Preliminary concept paper

Draft — Not for Implementation

For Discussion Purposes Only

Drug Interaction Studies —

Study Design, Data Analysis, and Implications for

Dosing and Labeling


PRELIMINARY CONCEPT PAPER

For Discussion Purposes Only

October 1, 2004

TABLE OF CONTENTS

I. INTRODUCTION 1

II. BACKGROUND 1

A. Metabolism 1

B. Metabolic Drug-Drug Interactions 2

III. GENERAL STRATEGIES 4

A. In Vitro Studies 5

B. Specific In Vivo Clinical Investigations 5

C. Population Pharmacokinetic Screens 6

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

A. Study Design 6

B. Study Population 9

C. Choice of Substrate and Interacting Drugs 10

D. Route of Administration 12

E. Dose Selection 13

F. Endpoints 13

G. Sample Size and Statistical Considerations 14

V. LABELING 15

B. Metabolic Drug-Drug Interaction Studies 16

VI. APPENDICES………………………………………………………………….. 21

A. Drug metabolizing enzyme identification including CYP enzymes………….21

B. Evaluation of CYP inhibition…………………………………………………..27

C. Evaluation of CYP induction…………………………………………………..31
VII. REFERENCES………………………………………………………………….34

Concept paper for discussion purposes only
Drug Interaction Studies —

Study Design, Data Analysis, and Implications for Dosing and Labeling
I. INTRODUCTION
This concept paper provides recommendations to sponsors of new drug applications (NDAs) and biologics license applications (BLAs) for therapeutic biologics (hereafter drugs) who intend to perform in vitro and in vivo drug metabolism and drug-drug interaction studies. The concept paper 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 concept paper 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, tissue and/or plasma binding, distribution, and excretion interactions. 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 concept paper.
Discussion of metabolic and other types of drug-drug interactions is provided in the following CDER guidances, Drug Metabolism/Drug Interaction Studies in the Drug Development Process: Studies In Vitro (1997), In Vivo Drug Metabolism/Drug Interaction Studies — Study Design, Data Analysis, and Recommendations for Dosing and Labeling (1999) and 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).

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 gut mucosa, 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 (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. 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.
B. 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. 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). 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 principles underlie the recommendations in this concept paper:
 Adequate assessment of the safety and effectiveness of a drug includes a description of its metabolism and the contribution of metabolism to overall elimination.

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  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.
  

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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. Although classical biotransformation studies are not a general requirement for the evaluation of therapeutic biologics (ICH document S6 “Preclinical Safety Evaluation of Biotechnology-derived Pharmaceuticals”), 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 the FDA is appropriate before initiating metabolic drug-drug interaction studies involving biologics.
 In some cases, metabolic drug-drug interaction studies are not informative until 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 extent of interactions may be defined by these variables (e.g., CYP2D6 genotypes). Further, a minor pathway may become important in subjects lacking a particular enzyme and the evaluation of the drug interaction via the minor pathway may be appropriate in these subjects.
 The impact of an investigational or approved interacting drug can be either to inhibit, stimulate, 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.
 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 (e.g., ritonavir and lopinavir). 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.

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  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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  Transporter-based interactions have been increasingly documented. Various reported interactions attributed to other mechanisms of interactions, such as protein-displacement or enzyme inhibition may be due in part to the inhibition of transport proteins, such as P-glycoprotein (P-gp), organic anion transporter (OAT), organic anion transport protein (OATP), organic cation transporter (OCT), etc. Examples of transporter-based interactions include the interactions between digoxin and quinidine, fexofenadine and ketoconazole or erythromycin, penicillin and probenecid, dofetilide and cimetidine, paclitaxel and valspodar, etc. Of the various transporters, P-gp is the most well understood and may be appropriate to evaluate during drug development.
  

