Drug-Drug Interactions in Pharmaceutical Development / Edition 1

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Addressing the potential for adverse interactions among coadministered drugs before marketing a new drug can save time, money, and lives. In this reference, distinguished international experts comprehensively review the issues, relevant science, industrial practice, and regulatory agency positions on drug-drug interactions. Focusing on evaluation during the drug discovery process, Drug-Drug Interactions in Pharmaceutical Development: Details the major scientific concepts and preclinical experimental approaches, Covers both clinical and nonclinical aspects, Discusses in vitro and in vivo methodologies, Covers genomic approaches, Addresses U.S., European, and Japanese regulations, Includes a chapter on herbal drug interactions.

Compiling current information into one accessible resource, this is an excellent reference for industrial scientists and regulatory specialists in drug development as well as academic researchers and students in the fields of pharmacology, drug metabolism, and toxicology.

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Editorial Reviews

From the Publisher
"I am pleased to have read this book from cover-to-cover. I will value owning it and keep it near the front of my bookshelf" (Good Clinical Practice Journal, June 2008)
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Product Details

Meet the Author

Albert P. Li is the President and CEO of In Vitro ADMET Laboratories, LLC (www.invitroadmet.com), and Advanced Pharmaceutical Sciences, Inc. (www.apsciences.com), and the cofounder, Chairman, and CSO of the ADMET Group (www.admetgroup.com). Dr. Li has over twenty-five years in the drug development industry, is a distinguished international speaker in the field, and has over 150 publications. He has edited several books.
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Table of Contents

