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Guidance for Industry drug interactions, in vitro and in vivo

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Guidance for Industry drug interactions, in vitro and in vivo

    Draft Not for Implementation

    For Discussion Purposes Only

    Drug Interaction Studies

    Study Design, Data Analysis, and Implications

    for

    Dosing and Labeling

    PRELIMINARY CONCEPT PAPER

    For Discussion Purposes Only

    October 1, 2004

    Topic 2A_Concept_paper_drug interactions_Oct_1_2004_Huang_v1

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    TABLE OF CONTENTS

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    21

     A. Drug metabolizing enzyme identification including CYP

    enzymes………….21

     B. Evaluation of CYP

    inhibition…………………………………………………..27

     C. Evaluation of CYP

    induction…………………………………………………..31

VII.

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

Topic 2A_Concept_paper_drug interactions_Oct_1_2004_Huang_v1

    Draft Not for Implementation

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1 Concept paper for discussion purposes only

    2

    3 Drug Interaction Studies

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

    6

    7 I. INTRODUCTION

    8

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

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

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

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

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

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

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

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

    32 the Clinical Evaluation of Drugs (July 1993).

    33

    34

    35 II. BACKGROUND

    36

    37 A. Metabolism

    38

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

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

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

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

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

    52 influence of concomitant medications on hepatic and intestinal metabolism becomes more 53 complicated when a drug, including a prodrug, is metabolized to one or more active 54 metabolites. In this case, the safety and efficacy of the drug/prodrug are determined not 55 only by exposure to the parent drug but by exposure to the active metabolites, which in 56 turn is related to their formation, distribution, and elimination.

    57

    58 B. Drug-Drug Interactions

    59

    60 Many metabolic routes of elimination, including most of those occurring via the P450 61 family of enzymes, can be inhibited, activated, or induced by concomitant drug treatment. 62 Observed changes arising from metabolic drug-drug interactions can be substantial an

    63 order of magnitude or more decrease or increase in the blood and tissue concentrations of 64 a drug or metabolite and can include formation of toxic metabolites or increased

    65 exposure to a toxic parent compound. These large changes in exposure can alter the 66 safety and efficacy profile of a drug and/or its active metabolites in important ways. This 67 is most obvious and expected for a drug with a narrow therapeutic range (NTR), but is 68 also possible for non-NTR drugs as well (e.g., HMG CoA reductase inhibitors). 69 Depending on the extent and consequence of the interaction, the fact that a drug’s 70 metabolism can be significantly inhibited by other drugs and that the drug itself can inhibit 71 the metabolism of other drugs can require important changes in either its dose or the doses 72 of drugs with which it interacts, that is, on its labeled conditions of use. Rarely, metabolic 73 drug-drug interactions may affect the ability of a drug to be safely marketed. 74

    75 The following general principles underlie the recommendations in this concept paper: 76

    77 Adequate assessment of the safety and effectiveness of a drug includes a description of 78 its metabolism and the contribution of metabolism to overall elimination. 79

    80 Metabolic drug-drug interaction studies should explore whether an investigational 81 agent is likely to significantly affect the metabolic elimination of drugs already in the 82 marketplace and, conversely, whether drugs in the marketplace are likely to affect the

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83 metabolic elimination of the investigational drug.

    84

    85 ;

    86 Even drugs that are not substantially metabolized can have important effects on the

    metabolism of concomitant drugs. For this reason, metabolic drug-drug interactions 87

    88 should be explored, even for an investigational compound that is not eliminated 89 significantly by metabolism. Although classical biotransformation studies are not a general

    requirement for the evaluation of therapeutic biologics (ICH document S6 Preclinical 90

    91 Safety Evaluation of Biotechnology-derived Pharmaceuticals‖), certain protein

    92 therapeutics modify the metabolism of drugs that are metabolized by the P450 enzymes. 93 Type I interferons, for example, inhibit CYP1A2 production at the transcriptional and 94 post-translational levels, inhibiting clearance of theophylline. The increased clinical use of 95 therapeutic proteins may raise concerns regarding the potential for their impacts on drug 96 metabolism. Generally, these interactions cannot be detected by in vitro assessment. 97 Consultation with the FDA is appropriate before initiating metabolic drug-drug interaction 98 studies involving biologics.

