Guidance for Industry
`
`In Vivo Drug Metabolism/Drug
`Interaction Studies -
`Study Design, Data Analysis, and
`Recommendations for
`Dosing and Labeling
`
`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)
`November 1999
`Clin/Pharm
`
`G DJ--
`
`)
`
`Roxane Labs., Inc.
`Exhibit 1005
`Page 001
`
`

`
`Guidance for Industry
`In Vivo Drug Metabolism/Drug
`Interaction Studies - Study Design,
`Data Analysis, and
`Recommendations for Dosing and
`Labeling
`
`Additional copies are available from:
`Drug Information Branch (HFD-210),
`Center for Drug Evaluation and Research (CDER),
`5600 Fishers Lane, Rockville, MD 20857 (Tel) 301-827-4573
`Internet at http://www.fda.gov/cderlguidance!index.htm
`or
`Office of Communication,
`Training, and Manufacturers Assistance (HFM-40)
`Center for Biologics Evaluation and Research (CBER)
`1401 Rockville Pike, Rockville, MD 20852-1448
`(Fax) 888-CBERFAX or 301-827-3844
`(Voice Information) 800-835-4709 or 301-827-1800
`http://www.fda.gov/cberlguide/ines.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)
`November 1999
`Clin/Pharm
`
`Roxane Labs., Inc.
`Exhibit 1005
`Page 002
`
`

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`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION .........•...........................................••. 1
`
`II. BACKGROUND .......................................................... 2
`A. Metabolism ..............................................••.......•.. 2
`B. Metabolic Drug-Drug Interactions ...................................•... 2
`
`ill. GENERAL STRATEGIES ...........................................•.•... 5
`In Vitro Studies ....................................•.................. 5
`A.
`B. Specific In Vivo Clinical Investigations ...........•...........•........•.. 6
`C. Population Pharmacokinetic Screens ........................•.•.......... 6
`
`IV. DESIGN OF IN VIVO METABOLIC 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 .................................•....•....................... 13
`A. Drug Metabolism ................................................••.. 13
`B. Metabolic Drug-Drug Interaction Studies ............................•... 13
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`Guidance for Industry1
`
`In Vivo Drug Metabolism/Drug Interaction Studies -
`Study Design, Data Analysis, and Recommendations for Dosing and
`Labeling
`
`I.
`
`INTRODUCTION
`
`This guidance provides recommendations to sponsors of new drug applications (NDAs) and biologics
`license applications (BLAs) for therapeutic biologics (hereafter drugs) who intend to perform in vivo
`drug metabolism and metabolic 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 metabolic drug-drug interactions, the approaches
`considered in the guidance are offered with the understanding that whether a particular study should be
`performed will vary, depending on the drug in development and its intended clinical use. Furthermore,
`not every drug-drug interaction is metabolism-based, but may arise from changes in pharmacokinetics
`caused by absorption, tissue and/or plasma binding, distribution, and excretion interactions. Drug
`interactions related to transporters are being documented with increasing frequency and may be
`addressed more fully in future guidances. 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.
`
`Previous guidance from FDA on the use of in vitro approaches to study drug metabolism and metabolic
`drug-drug interactions is available in a guidance document entitled Drug Metabolism/Drug Interaction
`Studies in the Drug Development Process: Studies In Vitro (Aprill997). The present guidance
`should be viewed as a companion to this earlier guidance. Discussion of metabolic and other types of
`drug-drug interactions is also provided in other guidances, including the International Conference on
`Harmonisation (ICH) E8 General Considerations for Clinical Trials (December 1997), E7 Studies
`in Support of Special Populations: Geriatrics (August 1994), and E3 Structure and Content of
`Clinical Study Reports (July 1996), and the Agency guidances Studying Drugs Likely to be Used in
`the Elderly (November 1989) and Study and Evaluation of Gender Differences in the Clinical
`Evaluation of Drugs (July 1993).
`
`1 This guidance has been prepared by the In Vivo Metabolic 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.
`This guidance document represents the Agency's current thinking on the subject of in vivo drug metabolism and
`metabolic drug-drug interactions. It does not create or confer any rights for or on any person and does not operate
`to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the
`applicable statutes, regulations, or both.
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`II.
`
`BACKGROUND
`
`A.