Preface     xi
Contributors     xiii
In Vitro Evaluation of Metabolic Drug-Drug Interactions: Concepts and Practice   Albert P. Li     1
Introduction     2
Mechanisms of Adverse Drug-Drug Interactions     4
Pharmacological Interactions     4
Pharmacokinetic Interactions     5
Drug Metabolism     5
Phase I Oxidation     5
Phase II Conjugation     5
CYP Isoforms     7
Human In Vitro Experimental Systems for Drug Metabolism     7
Hepatocytes     8
Liver Postmitochondrial Supernatant (PMS)     9
Human Liver Microsomes     9
Recombinant P450 Isoforms (rCYP)     9
Cytosol     9
Mechanisms of Metabolic Drug-Drug Interactions     9
Mechanism-Based Approach for Evaluation of Drug-Drug Interaction Potential     10
Metabolic Phenotyping     11
Evaluation of Inhibitory Potential for Drug-Metabolizing Enzymes     11
Induction Potential for Drug-Metabolizing Enzymes     11
Experimental Approaches for In Vitro Evaluation of Drug-Drug Interaction Potential     11
Study 1: Metabolic Phenotyping 1-Metabolite Identification     11
Study2: Metabolic Phenotyping 2-Identification of Major Metabolic Pathways     12
Study 3: Metabolic Phenotyping 3-Identification of P450 Isoform Pathways (P450 Phenotyping)     13
Study 4: CYP Inhibitory Potential     16
Study 5: Enzyme Induction Potential     19
Study 6: In Vitro Empirical Drug-Drug Interactions     22
Data Interpretation     22
Pathway Evaluation     22
P450 Inhibition     23
P450 Induction     24
Conclusion     25
References     26
In Vitro Approaches to Anticipating Clinical Drug Interactions   Laurie P. Volak   David J. Greenblatt   Lisa L. von Moltke     31
In Vitro Systems for Human CYP450 Metabolism     32
Incubation Buffer (pH and Ionic Strength)     33
MgCl[subscript 2] and Cytochrome b[subscript 5]     34
Nonspecific Binding     34
Organic Solvents and Excipients     35
Analysis of Data from In Vitro Systems     36
Linear Transformation of Michaelis-Menten Equation (Lineweaver-Burk and Eadie-Hofstee)     36
Nonlinear Regression Analysis of Hyperbolic Kinetic Data     37
Consideration of Non-Michaelis-Menten Kinetics     37
Use of In Vitro Kinetic Data to Predict In Vivo Clearance     39
Calculation of In Vitro (Predicted) Hepatic Clearance     40
Comparison of In Vitro (Predicted) with In Vivo Hepatic Clearance     41
Use of In Vitro Kinetic Data to Predict Drug-Drug Interactions     43
Choice of Probe Substrates for Inhibition Studies     43
Determining the Mechanism of CYP450 Inhibition     46
Prediction of In Vivo Drug-Drug Inhibition Interactions from In Vitro Data     53
Consideration of Non-CYP Enzymatic Systems     58
Flavin-Containing Monooxygenase (FMO)     58
UDP-glucuronosyltransferase (UGT)     59
Sulfotransferase (SULT)     61
N-Acetyltransferase (NAT)     61
Methyltransferase     62
Epoxidase Hydrolase     62
Aldehyde Oxidase and Dehydrogenase     63
Glutathione-S-transferase (GST)     63
Summary     63
Acknowledgments     64
References     64
Inhibition of Drug-Metabolizing Enzymes and Drug-Drug Interactions in Drug Discovery and Development   R. Scott Obach     75
Introduction     76
Laboratory Approaches Inhibiting Drug-Metabolizing Enzymes     76
Analytical Method     77
Determination of Linearity of Velocity     77
Substrate Saturation Experiment     80
Reversible Inhibition Experiments: K[subscript i]     81
Reversible Inhibition Experiments: IC[subscript 50]     84
Selection of Substrates for Inhibition Experiments in Drug Metabolism     85
Inhibition of Drug-Metabolizing Enzymes in Drug Discovery and Development     87
Inhibition Experiments in Early Drug Discovery     87
Inhibition Experiments in Late Drug Discovery     89
Inhibition Experiments During Drug Development     90
Summary     90
References     91
Mechanism-Based CYP Inhibition: Enzyme Kinetics, Assays, and Prediction of Human Drug-Drug Interactions   Magang Shou     95
Kinetic Model for Mechanism-Based Inhibition     97
Methodological Measurements of Kinetic Parameters     99
Incubation     100
CYP Isoform-Specific Assays     100
General Incubation Procedure and Sample Preparation     100
LC-MS-MS Analysis     100
Data Analysis     102
Prediction of Human DDIs from In Vitro MBI Data     103
Acknowledgments     108
References     108
Genomic Approaches To Drug-Drug Interactions    Yi Yang   Jeffrey F. Waring     113
Introduction     113
DNA Microarrays     114
Array Platforms     115
Gene Expression Profiling Using Microarray     115
Genotyping Using Microarray     117
Genomic Application Toward the Prediction of DDIs     117
Gene Expression Profiling of Compound Mixtures     118
Expression Profiling of DMEs and Transporters     118
Identification of Gene Expression Patterns Indicative of DDIs     120
Genomics Approach to Decipher the Molecular Basis of DDI: Nuclear Receptors     121
Genomic Approaches to Address the Genetic Variability in DDIs     122
Conclusion     124
References     124
Transporters and Drug Interactions   Yoshihisa Shitara   Toshiharu Horie   Yuichi Sugiyama     131
Introduction     131
Interactions Involving Liver Transporters     132
Role of Transporters in the Biliary Excretion of Drugs     132
Transporter-Mediated DDIs in the Process of Hepatobilary Excretion     137
Transporters as a Determinant of Metabolic Rate     141
Interactions in Intestine Transporters     143
Role of Transporters in Intestinal Absorption     143
Examples of Transporter-Mediated DDIs in the Process of Intestinal Absorption     144
Drug Toxicity Involving Drug Transporters     148
Drugs that Affect the Expression or Localization of Transporters     149
Conclusion     151
References     151
Transporter-Mediated Drug Interactions: Molecular Mechanisms and Clinical Implications   Jiunn H. Lin     159
Introduction     159
Tissue Distribution and Cellular Location of Transporters     161
Small Intestine     161
Liver     165
Kidney     167
Brain     170
Molecular Mechanisms for Transporter Inhibition and Induction     172
Inhibition of Transporters     173
Induction of Transporters     174
Drug Interactions Caused by Transporter Inhibition and Induction     176
Direct Evidence     176
Circumstantial Evidence     178
Clinical Significance of Transporter-Mediated Drug Interactions     183
Conclusion     184
References     185
Recent Case Studies of Clinically Significant Drug-Drug Interactions and the Limits of In Vitro Prediction Methodology   Rene H. Levy   Isabelle Ragueneau-Majlessi   Carol Collins     195
Introduction     195
Case Studies     196
Interaction Between Repaglinide and Gemfibrozil + Itraconazole     196
Interaction Between Ramelteon and Fluvoxamine     198
References     199
U.S. Regulatory Perspective: Drug-Drug Interactions   John Strong   Shiew-Mei Huang     201
Introduction     202
An Integrated Approach     202
Methods for Evaluating Metabolic Clearance In Vitro     204
CYP Reaction Phenotyping     204
CYP Inhibition     206
CYP Induction     208
Other Metabolic Enzymes     209
Transporters     209
GLP Versus Non-GLP Studies     210
In Vivo Approaches     211
Study Design     211
Data Analysis and Sample Size Consideration     214
Classification of Inhibitors and Labeling Considerations     214
Cocktail Approaches     216
P-gp and Other Transporters     216
Clinical Cases     216
Regulatory Considerations     217
Labeling     219
Summary     220
References      221
Herbal Drug Interactions-A Canadian Perspective   Brian C. Foster     227
Introduction     227
Interaction Risk Determination     229
NHP Products     231
NHP Characterization     232
Disposition     234
PD and PK interactions     235
Choice of Substance Concentration Range     236
Role of Animal Studies     236
Human Clinical Studies     237
Action     239
References     240
Index     241
Wiley Series in Drug Discovery and Development     244
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