    99

    100 In some cases, metabolic drug-drug interaction studies are not informative until 101 metabolites and prodrugs have been identified and their pharmacological properties 102 described.

    103

    104 Identifying metabolic differences in patient groups based on genetic polymorphism, 105 or on other readily identifiable factors, such as age, race, and gender, can aid in 106 interpreting results. The extent of interactions may be defined by these variables 107 (e.g., CYP2D6 genotypes). Further, a minor pathway may become important in 108 subjects lacking a particular enzyme and the evaluation of the drug interaction via 109 the minor pathway may be appropriate in these subjects.

    110

    111 The impact of an investigational or approved interacting drug can be either to 112 inhibit, stimulate, or induce metabolism.

    113

    114 A specific objective of metabolic drug-drug interaction studies is to determine 115 whether the interaction is sufficiently large to necessitate a dosage adjustment of 116 the drug itself or the drugs it might be used with, or whether the interaction would 117 require additional therapeutic monitoring.

    118

    119 In some instances, understanding how to adjust dosage in the presence of an 120 interacting drug, or how to avoid interactions, may allow marketing of a drug that 121 would otherwise have been associated with an unacceptable level of toxicity. 122 Sometimes a drug interaction may be used intentionally to increase levels or reduce 123 elimination of another drug (e.g., ritonavir and lopinavir). Rarely, the degree of 124 interaction caused by a drug, or the degree to which other drugs alter its

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125 metabolism, may be such that it cannot be marketed safely.

    126

    127 The blood or plasma concentrations of the parent drug and/or its active 128 metabolites (systemic exposure) may provide an important link between drug dose 129 (exposure) and desirable and/or undesirable drug effects. For this reason, the 130 development of sensitive and specific assays for a drug and its key metabolites is 131 critical to the study of metabolism and drug-drug interactions.

    132

    133 For drugs whose presystemic or systemic clearance occurs primarily by metabolism, 134 differences arising from various sources, including administration of another drug, 135 are an important source of inter-individual and intra-individual variability. 136

    137 Unlike relatively fixed influences on metabolism, such as hepatic function or 138 genetic characteristics, metabolic drug-drug interactions can lead to abrupt 139 changes in exposure. Depending on the nature of the drugs, these effects could 140 potentially occur when a drug is initially administered, when it has been titrated to 141 a stable dose, or when an interacting drug is discontinued. Interactions can occur 142 after even a single concomitant dose of an inhibitor.

    143

    144 The effects of an investigational drug on the metabolism of other drugs and the 145 effects of other drugs on an investigational drug’s metabolism should be assessed 146 relatively early in drug development so that the clinical implications of interactions 147 can be assessed as fully as possible in later clinical studies.

    148

    149 Transporter-based interactions have been increasingly documented. Various reported 150 interactions attributed to other mechanisms of interactions, such as protein-151 displacement or enzyme inhibition may be due in part to the inhibition of transport 152 proteins, such as P-glycoprotein (P-gp), organic anion transporter (OAT), organic 153 anion transport protein (OATP), organic cation transporter (OCT), etc. Examples of 154 transporter-based interactions include the interactions between digoxin and quinidine,

    fexofenadine and ketoconazole or erythromycin, penicillin and probenecid, dofetilide 155

    156 and cimetidine, paclitaxel and valspodar, etc. Of the various transporters, P-gp is the 157 most well understood and may be appropriate to evaluate during drug development. 158

    159

    160 III. GENERAL STRATEGIES

    161

    162 To the extent possible, drug development should follow a sequence where early in vitro and in

    163 vivo investigations can either fully address a question of interest or provide information to guide 164 further studies. Optimally, a sequence of studies should be planned, moving from in vitro studies,

    165 to early exploratory studies, to later more definitive studies, employing special study designs and 166 methodology where necessary and appropriate. In many cases, negative findings from early in

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    167 vitro and early clinical studies can eliminate the need for later clinical investigations. Early 168 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 169

    170 probes and careful selection of interacting drugs for early in vivo studies, the potential for drug-

    171 drug interactions can be studied early in the development process, with further study of observed 172 interactions assessed later in the process, as needed. In certain cases and with careful study 173 designs and planning, these early studies may also provide information about dose, concentration, 174 and response relationships in the general population, subpopulations, and individuals, which can 175 be useful in interpreting the consequences of a metabolic drug-drug interaction. 176

