Guidance for Industry
`
`Drug Interaction Studies —
`Study Design, Data Analysis, and
`Implications for Dosing and Labeling
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`DRAFT GUIDANCE
`This guidance document is being distributed for comment purposes only.
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`Comments and suggestions regarding this draft document should be submitted within 60 days of
`publication in the Federal Register of the notice announcing the availability of the draft
`guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and
`Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments
`should be identified with the docket number listed in the notice of availability that publishes in
`the Federal Register.
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`For questions regarding this draft document contact (CDER) Shiew-Mei Huang, 301-796-1541,
`or (CBER) Toni Stifano, 301-827-6190.
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`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`
`September 2006
`Clinical Pharmacology
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`TEVA1041
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`Guidance for Industry
`Drug Interaction Studies —
`Study Design, Data Analysis, and
`Implications for Dosing and Labeling
`
`
`
`Additional copies are available from:
`
`Office of Training and Communications
`Division of Drug Information, HFD-240
`Center for Drug Evaluation and Research
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, MD 20857
`(Tel) 301-827-4573
`http://www.fda.gov/cder/guidance/index.htm
`
`or
`
` Office of Communication, Training and
`Manufacturers Assistance, HFM-40
`Center for Biologics Evaluation and Research
` Food and Drug Administration
`1401 Rockville Pike, Rockville, MD 20852-1448
` http://www.fda.gov/cber/guidelines.htm
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`
`September 2006
`Clinical Pharmacology
`
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`I.
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`TABLE OF CONTENTS
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`INTRODUCTION..............................................................................................................................................1
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`II. BACKGROUND ................................................................................................................................................2
`A. METABOLISM...................................................................................................................................................2
`B. DRUG-DRUG INTERACTIONS ............................................................................................................................2
`III. GENERAL STRATEGIES ...............................................................................................................................4
`A.
`IN VITRO STUDIES............................................................................................................................................4
`SPECIFIC IN VIVO CLINICAL INVESTIGATIONS..................................................................................................5
`B.
`POPULATION PHARMACOKINETIC SCREENS .....................................................................................................6
`C.
`IV. DESIGN OF IN VIVO DRUG-DRUG INTERACTION STUDIES .............................................................6
`A.
`STUDY DESIGN.................................................................................................................................................6
`STUDY POPULATION.........................................................................................................................................8
`B.
`C. CHOICE OF SUBSTRATE AND INTERACTING DRUGS ..........................................................................................8
`D. ROUTE OF ADMINISTRATION..........................................................................................................................12
`E. DOSE SELECTION ...........................................................................................................................................12
`ENDPOINTS.....................................................................................................................................................13
`F.
`SAMPLE SIZE AND STATISTICAL CONSIDERATIONS ........................................................................................14
`G.
`V. LABELING IMPLICATIONS .......................................................................................................................15
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`APPENDIX A TABLES............................................................................................................................................17
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`APPENDIX B FIGURES..........................................................................................................................................24
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`APPENDIX C-1 IN VITRO DRUG METABOLIZING ENZYME IDENTIFICATION ..................................25
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`APPENDIX C-2 IN VITRO EVALUATION OF CYP INHIBITORS.................................................................31
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`APPENDIX C-3 IN VITRO EVALUATION OF CYP INDUCTION..................................................................35
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`APPENDIX D IN VITRO EVALUATION OF P-GLYCOPROTEIN (P-GP, MDR1) SUBSTRATES AND
`INHIBITORS.............................................................................................................................................................38
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`REFERENCES ..........................................................................................................................................................51
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`Contains Nonbinding Recommendations
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`Draft – Not for Implementation
`Guidance for Industry1
`
`Drug Interaction Studies — Study Design, Data Analysis, and
`Implications for Dosing and Labeling
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`
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`INTRODUCTION
`
`
`This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's)
`current thinking on this topic. It does not create or confer any rights for or on any person and does
`not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies
`the requirements of the applicable statutes and regulations. If you want to discuss an alternative
`approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify
`the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.
