安渡分享 | FDA指南摘要:《临床药物相互作用研究-CYP450酶介导的及药物转运体介导的药物相互作用》

This final guidance issued January 2020 describes clinical studies to evaluate the drug-drug interactions (DDIs) potential of an investigational drug, including:  (1) the timing and design of the clinical studies; (2) the interpretation of the study results; and (3) the options for managing DDIs in patients. Specifically, this guidance provides considerations for evaluating pharmacokinetic cytochrome P450 (CYP) enzyme- or transporter-mediated interactions.

It is related to another final January 2020 FDA guidance for industry entitled In Vitro Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions focuses on how to assess the DDI potential of a drug in vitro and how to use the results from those assessments to inform clinical DDI studies.  Together, these two final guidances on DDIs describe a systematic, risk-based approach for evaluating DDIs and determining essential information to communicate in labeling.

• Patients frequently use more than one medication at a time.  Unanticipated, unrecognized, or mismanaged DDIs are an important cause of morbidity and mortality associated with prescription drug use and have occasionally caused the withdrawal of approved drugs from the market.  In some instances, understanding how to safely manage a DDI may allow the FDA to approve a drug that would otherwise have an unacceptable level of risk.

• Clinically relevant DDIs between an investigational drug and other drugs should therefore be:  (1) defined during drug development as part of the sponsor’s assessment of the investigational drug’s benefits and risks; (2) understood via nonclinical and clinical assessment at the time of the investigational drug’s approval; (3) monitored after approval; and (4) communicated in the labeling.

The goals of studies that investigate CYP enzyme- and transporter-mediated DDIs are to:

• Determine whether the investigational drug alters the pharmacokinetics of other drugs

• Determine whether other drugs alter the pharmacokinetics of the investigational drug

• Determine the magnitude of changes in pharmacokinetic parameters

• Determine the clinical significance of the observed or expected DDIs

• Inform the appropriate management and prevention strategies for clinically significant DDIs 

• After conducting in vitro drug metabolism and drug transporter studies, sponsors should determine the need for and timing of clinical DDI studies with respect to other studies in their clinical development program.

• Sponsors should assess the DDI potential before the product is administered to patients who are likely to take concomitant medications that could interact with the investigational drug and collect enough DDI information to prevent patients from being unnecessarily excluded from any clinical study because of their concomitant medication use.

• Sponsors should summarize their DDI program at milestone meetings with the FDA.  Potential discussion topics at these meetings include the planning, timing, and evaluation of studies to determine the DDI potential of the investigational drug.

A. Types of DDI Studies

1. Prospective Studies and Retrospective Evaluations

Clinical DDIs can be evaluated in prospective studies and retrospective evaluations.

• Regulatory decision-making generally requires prospective studies specifically designed for this purpose.  Retrospective evaluation of drug concentrations from studies not designed to evaluate DDIs rarely includes sufficient precision to provide an adequate assessment.

• Protocols for prospective clinical DDI studies are specifically designed to detect DDIs as a major objective, and the data analysis method and study design elements.

• Prospective DDI studies are often stand-alone studies, however, a prespecified subgroup analysis within a larger study (e.g., a phase 3 study) may qualify as a prospective DDI study if it includes certain factors common to prospective studies.

2. DDI Studies With Index Perpetrators and Index Substrates:  Index Studies

• To test whether an investigational drug is a victim of DDIs, sponsors should use index perpetrators.  Index perpetrators predictably inhibit or induce drug metabolism by a given pathway and are commonly used in prospective DDI studies.

• Strong index perpetrators cause DDIs of the greatest magnitude when co-administered with the investigational drug (as a substrate) by altering the function of a given metabolic pathway.

• To test whether the investigational drug is a perpetrator, sponsors should use index substrates, which have defined changes in systemic exposure when administered with a strong inhibitor for a specific drug elimination pathway.

• A list of currently recommended index drugs for specific CYP pathways (either as substrates, inhibitors, or inducers) is maintained on the FDA’s Web site for Drug Development and Drug Interactions and clinical interaction studies conducted with these drugs can provide useful information about potential DDIs with concomitant drugs.