`
`Metabolism
`
`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 by
`excretion, usually by the kidneys and liver. In addition, protein therapeutics may be eliminated
`via 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 of enzymes located in the hepatic endoplasmic reticulum but may also occur by non(cid:173)
`P450 enzyme systems, such as N-acetyl and glucuronosyl transferases. P450 enzyme systems
`located in gut mucosa can also significantly affect the amount of drug absorbed into the systemic
`circulation. 2 Many factors can alter hepatic and intestinal drug metabolism, including the
`presence or absence of disease and/or concomitant medications. While most of these factors
`are usually relatively stable over time, concomitant medications can alter metabolic routes of
`absorption and elimination 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 a~tive metabolites, which in tum is related to their formation, distribution, and
`elimination.
`
`B.
`
`Metabolic Drug-Drug Interactions
`
`Many metabolic routes of elimination, including most of those occurring via the P450 family of
`enzymes, can be inhibited, activated, 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 metabolites or increased exposure to a toxic
`parent compound. Examples of substantially changed exposure associated with administration
`of another drug include (1) increased levels of terfenadine, cisapride, or astemizole with
`ketoconazole or erythromycin (inhibition of CYP3A4); (2) increased levels of simvastatin and
`its acid metabolite with mibefradil or itraconazole (inhibition of CYP3A4); (3) increased levels
`
`2 No distinction is made in this document between the effects of concomitant drugs and/or alterations in
`metabolism on gastrointestinal absorption and hepatic elimination, although the pharmacokinetic effects of the two
`may be different.
`
`2
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`of desipramine with fluoxetine, paroxetine, or quinidine (inhibition of CYP2D6); and ( 4)
`decreased carbamazepine levels with rifampin (induction of CYP3A4). 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 rriost 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).
`Depending on the extent and consequence of the interaction, the fact that a drug's metabolism
`can be significantly inhibited by other drugs and that the drug itself can inhibit the metabolism of
`other drugs can require important changes in either its dose or the doses of drugs with which it
`interacts, that is, on its labeled conditions of use. Rarely, metabolic drug-drug interactions may
`affect the ability of a drug to be safely marketed.
`
`The following general concepts underlie the recommendations in this guidance:
`
`Adequate assessment of the safety and effectiveness of a drug includes a description of
`its metabolism and the contribution of metabolism to overall elimination.
`
`Metabolic drug-drug interaction studies should explore whether an investigational agent
`is likely to significantly affect the metabolic elimination of drugs already in the
`marketplace 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.
`
`In some cases, metabolic drug-drug interaction studies cannot be informative unless
`metabolites and prodrugs have been identified and their pharmacological properties
`described.
`
`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 impact of an investigational or approved interacting drug can be either to inhibit or
`induce metabolism.
`
`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 it might be used with, or whether the interaction would require additional
`therapeutic monitoring.
`
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`•
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`In some instances, understanding how to adjust dosage 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 may be used intentionally to increase levels or reduce elimination of another
`drug. Rarely, the degree of interaction caused by a drug, or the degree to which other
`drugs alter its metabolism, may be such that it cannot be marketed safely.
`
`The blood or plasma concentrations of the parent drug and/or its active metabolites
`(systemic exposure) may provide an important link between drug dose (exposure) and
`desirable and/or undesirable drug effects. For this reason, the development of sensitive
`and specific assays for a drug and its key metabolites is critical to the study of
`metabolism and drug-drug interactions.
`
`For drugs whose presystemic or systemic clearance occurs primarily by metabolism,
`differences arising from various sources, including administration of another drug, are an
`important source of inter-individual and intra-individual variability.
`
`Unlike relatively fixed influences on metabolism, such as hepatic function or genetic
`characteristics, metabolic drug-drug interactions can lead to abrupt changes in
`exposure. Depending on the nature of the drugs, these effects could potentially occur
`when a drug is initially administered, when it has been titrated to a stable dose, or when
`an interacting drug is discontinued. Interactions can occur after even a single
`concomitant dose of an inhibitor.
`
`The effects of an investigational drug on the metabolism of other drugs and the effects of
`other drugs on an investigational drug's metabolism should be assessed relatively early
`in drug development so that the clinical implications of interactions can be assessed as
`fully as possible in later clinical studies.