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`
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`I.
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`This guidance provides recommendations for sponsors of new drug applications (NDAs) and
`biologics license applications (BLAs) for therapeutic biologics2 who are performing in vitro
`and in vivo drug metabolism, drug transport, and drug-drug interaction studies. The
`guidance reflects the Agency’s current view that the metabolism of an investigational new
`drug should be defined during drug development and that its interactions with other drugs
`should be explored as part of an adequate assessment of its safety and effectiveness. For
`drug-drug interactions, the approaches considered in the guidance are offered with the
`understanding that the relevance of a particular study depends on the characteristics and
`proposed indication of the drug under development. Furthermore, not every drug-drug
`interaction is metabolism-based, but may arise from changes in pharmacokinetics caused by
`absorption, distribution, and excretion interactions. Drug-drug interactions related to
`transporters are being documented with increasing frequency and are important to consider in
`drug development. Although less well studied, drug-drug interactions may alter
`pharmacokinetic/pharmacodynamic (PK/PD) relationships. These important areas are not
`considered in detail in this guidance.
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`Discussion of metabolic and other types of drug-drug interactions is also provided in other
`guidances, including the International Conference on Harmonization (ICH) E7 Studies in
`Support of Special Populations: Geriatrics, and E3 Structure and Content of Clinical Study
`Reports, and FDA guidances for industry on Studying Drugs Likely to be Used in the Elderly
`and Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs.
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`1 This guidance has been prepared by the Drug-Drug Interaction Working Group in the Clinical Pharmacology
`Section of the Medical Policy Coordinating Committee in the Center for Drug Evaluation and Research, with
`input from the Center for Biologics Evaluation and Research, at the Food and Drug Administration.
`2 For more information on what constitutes a therapeutic biologic product, please see Internet site
`http://www.fda.gov/cder/biologics/qa.htm.
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`Contains Nonbinding Recommendations
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`Draft – Not for Implementation
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`BACKGROUND
`
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`FDA’s guidance documents, including this guidance, do not establish legally enforceable
`responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and
`should be viewed only as recommendations, unless specific regulatory or statutory
`requirements are cited. The use of the word should in Agency guidances means that
`something is suggested or recommended, but not required.
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`II.
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`A. Metabolism
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`The desirable and undesirable effects of a drug arising from its concentrations at the sites of
`action are usually related either to the amount administered (dose) or to the resulting blood
`concentrations, which are affected by its absorption, distribution, metabolism, and/or
`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,
`protein therapeutics may be eliminated through a specific interaction with cell surface
`receptors, followed by internalization and lysosomal degradation within the target cell.
`Hepatic elimination occurs primarily by the cytochrome P450 family (CYP) of enzymes
`located in the hepatic endoplasmic reticulum, but may also occur by non-P450 enzyme
`systems, such as N-acetyl and glucuronosyl transferases. Many factors can alter hepatic and
`intestinal drug metabolism, including the presence or absence of disease and/or concomitant
`medications, or even some foods, such as grapefruit juice. While most of these factors are
`usually relatively stable over time, concomitant medications can alter metabolism abruptly
`and are of particular concern. The influence of concomitant medications on hepatic and
`intestinal metabolism becomes more complicated when a drug, including a prodrug, is
`metabolized to one or more active metabolites. In this case, the safety and efficacy of the
`drug/prodrug are determined not only by exposure to the parent drug but by exposure to the
`active metabolites, which in turn is related to their formation, distribution, and elimination.
`Therefore, adequate assessment of the safety and effectiveness of a drug includes a
`description of its metabolism and the contribution of metabolism to overall elimination. For
`this reason, the development of sensitive and specific assays for a drug and its important
`metabolites is critical to the study of metabolism and drug-drug interactions.
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`B.
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`Drug-Drug Interactions
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`1.
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`Metabolism-Based Drug-Drug Interactions
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`Many metabolic routes of elimination, including most of those occurring through the
`P450 family of enzymes, can be inhibited or induced by concomitant drug treatment.