    177 A. In Vitro Studies

    178

    179 A complete understanding of the relationship between in vitro findings and in vivo results

    180 of metabolism/drug-drug interaction studies is still emerging. Nonetheless, in vitro studies

    181 can frequently serve as an adequate screening mechanism to rule out the importance of a 182 metabolic pathway and drug-drug interactions that occur via this pathway so that 183 subsequent in vivo testing is unnecessary. This opportunity should be based on 184 appropriately validated experimental methods and rational selection of 185 substrate/interacting drug concentrations. For example, if suitable in vitro studies at

    186 therapeutic concentrations indicate that CYP1A2, CYP2C9, CYP2C19, CYP2D6, or 187 CYP3A enzyme systems do not metabolize an investigational drug, then clinical studies to 188 evaluate the effect of CYP2D6 inhibitors or CYP1A2, CYP2C9, CYP2C19, or CYP3A 189 inhibitors/inducers on the elimination of the investigational drug will not be needed. 190 Similarly, if in vitro studies indicate that an investigational drug does not inhibit CYP1A2, 191 CYP2C9, CYP2C19, CYP2D6 or CYP3A metabolism, then corresponding in vivo

    192 inhibition-based interaction studies of the investigational drug and concomitant 193 medications eliminated by these pathways are not needed.

    194

    195 The CYP2D6 enzyme has not been shown to be inducible. Recent data have shown co-196 induction of CYP3A and CYP2C/CYP2B enzymes. Therefore, if in vitro studies indicate

    197 that an investigational drug does not induce CYP1A2 or CYP3A metabolism, then 198 corresponding in vivo induction-based interaction studies of the investigational drug and 199 concomitant medications eliminated by CYP1A2, CYP2B6, CYP2C9, CYP2C19, and 200 CYP3A may not be needed.

    201

    202 Drug interactions based on CYP2B6 and CYP2C8 are emerging as important interactions. 203 When appropriate, in vitro evaluations based on these enzymes may be conducted. The 204 other CYP enzymes CYP2A6, CYP2E1, are less likely to be involved in clinically 205 important drug interactions, but should be considered when appropriate. 206

    207 Section VI describes general considerations in the in vitro evaluation of CYP-related

    208 metabolism and interactions. Appendices A, B, and C provide considerations in the

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    209 experimental design, data analysis, and data interpretation in drug metabolizing enzyme 210 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. 211

    212

    213

    214 B. Specific In Vivo Clinical Investigations

    215

    216 Appropriately designed pharmacokinetic studies, usually performed in the early phases of 217 drug development, can provide important information about metabolic routes of 218 elimination, their contribution to overall elimination, and metabolic drug-drug interactions.

    Together with information from in vitro studies, these investigations can be a primary 219

    220 basis of labeling statements and can often help avoid the need for further investigations. 221 Further recommendations about these types of studies appear in section IV of this concept 222 paper.

    223

    224 C. Population Pharmacokinetic Screens

    225

    226 Population pharmacokinetic analyses of data obtained from large-scale clinical studies with 227 sparse or intensive blood sampling can be valuable in characterizing the clinical impact of 228 known or newly identified interactions, and in making recommendations for dosage 229 modifications. The result from such analyses can be informative and sometimes conclusive 230 when the clinical studies are adequately designed to detect significant changes in drug 231 exposure due to drug-drug interactions. Simulations can provide valuable insights into 232 optimizing the study design. It may be possible that population pharmacokinetic analysis 233 could detect unsuspected drug-drug interactions. Population analysis can also provide 234 further evidence of the absence of a drug-drug interaction when this is supported by prior 235 evidence and mechanistic data. However, it is unlikely that population analysis can be 236 used to prove the absence of an interaction that is strongly suggested by information 237 arising from in vivo studies specifically designed to assess a drug-drug interaction. To be

    238 optimally informative, population pharmacokinetic studies should have carefully designed 239 study procedures and sample collections. A guidance for industry on population 1240 pharmacokinetics is available.

    241

    242

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

    244

    245 If in vitro studies and other information suggest a need for in vivo metabolic drug-drug

    246 interaction studies, the following general issues and approaches should be considered. In the 247 following discussion, the term substrate (S) is used to indicate the drug studied to determine if its 248 exposure is changed by another drug, which is termed the interacting drug (I). Depending on the

     1 CDER/CBER guidance for industry ―Population pharmacokinetics‖, February 1999

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    249 study objectives, the substrate and the interacting drug may be the investigational agents or 250 approved products.