III. 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 at therapeutic concentrations indicate that CYP1A2, 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, CYP2C9, CYP2C19, or CYP3A 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 CYP1A2, 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.
The CYP2D6 enzyme has not been shown to be inducible. Recent data have shown co-induction of CYP3A and CYP2C/CYP2B enzymes. Therefore, if in vitro studies indicate that an investigational drug does not induce CYP1A2 or CYP3A metabolism, then corresponding in vivo induction-based interaction studies of the investigational drug and concomitant medications eliminated by CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A may not be needed.
Drug interactions based on CYP2B6 and CYP2C8 are emerging as important interactions. When appropriate, in vitro evaluations based on these enzymes may be conducted. The other CYP enzymes CYP2A6, CYP2E1, are less likely to be involved in clinically important drug interactions, but should be considered when appropriate.
Section VI describes general considerations in the in vitro evaluation of CYP-related metabolism and interactions. Appendices A, B, and C 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.

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 concept paper.
C. Population Pharmacokinetic Screens
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 result 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. It may be possible that population pharmacokinetic analysis could 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. ¹

IV. DESIGN OF IN VIVO 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
In vivo drug-drug interaction studies generally are designed to compare substrate concentrations with and without the interacting drug. Because a specific study may consider a number of questions and clinical objectives, many study design 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 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 of the 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 exposures of both drugs are relevant to their clinical use. The following considerations may be useful:
 Changes in pharmacokinetic parameters may be used to indicate the clinical importance of drug-drug interactions. 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 or in specific populations. A guidance^ for industry published in April 2003 provides considerations in the evaluation of exposure-response relationships. 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 co-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 the 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 need to be studied at steady state because the effect of 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 important. 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. For a mechanism-based inhibitor, it may be important to administer the inhibitor prior to (e.g., 1 hour) the administration of the substrate drug to 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 via plasma level measurements of the interacting drug.

 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.

X In order to avoid variable study results due to 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 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.”
X If not precluded by considerations of safety or tolerability due to adverse effects, it may be appropriate to estimate the systemic concentrations of a drug and/or its metabolites when there is maximum inhibition of its clearance pathway. For example, there may be a need to evaluate the drug’s QT/QTc prolonging potential at substantially higher concentrations than those anticipated following the therapeutic doses². In these instances, higher systemic concentrations may be achieved by administration of supra-therapeutic doses or by maximum inhibition of a drug’s clearance pathway. If the drug is mainly metabolized by one single enzyme, high exposure can be achieved by the use of an inhibitor of this major metabolic pathway. In certain situations when there may be multiple metabolic pathways or multiple clearance pathways (metabolism and renal excretion), the studies may be conducted with the administration of multiple inhibitors or under multiple impaired conditions. ³ For example, for a drug that is mainly metabolized by CYP3A, the QT evaluation can be conducted with a strong CYP3A inhibitor. Studies of QT prolonging effect of telithromycin with co-administration of ketoconazole illustrate this. When a drug is a substrate for both CYP2D6 and CYP3A, a study involving co-administration of ketoconazole or ritonavir (for CYP3A inhibition) in poor metabolizers of CYP2D6 may be appropriate. For a drug that is both metabolized by CYP3A and excreted via the kidney, it may be appropriate to conduct a study when ketoconazole or ritonavir is co-administered with the investigational drug in patients with renal-impairment. For safety concerns, lower doses of the investigational drug may be appropriate for the initial evaluation to estimate the fold-increase in the systemic exposure. However, prior to the investigation using multiple inhibitors or multiple impaired conditions, the effect of individual inhibition should have been characterized and the combined effects deemed significant based on simulations.

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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, CYP2C19, and CYP2C9 - the CYP enzymes considered as known valid metabolic biomarkers. ⁴ The extent of drug interactions (inhibition or induction) may be different depending on the subjects’ genotype for the specific enzyme being evaluated. Similarly, drug interaction via a minor pathway may become important for subjects lacking the major enzyme that contribute to the metabolism of the drug in the general population.
C. Choice of Substrate and Interacting Drugs
1. 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 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 co-administration 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, (1) midazolam for CYP3A; (2) theophylline for CYP1A2; (3) S-warfarin for CYP2C9; (4) omeprazole for CYP2C19; and (5) desipramine for CYP2D6. Additional examples of substrates, along with inhibitors and inducers of specific CYP enzymes are listed in Table 1. If the initial study is positive for inhibition or induction, further studies of other substrates may be useful, representing a range of substrates based on the likelihood of co-administration.