`Observed changes arising from metabolic drug-drug interactions can be substantial —
`an order of magnitude or more decrease or increase in the blood and tissue
`concentrations of a drug or metabolite — and can include formation of toxic and/or
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`Contains Nonbinding Recommendations
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`Draft – Not for Implementation
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`active metabolites or increased exposure to a toxic parent compound. These large
`changes in exposure can alter the safety and efficacy profile of a drug and/or its
`active metabolites in important ways. This is most obvious and expected for a drug
`with a narrow therapeutic range (NTR), but is also possible for non-NTR drugs as
`well (e.g., HMG CoA reductase inhibitors).
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`It is important that metabolic drug-drug interaction studies explore whether an
`investigational agent is likely to significantly affect the metabolic elimination of
`drugs already in the marketplace and likely in medical practice to be taken
`concomitantly and, conversely, whether drugs in the marketplace are likely to affect
`the metabolic elimination of the investigational drug. Even drugs that are not
`substantially metabolized can have important effects on the metabolism of
`concomitant drugs. For this reason, metabolic drug-drug interactions should be
`explored, even for an investigational compound that is not eliminated significantly by
`metabolism.
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`Classical biotransformation studies are not a general requirement for the evaluation of
`therapeutic biologics (ICH guidance S6 Preclinical Safety Evaluation of
`Biotechnology-Derived Pharmaceuticals), although certain protein therapeutics
`modify the metabolism of drugs that are metabolized by the P450 enzymes. Type I
`interferons, for example, inhibit CYP1A2 production at the transcriptional and post-
`translational levels, inhibiting clearance of theophylline. The increased clinical use
`of therapeutic proteins may raise concerns regarding the potential for their impacts on
`drug metabolism. Generally, these interactions cannot be detected by in vitro
`assessment. Consultation with FDA is appropriate before initiating metabolic drug-
`drug interaction studies involving biologics.
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`Identifying metabolic differences in patient groups based on genetic polymorphism,
`or on other readily identifiable factors, such as age, race, and gender, can aid in
`interpreting results. The extent of interactions may be defined by these variables
`(e.g., CYP2D6 genotypes). Further, in subjects who lack the major clearance
`pathway, remaining pathways become important and should be understood and
`examined.
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`A specific objective of metabolic drug-drug interaction studies is to determine
`whether the interaction is sufficiently large to necessitate a dosage adjustment of the
`drug itself or the drugs with which it might be used, or whether the interaction would
`require additional therapeutic monitoring.
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`In some instances, understanding how to adjust dose or dosage regimen in the
`presence of an interacting drug, or how to avoid interactions, may allow marketing of
`a drug that would otherwise have been associated with an unacceptable level of
`toxicity. Sometimes a drug interaction can be used intentionally to increase levels or
`reduce elimination of another drug (e.g., ritonavir and lopinavir). Rarely, the degree
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`of interaction caused by a drug, or the degree to which other drugs alter its
`metabolism, can be such that it cannot be marketed safely.
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`Transporter-Based Drug-Drug Interactions
`2.
`Transporter-based interactions have been increasingly documented. Examples of
`these include the inhibition or induction of transport proteins, such as P-glycoprotein
`(P-gp), organic anion transporter (OAT), organic anion transporting polypeptide
`(OATP), organic cation transporter (OCT), multidrug resistance-associated proteins
`(MRP), and breast cancer resistant protein (BCRP). Examples of transporter-based
`interactions include the interactions between digoxin and quinidine, fexofenadine and
`ketoconazole (or erythromycin), penicillin and probenecid, and dofetilide and
`cimetidine. Of the various transporters, P-gp is the most well understood and may be
`appropriate to evaluate during drug development. Table 1 in Appendix A lists some
`of the major human transporters and known substrates, inhibitors, and inducers.