3. DDI Studies With Expected Concomitant Drugs:  Concomitant-Use Studies

• Index substrates and perpetrators are not chosen based on their use in the investigational drug’s target population, but rather because of their well-defined interaction effects that provide information about the DDI potential of the investigational drug.

• Results from DDI studies with index perpetrators or substrates are used to either extrapolate findings to concomitant medications sharing the same DDI properties or to help design DDI studies with commonly used concomitant medications in the investigational drug’s target population.

• The relevant concomitant medications for study include those used to treat the same condition for which the investigational drug is being studied or those used to treat common co-morbidities in the patient population.

• Examples and classifications of drugs for individual elimination pathways — either as substrates, inhibitors, or inducers — are maintained on the FDA’s Web site for Drug Development and Drug Interactions.

• The choice of victim or perpetrator drug for transporter studies should be based primarily on the likelihood of concomitant use of the two drugs and extrapolation of study results to other drugs is limited.

4. In Silico DDI Studies

• Physiologically based pharmacokinetic (PBPK) models can be used in lieu of some prospective DDI studies.

• Before using a PBPK modeling approach to predict the effects of moderate or weak perpetrator drugs on the exposure of an investigational drug, the sponsor should verify the models using human pharmacokinetic data and information from DDI studies that used strong index perpetrators.

• Because of evolving science, new uses of in silico methods to predict DDIs in lieu of clinical DDI studies are continuously being considered by the FDA.

• The FDA encourages sponsors to discuss issues and considerations related to the use of in silico models.

• FDA guidances for industry: In Vitro Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions.  January 2020 and 2018 FDA Physiologically Based Pharmacokinetic Analyses — Format and Content Suggestions for refer on how sponsors should conduct PBPK analyses.

B. Study Planning and Considerations for Stand-Alone Prospective DDI Studies

Protocol development and study design can vary depending on factors including:

• Whether the victim and/or perpetrator drugs are used acutely or chronically

• Whether there are exposure-related safety concerns with the substrate

• The pharmacokinetic and pharmacodynamic characteristics of the substrate and perpetrator drugs

• Whether both induction and inhibition will be assessed

• The mechanism of the DDI (e.g., time-dependent inhibition)

• Whether the persistence of inhibition or induction after withdrawal of the perpetrator drug will be assessed

The following considerations are important when designing prospective clinical DDI studies to unambiguously determine this ratio.

1.  Study Population and Number of Subjects

• Most clinical DDI studies can be conducted using healthy subjects, assuming that findings in healthy subjects can be used to predict findings in the intended patient population.

• The number of subjects included in a DDI study should be sufficient to provide a reliable estimate of the magnitude and variability of the interaction.

2.  Dose

• The doses of the perpetrator drug used in DDI studies should maximize the possibility of identifying a DDI.  The maximum dose and the shortest dosing interval of the perpetrator under the intended labelling conditions should be used.

• If the substrate drug has dose-proportional pharmacokinetics, the sponsor can use any dose in the range where exposure to the drug increases in a dose-proportional manner.

• If the substrate drug has dose-dependent pharmacokinetics, the sponsor should use the therapeutic dose most likely to demonstrate a DDI.

• A PBPK model verified for the mechanism of dose dependent pharmacokinetics of the substrate can be used to support dose selection.

3.  Single or Multiple Doses

• Single-dose administration of the perpetrator should be done only if the perpetrator is not a potential inducer or time-dependent inhibitor.

• An inhibitor can be administered as a single dose if it is justified that single-dose administration of the inhibitor has a similar effect on the enzyme or transporter of interest to that after multiple dosing.

• For substrates with long half-lives it may be necessary to administer a perpetrator multiple times to cover the full time-course of the substrate exposure.

• The sponsor should administer inducers as multiple doses to ensure the maximal induction of a specific pathway.

• When there are multiple mechanisms of interactions for a specific perpetrator, single-dose administration may be appropriate in certain situations while multiple-dose administration may be appropriate in other situations.

