Guidance for Industry
`
`
`Drug Interaction Studies —
`
`Study Design, Data Analysis, Implications
`
`for Dosing, and Labeling
`
`Recommendations
`
`
`
`
`
`
`DRAFT GUIDANCE
`
`This guidance document is being distributed for comment purposes only.
`
`
`
`U.S. Department of Health and Human Services
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research (CDER)
`
`
`
`
`February 2012
`
`Clinical Pharmacology
`
`
`
`
`
`
`
`
`Comments and suggestions regarding this draft document should be submitted within 90 days of
`publication in the Federal Register of the notice announcing the availability of the draft
`guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and
`Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments
`should be identified with the docket number listed in the notice of availability that publishes in
`the Federal Register.
`
`For questions regarding this draft document contact (CDER) Shiew-Mei Huang, 301-796-1541,
`or Lei Zhang, 301-796-1635.
`
`PAR1011
`IPR of U.S. Patent No. 8,772,306
`Page 1 of 79
`
`

`
`
`
`
`
`
`
`Guidance for Industry
`
`Drug Interaction Studies —
`
`Study Design, Data Analysis,
`
`Implications for Dosing, and Labeling
`
`Recommendations
`
`
`
`Additional copies are available from:
`
`
`Office of Communications
`
`Division of Drug Information, WO51, Room 2201
`
`Center for Drug Evaluation and Research
`
`Food and Drug Administration
`
`10903 New Hampshire Avenue
`
`Silver Spring, MD 20993-0002
`
`Phone: 301-796-3400; Fax: 301-847-8714
`
`
`druginfo@fda.hhs.gov
`
`
`
`http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
`
`U.S. Department of Health and Human Services
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research (CDER)
`
`
`
`
`February 2012
`
`Clinical Pharmacology
`
`
`
`
`
`
`
`
`PAR1011
`IPR of U.S. Patent No. 8,772,306
`Page 2 of 79
`
`

`
`
`
`TABLE OF CONTENTS
`
`
`
`
`
`
`LIST OF FIGURES ................................................................................................................ 2
`
`
`
`
`LIST OF TABLES ..................................................................................................................2
`
`
`
`
` I.
`
`INTRODUCTION.......................................................................................................... 1
`
`
`
`II. SUMMARY OF GUIDANCE....................................................................................... 2
`
`
`
`
`III. BACKGROUND ............................................................................................................ 6
`
`
`
`A. Relevance of Drug Interactions .................................................................................... 6
`
`B. Drug Interaction Considerations for Small Molecule Drugs........................................ 7
`
`C. Drug Interaction Considerations for Therapeutic Proteins......................................... 14
`
`IV. GENERAL STRATEGIES ......................................................................................... 14
`
`
`
`A.
`In Vitro Studies........................................................................................................... 15
`
`B.
`In Vivo Studies ........................................................................................................... 33
`
`1. In Vivo Drug-Drug Interactions ............................................................................. 33
`
`2. In Vivo Drug-Therapeutic Protein (TP) Interactions ............................................. 33
`
`C. Using a Population Pharmacokinetic Approach to Assess Drug-Drug Interactions .. 36
`
`V. DESIGN OF IN VIVO DRUG-DRUG INTERACTION STUDIES ....................... 36
`
`
`
`A. Study Design............................................................................................................... 36
`
`B. Study Population......................................................................................................... 39
`C. Choice of Substrate and Interacting Drugs................................................................. 39
`
`D. Route of Administration ............................................................................................. 55
`
`
`E. Dose Selection ............................................................................................................ 55
`
`F. Endpoints .................................................................................................................... 56
`
`G. Statistical Considerations and Sample Size................................................................ 57
`
`VI. LABELING RECOMMENDATIONS....................................................................... 58
`
`
`
`A. Drug Interactions Section of Labeling........................................................................ 59
`
`B. Clinical Pharmacology Section of Labeling ............................................................... 60
`
`C. Other Labeling Sections.............................................................................................. 62
`
`LIST OF FIGURES IN THE APPENDIX.......................................................................... 63
`
`
`
`
`
`
`APPENDIX............................................................................................................................ 64
`
`
`REFERENCES......................................................................................................................71
`
`
`ABBREVIATIONS............................................................................................................... 75
`
`
`
`
`
`
`
`PAR1011
`IPR of U.S. Patent No. 8,772,306
`Page 3 of 79
`
`
`
`