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`
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`III. GENERAL STRATEGIES
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`To the extent possible, drug development should follow a sequence in which early in vitro
`and in vivo investigations can either fully address a question of interest or provide
`information to guide further studies. Optimally, a sequence of studies could be planned,
`moving from in vitro studies to in vivo human studies, including those employing special
`study designs and methodologies where appropriate. In many cases, negative findings from
`early in vitro and early clinical studies can eliminate the need for later clinical investigations.
`Early investigations should explore whether a drug is eliminated primarily by excretion or
`metabolism, with identification of the principal metabolic routes in the latter case. Using
`suitable in vitro probes and careful selection of interacting drugs for early in vivo studies, the
`potential for drug-drug interactions can be studied early in the development process, with
`further study of observed interactions assessed later in the process, as needed. These early
`studies can also provide information about dose, concentration, and response relationships in
`the general population, specific populations, and individuals, which can be useful in
`interpreting the consequences of a drug-drug interaction. Once potential drug-drug
`interactions have been identified, based on in vitro and/or in vivo studies, sponsors are
`encouraged to design and examine the safety and efficacy databases of larger clinical studies,
`as feasible, to (1) permit confirmation/discovery of the interactions predicted from earlier
`studies and/or (2) verify that dosage adjustments or other prescribing modifications made in
`response to the potential interaction(s) have been adequate to avoid undesired consequences
`of the drug-drug interaction.
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`A.
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`A complete understanding of the quantitative relationship between the in vitro findings and
`in vivo results of metabolism/drug-drug interaction studies is still emerging. Nonetheless, in
`vitro studies can frequently serve as a screening mechanism to rule out the importance of a
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`In Vitro Studies
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`metabolic pathway and the drug-drug interactions that occur through this pathway so that
`subsequent in vivo testing is unnecessary. This opportunity should be based on appropriately
`validated experimental methods and rational selection of substrate/interacting drug
`concentrations.
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`For example, if suitable in vitro studies at therapeutic concentrations indicate that CYP1A2,
`CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A enzyme systems do not metabolize an
`investigational drug, then clinical studies to evaluate the effect of CYP2D6 inhibitors or
`CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP3A inhibitors/inducers on the elimination
`of the investigational drug will not be needed.
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`Similarly, if in vitro studies indicate that an investigational drug does not inhibit CYP1A2,
`CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A metabolism, then corresponding in vivo
`inhibition-based interaction studies of the investigational drug and concomitant medications
`eliminated by these pathways are not needed. Figure 1 in Appendix B shows a decision tree
`on when in vivo interaction studies are indicated based on in vitro metabolism, inhibition,
`and induction and in vivo metabolism data.
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`The CYP2D6 enzyme has not been shown to be inducible. Recent data have shown co-
`induction of CYP2C, CYP2B and ABCB1 (P-gp) transporter with CYP3A. CYP3A appears
`to be sensitive to all known co-inducers. Therefore, to evaluate whether an investigational
`drug induces CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP3A, the initial in vitro
`induction evaluation may include only CYP1A2 and CYP3A. If in vitro studies indicate that
`an investigational drug does not induce CYP3A metabolism, then in vivo induction-based
`interaction studies of the investigational drug and concomitant medications eliminated by
`CYP2C/CYP2B and CYP3A may not be needed.
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`Drug interactions based on CYP2B6 are emerging as important interactions. When
`appropriate, in vitro evaluations based on this enzyme can be conducted. Other CYP
`enzymes, including CYP2A6 and CYP2E1, are less likely to be involved in clinically
`important drug interactions, but should be considered when appropriate.
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`Appendix C describes general considerations in the in vitro evaluation of CYP-related
`metabolism and interactions. Appendices C-1, C-2, and C-3 provide considerations in the
`experimental design, data analysis, and data interpretation in drug metabolizing enzyme
`identification, including CYP enzymes (new drug as a substrate), CYP inhibition (new drug
`as an inhibitor), and CYP induction (new drug as an inducer), respectively. Appendix D
`describes general considerations in the in vitro evaluation of P-gp substrates and inhibitors.
`Figures 1 and 2 in Appendix D provide decision trees on when in vivo P-gp based interaction
`studies are indicated based on in vitro evaluation.
