a Determinant of Metabolic Rate	p. 141
Interactions in Intestine Transporters	p. 143
Role of Transporters in Intestinal Absorption	p. 143
Examples of Transporter-Mediated DDIs in the Process of Intestinal Absorption	p. 144
Drug Toxicity Involving Drug Transporters	p. 148
Drugs that Affect the Expression or Localization of Transporters	p. 149
Conclusion	p. 151
References	p. 151
Transporter-Mediated Drug Interactions: Molecular Mechanisms and Clinical Implications	p. 159
Introduction	p. 159
Tissue Distribution and Cellular Location of Transporters	p. 161
Small Intestine	p. 161
Liver	p. 165
Kidney	p. 167
Brain	p. 170
Molecular Mechanisms for Transporter Inhibition and Induction	p. 172
Inhibition of Transporters	p. 173
Induction of Transporters	p. 174
Drug Interactions Caused by Transporter Inhibition and Induction	p. 176
Direct Evidence	p. 176
Circumstantial Evidence	p. 178
Clinical Significance of Transporter-Mediated Drug Interactions	p. 183
Conclusion	p. 184
References	p. 185
Recent Case Studies of Clinically Significant Drug-Drug Interactions and the Limits of In Vitro Prediction Methodology	p. 195
Introduction	p. 195
Case Studies	p. 196
Interaction Between Repaglinide and Gemfibrozil + Itraconazole	p. 196
Interaction Between Ramelteon and Fluvoxamine	p. 198
References	p. 199
U.S. Regulatory Perspective: Drug-Drug Interactions	p. 201
Introduction	p. 202
An Integrated Approach	p. 202
Methods for Evaluating Metabolic Clearance In Vitro	p. 204
CYP Reaction Phenotyping	p. 204
CYP Inhibition	p. 206
CYP Induction	p. 208
Other Metabolic Enzymes	p. 209
Transporters	p. 209
GLP Versus Non-GLP Studies	p. 210
In Vivo Approaches	p. 211
Study Design	p. 211
Data Analysis and Sample Size Consideration	p. 214
Classification of Inhibitors and Labeling Considerations	p. 214
Cocktail Approaches	p. 216
P-gp and Other Transporters	p. 216
Clinical Cases	p. 216
Regulatory Considerations	p. 217
Labeling	p. 219
Summary	p. 220
References	p. 221
Herbal Drug Interactions-A Canadian Perspective	p. 227
Introduction	p. 227
Interaction Risk Determination	p. 229
NHP Products	p. 231
NHP Characterization	p. 232
Disposition	p. 234
PD and PK interactions	p. 235
Choice of Substance Concentration Range	p. 236
Role of Animal Studies	p. 236
Human Clinical Studies	p. 237
Action	p. 239
References	p. 240
Index	p. 241
Wiley Series in Drug Discovery and Development	p. 244
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