`
`
`
`List of Figures
`
`
`Figure 1. Illustration of Examples of Efflux and Uptake Transporters in the Gut Wall (A), Liver
`
`
`(B), and Kidneys (C) that May Be Involved in a Drug’s Absorption, Distribution, Metabolism,
`
`and Excretion. ................................................................................................................................. 9
`
`Figure 2. Metabolism-Based Drug-Drug Interaction Studies — Decision Tree ......................... 16
`
`Figure 3. Evaluation of Investigational Drugs as UGT Substrates.............................................. 20
`
`Figure 4. General Scheme of Model-Based Prediction: The Investigational Drug (and
`
`Metabolite Present at ≥25% of Parent AUC) as an Interacting Drug of CYP Enzymes .............. 23
`
`Figure 5. Using a PBPK Model to Explore Drug-Drug Interaction Potential Between a Substrate
`
`Drug and an Interacting Drug. ...................................................................................................... 29
`
`Figure 6. Evaluation of Investigational Drugs as Substrates for P-gp, BCRP, OATP1B1,
`
`OATP1B3, OAT1, OAT3, and OCT2 Transporters. .................................................................... 31
`
`Figure 7. Summary of The Types of Studies That Have Been Used During Drug Development to
`
`Evaluate Therapeutic Protein (TP)–Small-Molecule Drug (D) Interactions................................ 35
`
`Figure 8. The Effect of Various CYP Inhibitors on a Hyperthetical Drug’s PK as Displayed as
`
`90% Confidence Interval of Geometric Mean AUC and Cmax Ratios.......................................... 61
`
`
`
`
`List of Tables
`
`Table 1. Selected Transporter-Mediated Clinical Significant Drug-Drug Interactions............... 12
`
`Table 2. In Vitro CYP Inducers ................................................................................................... 27
`
`Table 3. Classification of In Vivo Inhibitors of CYP Enzymes .................................................. 41
`
`Table 4. Classification of In Vivo Inducers of CYP Enzymes .................................................... 43
`
`Table 5. Examples of Sensitive In Vivo CYP Substrates and CYP Substrates with Narrow
`
`Therapeutic Range ........................................................................................................................ 44
`
`Table 6. Examples of In Vivo Inhibitors and Inducers of Selected Transporters........................ 49
`
`
`Table 7. Examples of In Vivo Substrates of Selected Transporters ............................................ 51
`
`Table 8. Examples of In Vivo CYP3A and P-gp Inhibitors and Their Relative Potency............ 53
`
`
`
`PAR1011
`IPR of U.S. Patent No. 8,772,306
`Page 4 of 79
`
`