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`B.
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`In addition to in vitro metabolism and drug-drug interaction studies, appropriately designed
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`Specific In Vivo Clinical Investigations
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`Population Pharmacokinetic Screens
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`Draft – Not for Implementation
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`pharmacokinetic studies, usually performed in the early phases of drug development, can
`provide important information about metabolic routes of elimination, their contribution to
`overall elimination, and metabolic drug-drug interactions. Together with information from in
`vitro studies, these in vivo investigations can be a primary basis of labeling statements and
`can often help avoid the need for further investigations. Further recommendations about
`these types of studies appear in section IV of this guidance.
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`C.
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`Population pharmacokinetic analyses of data obtained from large-scale clinical studies with
`sparse or intensive blood sampling can be valuable in characterizing the clinical impact of
`known or newly identified interactions, and in making recommendations for dosage
`modifications. The results from such analyses can be informative and sometimes conclusive
`when the clinical studies are adequately designed to detect significant changes in drug
`exposure due to drug-drug interactions. Simulations can provide valuable insights into
`optimizing the study design. Population pharmacokinetic evaluations may detect
`unsuspected drug-drug interactions. Population analysis can also provide further evidence of
`the absence of a drug-drug interaction when this is supported by prior evidence and
`mechanistic data. However, it is unlikely that population analysis can be used to prove the
`absence of an interaction that is strongly suggested by information arising from in vivo
`studies specifically designed to assess a drug-drug interaction. To be optimally informative,
`population pharmacokinetic studies should have carefully designed study procedures and
`sample collections. A guidance for industry on population pharmacokinetics is available
`(Ref. 11).
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`IV. DESIGN OF IN VIVO DRUG-DRUG INTERACTION STUDIES
`
`If in vitro studies and other information suggest that in vivo drug-drug interaction studies
`would be helpful (e.g., based on Figure 1 in Appendix B), the following general issues and
`approaches should be considered. Consultation with FDA regarding study protocols is
`recommended. In the following discussion, the term substrate (S) is used to indicate the
`drug studied to determine whether its exposure is changed by another drug, termed the
`interacting drug (I). Depending on the study objectives, the substrate and the interacting
`drug can be the investigational agents or approved products.
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`A.
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`In vivo drug-drug interaction studies generally are designed to compare substrate
`concentrations with and without the interacting drug. Because a specific study can consider
`a number of questions and clinical objectives, many study designs for studying drug-drug
`interactions can be considered. A study can use a randomized crossover (e.g., S followed by
`S+I, S+I followed by S), a one-sequence crossover (e.g., S always followed by S+I or the
`reverse), or a parallel design (S in one group of subjects and S+I in another). The following
`possible dosing regimen combinations for a substrate and interacting drug can also be used:
`
`Study Design
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`single dose/single dose, single dose/multiple dose, multiple dose/single dose, and multiple
`dose/multiple dose. The selection of one of these or another study design depends on a
`number of factors for both the substrate and interacting drug, including (1) acute or chronic
`use of the substrate and/or interacting drug; (2) safety considerations, including whether a
`drug is likely to be an NTR (narrow therapeutic range) or non-NTR drug; (3)
`pharmacokinetic and pharmacodynamic characteristics of the substrate and interacting drugs;
`and (4) assessment of induction as well as inhibition. The inhibiting/inducing drugs and the
`substrates should be dosed so that the exposures of both drugs are relevant to their clinical
`use, including the highest doses likely to be used. Simulations can be helpful in selecting an
`appropriate study design. The following considerations may be useful:
`
`•
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`When attainment of steady state is important and either the substrate or interacting
`drugs and/or their metabolites have long half-lives and a loading dose to reach steady
`state promptly cannot be used, special approaches may be needed. These include the
`selection of a one-sequence crossover or a parallel design, rather than a randomized
`crossover study design.