• Single-dose administration of the substrate is acceptable if the substrate does not show time dependent pharmacokinetics. In those situations, the observed magnitude increase in exposure in single-dose studies can be extrapolated to steady state conditions.

• Multiple-dose administration of the substrate and a perpetrator should be studied, in vivo or in silico, based on in vivo single dose administration if the substrate demonstrates time-dependent pharmacokinetics.

4. Route of Administration

• For in vivo DDI studies, the route of administration of the investigational drug should generally be the one planned for routine clinical use.

• When multiple routes of administration are developed for clinical use, the route of drug administration for DDI studies should be selected based on the expected mechanisms of the DDIs and the similarity of the corresponding concentration-time profiles for the parent drug and metabolites after different routes of administration.

5.  Parallel Versus Crossover Studies

• A study can use a randomized crossover, a one-sequence crossover or a parallel design

• Crossover studies (one-sequence or randomized) are preferred over parallel study designs in order to reduce inter-subject variability

• Parallel, two-arm studies can be appropriate when a crossover study design is not feasible.  Typically, parallel-design studies require larger sample sizes than crossover studies

6. Timing of Drug Administration

• In most cases, the perpetrator and substrate drugs can be administered at the same time.  However, the timing of administration of the perpetrator is critical if it is both an inhibitor and an inducer, in such cases, delayed administration of the substrate is recommended.

• Sometimes multiple drug-dosing schedules can be studied (in vivo or in silico) to understand whether staggered dosing is a viable mitigation strategy for the DDI.

• When evaluating the interaction between drugs that require different food conditions for optimal absorption, the sponsor should adjust the timing of drug administration to maximize the potential to detect an interaction and/or to reflect the clinically relevant conditions.

7. Co-Medications and Other Extrinsic Factors Affecting DDIs

• To reduce variability in the magnitude of DDIs, the sponsor should exclude and/or account for the use of prescription or over-the-counter medications, dietary/nutritional supplements, tobacco, alcohol, foods, and fruit juices that may affect the expression or function of enzymes and transporters for a sufficient time before subject enrollment.

8. Sample and Data Collection

Pharmacokinetic sampling times should be sufficient to characterize the AUC0-INF (for single dose studies) or the AUC0-TAU (for multiple-dose studies) and the maximum concentration (Cmax) of the substrate drug administered alone and under conditions of the anticipated interaction.

Sponsors should collect data on additional pharmacokinetic parameters based upon the pharmacokinetic or pharmacological relevance for the proposed indication (e.g., the minimal concentration (Cmin), partial AUC).

9. Pharmacodynamic Endpoints

• In some situations, pharmacodynamic endpoints indicate changes in efficacy or toxicity that systemic drug exposures do not predict anticipating clinical consequences such as altered efficacy or increased toxicity.

• When in vitro data provide a plausible DDI mechanism that cannot be evaluated with systemic drug exposure, sponsors can collect and analyze pharmacodynamic endpoint data.

C. Study Planning and Considerations for Prospective Nested DDI Studies

• Prospective nested DDI studies should be carefully designed mostly if the DDI studies are part of another study (e.g., large phase 2 or phase 3 studies) and rely on sparse pharmacokinetic sampling with fewer samples per subject.

• Population pharmacokinetic analyses of data obtained from large-scale clinical studies can help characterize the clinical impact of known or newly identified interactions and determine recommendations for dosage modifications when the investigational drug is a substrate.

• The results of such analyses can be informative, and sometimes conclusive, when the clinical studies are adequately designed to detect significant changes in drug exposure due to DDIs.

• To be optimally informative, population pharmacokinetic analysis for prospective DDI evaluation should have carefully designed study procedures and sample collection protocols simulating various DDI scenarios using available pharmacokinetic models.

• Analyses should focus on detecting a specific clinically meaningful change in drug exposure and the population pharmacokinetic DDI assessment should be specified before conducting the prospective nested DDI study to increase confidence in the study's results.