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`Ill. GENERAL STRATEGIES
`
`To the extent possible, drug development should follow a sequence where 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 should be planned, moving from in vitro studies, to early
`exploratory studies, to later more definitive studies, employing special study designs and methodology
`where necessary and 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. In certain cases and with careful study designs and planning, these early studies may also
`provide information about dose, concentration, and response relationships in the general population,
`subpopulations, and individuals, which can be useful in interpreting the consequences of a metabolic
`drug-drug interaction.
`
`A.
`
`In Vitro Studies
`
`A complete understanding of the relationship between in vitro findings and in vivo results of
`metabolism/drug-drug interaction studies is still emerging. Nonetheless, in vitro studies can
`frequently serve as an adequate screening mechanism to rule out the importance of a metabolic
`pathway and drug-drug interactions that occur via 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. For
`example, if suitable in vitro studies indicate that CYP2D6 or 3A4 enzyme systems do not
`metabolize an investigational drug, then clinical studies to identify the impact ofthe CYP2D6
`slow metabolizer phenotype or to study the effect of CYP2D6 inhibitors or CYP3A4
`inhibitors/inducers on the elimination of the investigational drug will not be needed. Similarly, if
`in vitro studies indicate that an investigational drug does not inhibit CYP2D6 or 3A4
`metabolism, then corresponding in vivo drug-drug interaction studies of the investigational drug
`and concomitant medications eliminated by these pathways are not needed.
`
`In contrast, when positive findings arise in in vitro metabolic and/or drug-drug interaction
`studies, clinical studies are recommended because of the limited ability at present of in vitro
`findings to give a good quantitative estimate of the clinical importance of a metabolic pathway
`or interaction. Further evaluation of the utility of parameters such as the ratio between the
`concentration of drug and the Ki (inhibition constant) for the interaction may lead to continued
`improvements in the ability of in vitro studies to predict in vivo results, but the overall
`experience to date is not large enough to allow reliable conclusions. Although in vitro studies
`can assess the presence or absence of inhibition, they have limited capability to identify
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`induction. For this reason, in vivo studies remain the primary source of information about
`induction of metabolic pathways caused by concomitant medications.
`
`B.
`
`Specific In Vivo Clinical Investigations
`
`Appropriately designed 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 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.
`
`C.
`
`Population Pharmacokinetic Screens
`
`Population pharmacokinetic analyses of data obtained from blood samples collected
`infrequently (sparse sampling) in clinical studies conducted in the later phase of clinical drug
`development can be valuable in characterizing the clinical impact of known or newly identified
`interactions, and in making recommendations for dosage modifications. It may be possible that
`analysis or skillful examination of such data could detect unsuspected drug-drug interactions.
`Population pharmacokinetic data can also provide further evidence of the absence of a
`pharmacokinetic drug-drug interaction when this is suggested by in vitro drug-drug interaction
`studies. The power of a sparse sampling strategy to detect drug-drug interactions is not yet
`well established, however, and 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 vitro or 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 entitled Population Pharmacokinetics was
`published in February 1999.
`
`IV.
`
`DESIGN OF IN VIVO METABOLIC DRUG-DRUG INTERACTION STUDIES
`
`If in vitro studies and other information suggest a need for in vivo metabolic drug-drug interaction
`studies, the following general issues and approaches should be considered. In the following discussion,
`the term substrate (S) is used to indicate the drug studied to determine if its exposure is changed by
`another drug, which is termed the interacting drug (I). Depending on the study objectives, the
`substrate and the interacting drug may be the investigational agents or approved products.
`
`A.
`
`Study Design
`
`6
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`In vivo metabolic drug-drug interaction studies generally are designed to compare substrate
`levels with and without the interacting drug. Because a specific study may consider a number of
`questions and clinical objectives, no one correct study design for studying drug-drug
`interactions can be defined. 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 may also be used: 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 ofthe substrate and interacting drugs; and (4) the need to
`assess induction as well as inhibition. The inhibiting/inducing drugs and the substrates should be
`dosed so that the exposure of both drugs are relevant to their clinical use. The following
`considerations may be useful:
`
`Pharmacokinetic measures and/or parameters may be used to indicate clinically
`important routes of metabolism and drug-drug interactions. Subsequent interpretation
`of findings from these studies will be aided by a good understanding of
`dose/concentration and concentration/response relationships for both desirable and
`undesirable drug effects in the general population, in subpopulations, and within
`individuals. In certain instances, reliance on endpoints other than pharmacokinetic
`measures/parameters may be useful.