`
`When it is important that a substrate and/or an interacting drug be studied at steady
`state because the effect of an interacting drug is delayed, as is the case for inducers
`and certain inhibitors, documentation that near steady state has been attained for the
`pertinent drug and metabolites of interest is critical. This documentation can be
`accomplished by sampling over several days prior to the periods when test samples
`are collected. This is important for both metabolites and the parent drug, particularly
`when the half-life of the metabolite is longer than the parent, and is especially
`important if both parent drug and metabolites are metabolic inhibitors or inducers.
`
`Studies can usually be open label (unblinded), unless pharmacodynamic endpoints
`(e.g., adverse events that are subject to bias) are critical to the assessment of the
`interaction.
`
`For a rapidly reversible inhibitor, administration of the interacting drug either just
`before or simultaneously with the substrate on the test day might increase sensitivity.
`For a mechanism-based inhibitor (a drug that requires metabolism prior to its
`inactivation of the enzyme; examples include erythromycin), administration of the
`inhibitor prior to the administration of the substrate drug can maximize the effect. If
`the absorption of an interacting drug (e.g., an inhibitor or an inducer) may be affected
`by other factors (e.g., the gastric pH), it may be appropriate to control the variables
`and confirm the absorption through plasma level measurements of the interacting
`drug.
`
`When the effects of two drugs on one another are of interest, the potential for
`interactions can be evaluated in a single study or two separate studies. Some design
`options are randomized three-period crossover, parallel group, and one-sequence
`crossover.
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`B.
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`Clinical drug-drug interaction studies can generally be performed using healthy volunteers.
`Findings in this population should predict findings in the patient population for which the
`drug is intended. Safety considerations may preclude the use of healthy subjects, however,
`and in certain circumstances, subjects drawn from the population of patients for whom the
`investigational drug is intended offer advantages, including the opportunity to study
`pharmacodynamic endpoints not present in healthy subjects. Performance of phenotype or
`genotype determinations to identify genetically determined metabolic polymorphisms is
`important in evaluating effects on enzymes with polymorphisms, notably CYP2D6,
`CYP2C19, and CYP2C9. The extent of drug interactions (inhibition or induction) may be
`different depending on the subjects’ genotype for the specific enzyme being evaluated.
`Subjects lacking the major clearance pathway, for example, cannot show metabolism and
`remaining pathways can become important and should be understood and examined.
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`C.
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`Contains Nonbinding Recommendations
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`Draft – Not for Implementation
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`To avoid variable study results because of uncontrolled use of dietary supplements,
`juices, or other foods that may affect various metabolizing enzymes and transporters
`during in vivo studies, it is important to exclude their use when appropriate.
`
`Examples of statements in a study protocol could include “Participants will be
`excluded for the following reasons: Use of prescription or over-the-counter
`medications, including herbal products, or alcohol within two weeks prior to
`enrollment,” “For at least two weeks prior to the start of the study until its conclusion,
`volunteers will not be allowed to eat any food or drink any beverage containing
`alcohol, grapefruit or grapefruit juice, apple or orange juice, vegetables from the
`mustard green family (e.g., kale, broccoli, watercress, collard greens, kohlrabi,
`brussels sprouts, mustard) and charbroiled meats.”
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`Study Population
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`Choice of Substrate and Interacting Drugs
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`1.
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`Investigational Drug as an Inhibitor or an Inducer of CYP Enzymes
`
`In contrast to earlier approaches that focused mainly on a specific group of approved
`drugs (digoxin, hydrochlorothiazide) where co-administration was likely or the
`clinical consequences of an interaction were of concern, improved understanding of
`the mechanistic basis of metabolic drug-drug interactions enables more general
`approaches to and conclusions from specific drug-drug interaction studies. In
`studying an investigational drug as the interacting drug, the choice of substrates
`(approved drugs) for initial in vivo studies depends on the P450 enzymes affected by
`the interacting drug. In testing inhibition, the substrate selected should generally be
`one whose pharmacokinetics are markedly altered by co-administration of known
`specific inhibitors of the enzyme systems to assess the impact of the interacting
`investigational drug. Examples of substrates include (1) midazolam for CYP3A; (2)
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