D. Specific Considerations for CYP-Mediated Interactions

1.  The Investigational Drug as a Substrate for CYP Enzymes

• When evaluating the investigational drug as a substrate, clinical DDI studies should start with a strong index inhibitor and a strong index inducer.  Moderate index inhibitors or inducers are acceptable if strong index inhibitors or inducers are not available for a particular enzyme.

• These index inhibitors and inducers are preferred because there is a large body of information about:  (1) their defined effects on specific CYP pathways; (2) their appropriate dosing regimens; (3) their safety profiles; and (4) their anticipated effects on their respective sensitive substrates.

• When selecting index inhibitors and inducers for prospective DDI studies, the sponsor should consider the elimination pathways of the investigational drug as a substrate.

• If a DDI study with a strong index inducer or inhibitor indicates that no DDI is present, additional clinical studies with other inhibitors or inducers of the same enzyme are not needed.  If a DDI study with strong index inhibitors or inducers indicates that there is a clinically significant interaction, the Agency recommends evaluating the impact of other moderate inhibitors or inducers to gain a full understanding of the investigational drug’s DDI potential.

• The effect of the additional inhibitors and inducers can be evaluated in a clinical interaction study or through modeling and simulation approaches, such as PBPK modeling with a verified perpetrator (inhibitor or inducer) and substrate models.  DDI studies with index substrates and perpetrators can be used to inform potential future concomitant-use studies.

• If the investigational drug is subject to significant metabolism by a genetically polymorphic enzyme a comparison of the pharmacokinetic parameters of the drug in individuals with the PM phenotype versus those with an extensive metabolizer (EM) phenotype can substitute for an interaction study for that particular pathway.

• The effect of a PM phenotype is expected to be similar to the effect of a strong inhibitor of that pathway. If this comparison reveals a clinically significant difference in exposure between individuals with the PM and EM phenotypes, potential for DDIs with moderate inhibitors or inducers of the enzymes should be evaluated.

2. The Investigational Drug as an Inhibitor or an Inducer of CYP Enzymes

• When studying an investigational drug as a potential inhibitor or inducer of a CYP enzyme, the index substrate selected for the initial clinical studies should be sensitive to changes in activity or amount of the CYP enzyme being evaluated.  These sensitive index substrates are preferred because there is a large body of information about:  (1) the relative contribution of specific CYP pathways on their overall elimination; (2) their appropriate dosing regimens; (3) their safety profiles; and (4) their anticipated interaction effects when co-administered with strong index inhibitors and inducers.

• When determining which index substrates to use for prospective DDI studies, the sponsor should consider the inhibition and/or induction properties of the investigational drug.  Other CYP enzyme substrates can also be appropriate.

• If an initial study determines that an investigational drug either inhibits or induces the metabolism of sensitive index substrates, further studies using other substrates  can be useful.

• The sponsor should consider additional studies, depending on the magnitude of the effect of the investigational drug on the sensitive index substrate and the potential for concomitant use with other drugs that are substrates of the same enzyme.

• When conducting a DDI study, using a substrate metabolized by more than one enzyme is only appropriate if the investigational drug is a selective inhibitor or inducer of the substrate’s primary CYP metabolizing enzyme.

• If the investigational drug is both an inducer and an inhibitor of an enzyme, the net effect of the drug on enzyme function may be time dependent.  The timing of pharmacokinetic endpoints should permit an understanding of the changes in effects over time.

E. Specific Considerations for Transporter-Mediated Interactions

1. The Investigational Drug as a Substrate of Transporters

If in vitro studies indicate that the investigational drug is a transporter substrate, the need for clinical DDI studies is determined based on the drug’s putative site of action, route of elimination, likely concomitant drugs, and safety considerations.

The following general guidelines help to determine when a sponsor should perform a clinical DDI study for investigational drugs that are transporter substrates in vitro:

• P-glycoprotein (P-gp)- and breast cancer resistance protein (BCRP)-mediated DDIs:

• OATP1B1- and OATP1B3-mediated DDIs:

• When the investigational drug undergoes significant active renal secretion or there are concerns about renal toxicity.

• When testing an investigational drug as a substrate in transporter-mediated DDIs, the selected perpetrator drug should be a known inhibitor of the transporter under investigation.