    251

    252 A. Study Design

    253

    254 In vivo drug-drug interaction studies generally are designed to compare substrate 255 concentrations with and without the interacting drug. Because a specific study may 256 consider a number of questions and clinical objectives, many study design for studying 257 drug-drug interactions can be considered. A study can use a randomized crossover (e.g., 258 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). 259

    260 The following possible dosing regimen combinations for a substrate and interacting drug 261 may also be used: single dose/single dose, single dose/multiple dose, multiple dose/single 262 dose, and multiple dose/multiple dose. The selection of one of these or another study 263 design depends on a number of factors for both the substrate and interacting drug, 264 including (1) acute or chronic use of the substrate and/or interacting drug; (2) safety 265 considerations, including whether a drug is likely to be an NTR (narrow therapeutic range) 266 or non-NTR drug; (3) pharmacokinetic and pharmacodynamic characteristics of the 267 substrate and interacting drugs; and (4) the need to assess induction as well as inhibition. 268 The inhibiting/inducing drugs and the substrates should be dosed so that the exposures of 269 both drugs are relevant to their clinical use. The following considerations may be useful: 270

    271 Changes in pharmacokinetic parameters may be used to indicate the clinical 272 importance of drug-drug interactions. Interpretation of findings from these studies 273 will be aided by a good understanding of dose/concentration and

    274 concentration/response relationships for both desirable and undesirable drug 275 effects in the general population or in specific populations. A guidance for

    276 industry published in April 2003 provides considerations in the evaluation of 277 exposure-response relationships. In certain instances, reliance on endpoints other 278 than pharmacokinetic measures/parameters may be useful.

    279

    280 When both substrate and interacting drug are likely to be given chronically over an 281 extended period of time, administration of the substrate to steady state with 282 collection of blood samples over one or more dosing intervals could be followed 283 by multiple dose co-administration of the interacting drug, again with collection of 284 blood for measurement of both the substrate and the interacting drug (as feasible)

     1 CDER/CBER guidance for industry ―Exposure-response relationships- study design, data analysis and

    regulatory applications‖ April 2003

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    285 over the same intervals. This is an example of a one-sequence crossover design. 286

    287 The time at steady state before collection of endpoint observations depends on 288 whether inhibition or induction is to be studied. Inducers can take several days or 289 longer to exert their effects, while inhibitors generally exert their effects more 290 rapidly. For this reason, a more extended period of time after attainment of steady 291 state for the substrate and interacting drug may be necessary if induction is to be 292 assessed.

    293

    294 When attainment of steady state is important and either the substrate or interacting 295 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 296

    297 design, rather than a randomized crossover study design.

    298

    299 When a substrate and/or an interacting drug need to be studied at steady state 300 because the effect of interacting drug is delayed as is the case for inducers and 301 certain inhibitors, documentation that near steady state has been attained for the 302 pertinent drug and metabolites of interest is important. This documentation can be 303 accomplished by sampling over several days prior to the periods when samples are 304 collected. This is important for both metabolites and the parent drug, particularly 305 when the half-life of the metabolite is longer than the parent, and is especially 306 important if both parent drug and metabolites are metabolic inhibitors or inducers. 307

    308 Studies can usually be open label (unblinded), unless pharmacodynamic endpoints 309 (e.g., adverse events that are subject to bias) are part of the assessment of the 310 interaction.

    311

    312 For a rapidly reversible inhibitor, administration of the interacting drug either just 313 before or simultaneously with the substrate on the test day might be the 314 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 315

    316 the substrate drug to maximize the effect. If the absorption of an interacting drug 317 (e.g., an inhibitor or an inducer) may be affected by other factors (e.g., the gastric 318 pH), it may be appropriate to control the variables and confirm the absorption via 319 plasma level measurements of the interacting drug.

    320

    321 If the drug interaction effects are to be assessed for both agents in a combination 322 regimen, the assessment can be done in two separate studies. If the 323 pharmacokinetic and pharmacodynamic characteristics of the drugs make it 324 feasible, the dual assessment can be done in a single study. Some design options 325 are randomized three-period crossover, parallel group, and one-sequence 326 crossover.

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