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Guidance for Industry drug interactions, in vitro and in vivo

By Randall Hill,2014-04-16 21:29
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Guidance for Industry drug interactions, in vitro and in vivo

    Draft Not for Implementation

    For Discussion Purposes Only

    Drug Interaction Studies

    Study Design, Data Analysis, and Implications

    for

    Dosing and Labeling

    PRELIMINARY CONCEPT PAPER

    For Discussion Purposes Only

    October 1, 2004

    Topic 2A_Concept_paper_drug interactions_Oct_1_2004_Huang_v1

    Draft Not for Implementation

    For Discussion Purposes Only

    TABLE OF CONTENTS

    I. INTRODUCTION .................................................................................................. 1

    II. BACKGROUND .................................................................................................... 2

     A. Metabolism ......................................................................................................... 2

     B. Drug-Drug Interactions ..................................................................................... 2

    III. GENERAL STRATEGIES .................................................................................... 5

     A. In Vitro Studies ................................................................................................... 5

     B. Specific In Vivo Clinical Investigations ............................................................. 6

     C. Population Pharmacokinetic Screens ................................................................ 6

IV. DESIGN OF IN VIVO DRUG-DRUG INTERACTION STUDIES .................... 6

     A. Study Design ....................................................................................................... 6

     B. Study Population ................................................................................................ 8

     C. Choice of Substrate and Interacting Drugs ....................................................... 8

     D. Route of Administration .................................................................................. 10

     E. Dose Selection ................................................................................................... 10

     F. Endpoints ......................................................................................................... 10

     G. Sample Size and Statistical Considerations ..................................................... 11

    V. LABELING IMPLICATIONS ........................................................................ 16

     A. Drug Metabolism ............................................................................................. 16

     B. Drug-Drug Interaction Studies ........................................................................ 16

VI. APPENDICES…………………………………………………………………..

    21

     A. Drug metabolizing enzyme identification including CYP

    enzymes………….21

     B. Evaluation of CYP

    inhibition…………………………………………………..27

     C. Evaluation of CYP

    induction…………………………………………………..31

VII.

    REFERENCES………………………………………………………………….34

Topic 2A_Concept_paper_drug interactions_Oct_1_2004_Huang_v1

    Draft Not for Implementation

    For Discussion Purposes Only

1 Concept paper for discussion purposes only

    2

    3 Drug Interaction Studies

    4 Study Design, Data Analysis, and Implications for Dosing and 5 Labeling

    6

    7 I. INTRODUCTION

    8

    9 This concept paper provides recommendations to sponsors of new drug applications (NDAs) and 10 biologics license applications (BLAs) for therapeutic biologics (hereafter drugs) who intend to 11 perform in vitro and in vivo drug metabolism and drug-drug interaction studies. The concept 12 paper reflects the Agency’s current view that the metabolism of an investigational new drug 13 should be defined during drug development and that its interactions with other drugs should be 14 explored as part of an adequate assessment of its safety and effectiveness. For drug-drug 15 interactions, the approaches considered in the concept paper are offered with the understanding 16 that the relevance of a particular study depends on the characteristics and proposed indication of 17 the drug under development. Furthermore, not every drug-drug interaction is metabolism-based, 18 but may arise from changes in pharmacokinetics caused by absorption, tissue and/or plasma 19 binding, distribution, and excretion interactions. Drug interactions related to transporters are 20 being documented with increasing frequency and are important to consider in drug development. 21 Although less well studied, drug-drug interactions may alter pharmacokinetic/pharmacodynamic 22 (PK/PD) relationships. These important areas are not considered in detail in this concept paper. 23

    24 Discussion of metabolic and other types of drug-drug interactions is provided in the following 25 CDER guidances, Drug Metabolism/Drug Interaction Studies in the Drug Development Process:

    26 Studies In Vitro (1997), In Vivo Drug Metabolism/Drug Interaction Studies Study Design, Data

    27 Analysis, and Recommendations for Dosing and Labeling (1999) and International Conference

    28 on Harmonisation (ICH) E8 General Considerations for Clinical Trials (December 1997), E7

    29 Studies in Support of Special Populations: Geriatrics (August 1994), and E3 Structure and

    30 Content of Clinical Study Reports (July 1996), and the Agency guidances Studying Drugs Likely

    31 to be Used in the Elderly (November 1989) and Study and Evaluation of Gender Differences in

    32 the Clinical Evaluation of Drugs (July 1993).

    33

    34

    35 II. BACKGROUND

    36

    37 A. Metabolism

    38

    39 The desirable and undesirable effects of a drug arising from its concentrations at the sites 40 of action are usually related either to the amount administered (dose) or to the resulting

     1

    Draft Not for Implementation

    For Discussion Purposes Only

    41 blood concentrations, which are affected by its absorption, distribution, metabolism and/or 42 excretion. Elimination of a drug or its metabolites occurs either by metabolism, usually by

    the liver or gut mucosa, or by excretion, usually by the kidneys and liver. In addition, 43

    44 protein therapeutics may be eliminated via a specific interaction with cell surface receptors, 45 followed by internalization and lysosomal degradation within the target cell. Hepatic 46 elimination occurs primarily by the cytochrome P450 family (CYP) of enzymes located in 47 the hepatic endoplasmic reticulum but may also occur by non-P450 enzyme systems, such 48 as N-acetyl and glucuronosyl transferases. Many factors can alter hepatic and intestinal 49 drug metabolism, including the presence or absence of disease and/or concomitant 50 medications. While most of these factors are usually relatively stable over time,

    concomitant medications can alter metabolism abruptly and are of particular concern. The 51

    52 influe