`
`•
`
`•
`
`When both substrate and interacting drug are likely to be given chronically over an
`extended period of time, administration of the substrate to steady state with collection
`of blood samples over one or more dosing intervals could be followed by multiple dose
`administration of the interacting drug, again with collection of blood for measurement of
`both the substrate and the interacting drug (as feasible) over the same intervals. This is
`an example of a one-sequence crossover design.
`
`The time at steady state before collection of endpoint observations depends on whether
`inhibition or induction is to be studied. Inducers can take several days or longer to
`exert their effects, while inhibitors generally exert their effects more rapidly. For this
`reason, a more extended period of time after attainment of steady state for the substrate
`and interacting drug may be necessary if induction is to be assessed.
`
`When attainment of steady state is important and either the substrate or interacting
`drugs and/or their metabolites exhibit long half-lives, special approaches may be useful.
`These include use of a loading dose to achieve steady state conditions more rapidly and
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`selection of a one-sequence crossover or a parallel design, rather than a randomized
`crossover study design.
`
`•
`
`When a substrate and/or an interacting drug is to be studied at steady state,
`documentation that near steady state has been attained is important both for each drug
`and its metabolites of interest. This documentation can be accomplished by sampling
`over several days prior to the periods when 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 part of 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 be the appropriate design to
`increase sensitivity.
`
`If the drug interaction effects are to be assessed for both agents in a combination
`regimen, the assessment can be done in two separate studies. If the pharmacokinetic
`and pharmacodynamic characteristics of the drugs make it feasible, the dual assessment
`can be done in a single study. Some design options are randomized three-period
`crossover, parallel group, and one-sequence crossover.
`
`B.
`
`Study Population
`
`Clinical drug-drug interaction studies may generally be performed using healthy volunteers or
`volunteers drawn from the general population, on the assumption that findings in this population
`should predict findings in the patient population for which the drug is intended. Safety
`considerations, however, may preclude the use of healthy subjects. In certain circumstances,
`subjects drawn from the general population and/or patients for whom the investigational drug is
`intended offer certain advantages, including the opportunity to study pharmacodynamic
`endpoints not present in healthy subjects and reduced reliance on extrapolation of findings from
`healthy subjects. In either patient or healthy/general population subject studies, performance of
`phenotype or genotype determinations to identify genetically determined metabolic
`polymorphisms is often important in evaluating effects on enzymes with polymorphisms, notably
`CYP2D6 and CYP2C19.
`
`C.
`
`Choice of Substrate and Interacting Drugs
`
`1.
`
`Substrates for an Investigational Drug
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`In contrast to earlier approaches that focused mainly on a specific group of approved
`drugs (digoxin, hydrochlorothiazide) where coadministration was likely or the clinical
`consequences of an interaction were of concern, improved understanding of the
`metabolic basis of 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 is
`markedly altered by coadministration of known specific inhibitors of the enzyme
`systems (i.e., a very sensitive substrate should be chosen) to assess the impact of the
`interacting investigational drug. Examples of substrates include, but are not limited to,
`(I) midazolam, buspirone, felodipine, simvastatin, or lovastatin for CYP3A4; (2)
`theophylline for CYPIA2; (3) S-warfarin for CYP2C9; and (4) desipramine for
`CYP2D6. If the initial study is positive for inhibition, further studies of other substrates
`may be useful, representing a range of substrates based on the likelihood of
`coadministration. For example, possible substrates for further study of a CYP3A4
`interacting investigational drug might include dihydropyridine calcium channel blockers
`and triazolobenzodiazepines, or for a CYP2D6 inhibiting investigational drug might
`include metoprolol. If the initial study is negative with the most sensitive substrates, it
`can be presumed that less sensitive substrates will also be unaffected.
`
`2.