• Because of a general lack of index perpetrators for transporter-mediated pathways, the choice of transporter perpetrators is typically based on the likelihood of concomitant use.

• A few transporter perpetrators can also be used to understand the underlying mechanisms of transporter-mediated DDIs or to study the worst-case DDI scenario.

• A few inhibitors block specific transporter pathways in a relatively selective manner.

• Results from most transporter inhibition studies are not easily extrapolated to other drugs and interpretation of the study results requires knowledge of the transport and metabolic pathways for the investigational drug.

• Examples of transporter inhibitors are listed on the FDA’s Web site on Drug Development and Drug Interactions.

2. The Investigational Drug as an Inhibitor or an Inducer of Transporters

If in vitro studies, as described in the FDA guidance for industry In Vitro Drug Interaction

• Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions, indicate that the investigational drug is a transporter inhibitor, the sponsor should consider a clinical drug interaction study based on likely concomitant drugs and safety considerations.

• When studying the investigational drug’s potential to act as a perpetrator drug for a transporter, the sponsor should select a substrate whose pharmacokinetic profile is markedly altered by coadministration of known inhibitors of that transporter and is also a likely concomitant drug.

• Many drugs are substrates of multiple transporters and/or enzymes.  The observed clinical interactions can be a result of the inhibition of multiple pathways if the investigational drug is also an inhibitor for the same pathways.

• The choice of substrates can be determined by the therapeutic area of the investigational drug and the probable concomitant drugs that are known substrates of the transporters.

F. Cocktail Approaches

A cocktail study includes the simultaneous administration of substrates of multiple CYP enzymes and/or transporters to study subjects.

A cocktail approach can simultaneously evaluate a drug’s inhibition or induction potential for multiple CYPs and transporters as long as the study is properly designed, and the following conditions are satisfied: (1) the substrates are specific for individual CYP enzymes or transporters; (2) there are no interactions among the substrates; and (3) the study is conducted with a sufficient number of subjects.

Negative results from a well conducted cocktail study can eliminate further evaluation of particular CYP enzymes or transporters.  Positive results from a well-conducted cocktail study that includes all elements of a prospective DDI study can be interpreted and presented in labeling the same way as positive results from any other well-conducted drug interaction study.

G. Other Considerations

1. Genetics

• If a drug is a substrate for a polymorphic enzyme or transporter, a subject’s genotype for a specific enzyme or transporter affects the extent of drug induction or drug inhibition.

• When a DDI study uses an index inhibitor or substrate to evaluate pharmacokinetic changes, individuals who have no functional enzyme activity should typically be excluded, or the study should be sufficiently powered to evaluate DDIs in subjects with functional enzymes.

• In cases where study enrollment is not based on the genotype of a polymorphic enzyme or transporter, sponsors should still routinely collect DNA from all subjects for retrospective analysis of the enzymes or transporters of interest to characterize differences in the magnitude of the DDI across genotype groups and to understand why some subjects have unusual increases or decreases in drug concentrations.

• The combined effects of different genotypes of polymorphic enzymes and transporters can also be explored in a drug interaction study by prospective enrichment of poor metabolizers or through retrospective analysis, provided that a sufficient number of poor metabolizers are enrolled.

• In some instances, a gene-drug interaction study may substitute for a prospective DDI study and vice versa.  Suitable substrates for these studies have a high fraction of metabolism by a single CYP enzyme that has loss-of-function alleles.

• Comparing the pharmacokinetics of an investigational drug in subjects with different genotypes of specific transporters can help determine the importance of a specific transporter in the drug’s clearance pathway.

2. Smokers

• Smoking induces CYP1A2 activity.  If an investigational drug is a CYP1A2 substrate, the sponsor should consider conducting a study in smokers based on the intended patient population and the effect of CYP1A2 induction on the drug’s exposure.

• The study arms for a smoking study include nonsmokers in the control arm and current smokers in the investigational arm.

• Data collected in the smoking study should include the number of cigarettes smoked per day and, when feasible, plasma nicotine levels in both smokers and nonsmokers.