`
`Investigational Drug as Substrate
`
`In testing an investigational drug for the possibility that its metabolism is inhibited or
`induced (i.e., as a substrate), selection of the interacting drugs should be based on in
`vitro or other metabolism studies identifying the enzyme systems that metabolize the
`drug. The choice of interacting drug should then be based on known, important
`inhibitors of the pathway under investigation. For example, if the investigational drug is
`shown to be metabolized by CYP3A4 and the contribution of this enzyme to the overall
`elimination of this drug is substantial, the choice of inhibitor and inducer could be
`ketoconazole and rifampin, respectively, because of the substantial effects of these
`interacting drugs on CYP3A4 metabolism (i.e., they are the most sensitive in identifying
`an effect of interest). If the study results are negative, then absence of a clinically
`important drug-drug interaction for the metabolic pathway could be claimed. If the
`clinical study of the most potent specific inhibitor/inducer is positive and the sponsor
`wishes to claim lack of an interaction between the test drug and other less potent
`specific inhibitors, or give advice on dosage adjustment, further clinical studies would
`generally be recommended. Certain approved drugs are not optimal selections as the
`interacting drug. For example, cimetidine is not considered an optimal choice to
`represent drugs inhibiting a given pathway because its inhibition affects multiple
`metabolic pathways as well as certain drug transporters.
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`D.
`
`Route of Administration
`
`The route of administration chosen for a metabolic drug-drug interaction study is important.
`For an investigational agent used as either an interacting drug or substrate, the route of
`administration should generally be the one planned for in product labeling. When multiple
`routes are being developed, the necessity for doing metabolic drug-drug interaction studies by
`all routes should be based on the expected mechanism of interaction and the similarity of
`corresponding concentration-time profiles for parent and metabolites. If only oral dosage forms
`will be marketed, studies with an intravenous formulation would not usually be needed, although
`information from oral and intravenous dosings may be useful in discerning the relative
`contributions of alterations in absorption and/or presystemic clearance to the overall effect
`observed for a drug interaction. Sometimes certain routes of administration can reduce the
`utility of information from a study. For example, an intravenous study would not reveal an
`interaction for any substrate that exhibits a high extraction ratio or for a low hepatic extraction
`drugs where intestinal CYP3A4 activity markedly alters bioavailability. For an approved agent
`used either as a substrate or interacting drug, the route of administration will depend on
`available marketed formulations, which in most instances will be oral.
`
`E.
`
`Dose Selection
`
`For both a substrate (investigational drug or approved drug) and interacting drug
`(investigational drug or approved drug), testing should maximize the possibility of finding an
`interaction. For this reason, the maximum planned or approved dose and shortest dosing
`interval of the interacting drug (as inhibitors or inducers) should be used. Doses smaller than
`those to be used clinically may be needed for substrates on safety grounds and may be more
`sensitive to the effect of the interacting drug.
`
`F.
`
`Endpoints
`
`1.
`
`Pharmacokinetic Endpoints
`
`The following measures and parameters are recommended for assessment of the
`substrate: (1) exposure measures such as AUC, Cmax, time to Cmax (Tmax), and
`others as appropriate; and (2) pharmacokinetic parameters such as clearance, volumes
`of distribution, and half-lives. In some cases, these measures may be of interest for the
`inhibitor or inducer as well, notably where the study is assessing possible interactions
`between both study drugs. Additional measures may help in steady state studies (e.g.,
`trough concentration (Cmin)) to demonstrate that dosing strategies were adequate to
`achieve near steady state before and during the interaction. In certain instances, an
`understanding of the relationship between dose, blood levels, and response may lead to
`a special interest in certain pharmacokinetic measures and/or parameters. For
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`example, if a clinical outcome is most closely related to peak concentration (e.g.,
`tachycardia with sympathomimetics), Cmax or another early exposure measure might
`be most appropriate. Conversely, if the clinical outcome is related more to extent of
`absorption, AUC would be preferred. The frequency of sampling should be adequate
`to allow accurate determination of the relevant measures and/or parameters for the
`parent and metabolites. For the substrate, whether the inv~stigational drug or approved
`drug, determination of the pharmacokinetics of important active metabolites is
`important. Because this guidance focuses on metabolic drug-drug interactions, protein
`binding determinations are considered unnecessary except for data interpretation.
`
`2.
`
`Pharmacodynamic Endpoints
`
`Pharmacokinetic measures are usually sufficient for metabolic drug-drug interaction
`studies, although phannacodynamic measures can sometimes provide additional useful
`information. This may occur when a pharmacokinetic/pharmacodynamic relationship