3. Complex Drug Interactions

• When there are multiple factors that affect the absorption and disposition of an investigational drug as well as multiple mechanisms of DDIs the sponsor should evaluate the investigational drug’s DDI potential by integrating knowledge from multiple in vitro and clinical studies.

• PBPK models may be useful to:  (1) integrate the information from multiple studies; (2) determine whether a clinical study is appropriate; and (3) inform the design of clinical studies.

A. Study Results Reporting

• Pharmacokinetic endpoints for DDI studies include changes in drug exposure parameters such as AUC0-INF and Cmax.

• Sponsors should report the pharmacokinetic results of DDI studies as the geometric mean ratio of the observed pharmacokinetic exposure measures with and without the perpetrator drug.

• The sponsor should summarize all information on pharmacodynamic endpoints.  If the pharmacodynamic endpoint is a continuous response the sponsor can analyze the data and report the results in the same manner as for pharmacokinetic endpoints.

• If the pharmacodynamic endpoint is not a continuous response, the sponsor should consult with the FDA to determine an appropriate data analysis method.

• When possible, the sponsor should specify the criteria for defining outliers in the protocol and make a distinction between outlying individuals versus outlying data points.

• The sponsor should report AUC0-INF values for all individuals and include the percentage of extrapolation.  Sponsors should highlight individuals with more than 20 percent extrapolated AUC0-INF, report the results with and without those subjects, and discuss the potential impact on the interpretation of the findings.

1. Non-Compartmental Analysis

• The sponsor should report substrate exposure measures for all subjects, the percentage extrapolated AUC0-INF, the Cmax, and Tmax.

• For multiple-dose studies, sponsors should also report the Cmin and the AUC0-TAU at steady-state.

• Sponsors should report additional pharmacokinetic parameters such as the clearance, the volume of distribution, and the half-life if they help interpret the pharmacokinetic results and also consider collecting and reporting pharmacokinetic parameters that are relevant to the clinical significance of the interaction.

2. Population Pharmacokinetic Analysis

• When relevant, population pharmacokinetic analysis should derive pharmacokinetic exposure parameters, such as AUC0-INF, AUC0-t, Cmax, and Tmax.  For multiple-dose studies, sponsors should also report the Cmin and the AUC0-TAU at the steady-state.

• Sponsors should investigate the DDI using all plausible structural elements of the pharmacokinetic model such as clearance (CL/F), relative bioavailability and rate of absorption.

• If traditional pharmacokinetic data analysis using non-compartmental analysis methods are not adequate the studies could be analyzed with population pharmacokinetic methods in addition to non-compartmental analysis.

B. Interpreting DDI Studies

• The goal of a DDI study with pharmacokinetic endpoints is to inform management and prevention strategies by determining whether there is a clinically significant increase or decrease in exposure to the substrate in the presence of the perpetrator.

• The results of a DDI study are interpreted based on the no-effect boundaries for the substrate drug.  No-effect boundaries represent the interval within which a change in a systemic exposure measure is considered not significant enough to warrant clinical action.

1. Approaches for Determining No-Effect Boundaries

There are two approaches to determining no-effect boundaries:

• Approach 1 (Preferred) — When possible, no-effect boundaries can be based on concentration-response relationships derived from pharmacokinetic and pharmacodynamic analyses, as well as other available information for the substrate drug such as the maximum-tolerated dose.

• Approach 2 (In the absence of no-effect boundaries defined in Approach 1 or when the aim of the study is to determine whether a drug is a perpetrator or not when using index substrates) — The sponsor can use a default no-effect boundary of 80 to 125 percent in these instances.  When the 90 percent confidence intervals for systemic exposure ratios fall entirely within the equivalence range of 80 to 125 percent, the FDA concludes that there is no clinically significant DDI.

2. Interpreting Results From Retrospective DDI Evaluations

• Retrospective DDI evaluations can be useful to identify DDIs that were unanticipated at the start of clinical development.  Sponsors should confirm results from retrospective DDI studies that suggest clinical management or prevention strategies are warranted with a prospective DDI study.

• Negative findings from retrospective studies generally do not provide useful information to include in labeling.

3. Classifying the Investigational Drug as an Inhibitor or Inducer

If an investigational drug is a CYP inhibitor, it can be classified as a strong, moderate, or weak inhibitor based on its effect on an index CYP substrate.  The convention is to categorize CYP inhibition in the following way:

• A strong inhibitor increases the AUC of a sensitive index CYP substrate ≥ 5-fold

• A moderate inhibitor increases the AUC of a sensitive index CYP substrate by ≥ 2- to < 5-fold

• A weak inhibitor increases the AUC of a sensitive index CYP substrate by ≥ 1.25- to < 2fold

These categories typically describe the effect of the investigational drug when given at the highest clinical dose and the shortest dosing interval within its therapeutic dose range/dosing regimen.

If an investigational drug is a CYP inducer, it can be classified as a strong, moderate, or weak inducer based on its effect on an index CYP substrate.  The convention is to categorize CYP induction in the following ways:

• A strong inducer decreases the AUC of a sensitive index CYP substrate by ≥ 80 percent

• A moderate inducer decreases the AUC of a sensitive index CYP substrate by ≥ 50 to < 80 percent

• A weak inducer decreases the AUC of a sensitive index CYP substrate by ≥ 20 to < 50 percent

This classification information helps to determine whether other drugs that have not been investigated in a DDI study have clinically significant DDIs with the investigational drug and therefore need to be mentioned in labeling.

Currently, there is no standardized classification system for transporter and phase II metabolizing enzyme inducers or inhibitors.

3. Development of DDI Clinical Management and Prevention Strategies

The FDA recommends developing DDI management and prevention strategies when a clinically significant DDI is identified.  An interaction is clinically significant if concomitant use of the drugs leads to safety, efficacy, or tolerability concerns greater than those present when the drugs are administered alone.

In general, DDI clinical management and prevention strategies should result in drug concentrations of the victim drug that are within the no-effect boundaries.  In addition, such strategies should consider several factors, including, but not limited to:

• The exposure-response relationships for safety and efficacy

• The variability of the observed DDI data, if available

• The expected duration of concomitant drug use (e.g., acute, short-term, or chronic use of one or both drugs)

• The timing of the introduction of the concomitant medication (e.g., will the new drug be given to a patient already taking a concomitant medication or will the concomitant medication be given to a patient already taking the new drug)

• The mechanism of the DDI (e.g., competitive, noncompetitive or time-dependent inhibition, induction, combined inhibition and induction)

• The availability of monitoring parameters (e.g., therapeutic drug monitoring, laboratory tests)

• The medical need for the new drug, the ability to interrupt concomitant interacting medications, and the availability of other therapeutic choices in patients with potentially clinically important interactions with the new drug.

With the above considerations, DDI management and prevention strategies may include:

• Contraindicating concomitant use

• Avoiding concomitant use

• Temporarily discontinuing one of the interacting drugs

• Modifying the dosage of the new drug

• Staggering drug administration (e.g., administer the new drug at a different time than an acid-reducing agent)

• Implementing specific monitoring strategies (e.g., therapeutic drug monitoring, laboratory testing)

a. Extrapolating Study Results

• Clinical evaluation of all possible combinations of drugs is not feasible.  When possible, results from DDI studies should be extrapolated to other drugs and clinical situations.

• Results from DDI studies with index drugs are generally relevant to other drugs and may represent a worst-case scenario for other drugs.

• If a strong CYP2D6 index inhibitor results in a significant increase in exposure of the investigational drug, these results can be directly extrapolated to other strong CYP2D6 inhibitors.

• Extrapolation of positive findings to moderate and weak inhibitors is not always possible then a dedicated clinical DDI study is recommended.

• Concomitant-use DDI studies can be warranted in cases when extrapolation is not feasible and drugs with DDI potential are likely to be co-administered.  Although concomitant-use studies have limited potential for extrapolation to other drugs, they may have great relevance to practitioners and patients.