`
`
`Contains Nonbinding Recommendations
`
`Draft – Not for Implementation
`
` Guidance for Industry1
`
`Drug Interaction Studies — Study Design, Data Analysis,
`Implications for Dosing, and Labeling Recommendations
`
`
`
`
`
`
`
`
`
`INTRODUCTION
`
`
`This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current
`thinking on this topic. It does not create or confer any rights for or on any person and does not operate to
`bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of
`the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA
`staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call
`the appropriate number listed on the title page of this guidance.
`
`
`
`I.
`
`This guidance provides recommendations for sponsors of new drug applications (NDAs) and
`biologics license applications (BLAs) for therapeutic biologics regulated by CDER regarding in
`vitro and in vivo studies of drug metabolism, drug transport, and drug-drug or drug-therapeutic
`protein interactions. Drug interactions can result when one drug alters the pharmacokinetics of
`another drug or its metabolites. Drug interactions also can reflect the additive nature of the
`pharmacodynamic effect of either drug when taken with the other drug. The main focus of this
`guidance is pharmacokinetic drug interactions. This guidance reflects the Agency’s view that
`the pharmacokinetic interactions between an investigational new drug and other drugs should be
`defined during drug development, as part of an adequate assessment of the drug’s safety and
`effectiveness. It is important to understand the nature and magnitude of drug-drug interactions
`(DDI) for several reasons. Concomitant medications, dietary supplements, and some foods, such
`as grapefruit juice, may alter metabolism and/or drug transport abruptly in individuals who
`previously had been receiving and tolerating a particular dose of a drug. Such an abrupt
`alteration in metabolism or transport can change the known safety and efficacy of a drug.
`
`FDA’s guidance documents, including this guidance, do not establish legally enforceable
`responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should
`be viewed only as recommendations, unless specific regulatory or statutory requirements are
`cited. The use of the word should in Agency guidances means that something is suggested or
`recommended, but not required.
`
`
`
`
`
` 1 This guidance has been prepared by the Drug-Drug Interaction Working Group in the Office of Clinical
`
` Pharmacology, Office of Translational Sciences, in the Center for Drug Evaluation and Research (CDER), with
`
`
`input from other offices in CDER.
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`38
`39
`
`
`
`PAR1011
`IPR of U.S. Patent No. 8,772,306
`Page 5 of 79
`
`

`
`Contains Nonbinding Recommendations
`
`Draft – Not for Implementation
`
`SUMMARY OF GUIDANCE
`
`
`
`
`II.
`
`The key recommendations for sponsors to consider when evaluating drug-drug interactions
`during drug development are listed below. The various sections of this guidance provide more
`details for each recommendation.
`
`
`
`
`Interactions between an investigational new drug and other drugs should be defined during
`drug development, as part of an adequate assessment of the drug’s safety and effectiveness.
`The objective of drug-drug interaction studies is to determine whether potential interactions
`between the investigational drug and other drugs exist and, if so, whether the potential for
`such interactions indicates the need for dosage adjustments, additional therapeutic
`monitoring, a contraindication to concomitant use, or other measures to mitigate risk.
`
`
`
` Development of a drug should include identification of the principal routes of elimination,
`quantitation of the contribution by enzymes and transporters to drug disposition, and
`characterization of the mechanism of drug-drug interactions.
`
`
`
` Sponsors who believe a complete evaluation of the potential for drug-drug interactions is not
`necessary for an investigational drug because of the target population and likely co­
`administered drugs should contact the Office of Clinical Pharmacology and the clinical
`division in the Office of New Drugs.
`
`
`
` This guidance and its appendices include numerous decision trees intended to help sponsors
`determine what types of drug-drug interaction studies may be needed (see Figures 2 through
`7 and Appendix Figures A-1 through A-6).
`
`
`
` The study of drug-drug interaction for a new drug generally begins with in vitro studies to
`determine whether a drug is a substrate, inhibitor, or inducer of metabolizing enzymes. The
`results of in vitro studies will inform the nature and extent of in vivo studies that may be
`
` required to assess potential interactions. Along with clinical pharmacokinetic data, results
`from in vitro studies may serve as a screening mechanism to rule out the need for additional
`in vivo studies, or provide a mechanistic basis for proper design of clinical studies using a
`modeling and simulation approach.
`
`
`
` When 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
`in vivo studies identifying the enzyme systems that metabolize the investigational drug. The
`choice of the interacting drug can then be based on known, important inhibitors and inducers
`of the pathway under investigation. Strong inhibitors and inducers provide the most sensitive
`assessment and should generally be tested first (see section V.C).
`
`
`
`
`
`If potential drug-drug interactions are identified based on in vitro and/or in vivo studies,
`sponsors should design further studies or collect information to determine (1) whether
`
`40
`41
`42
`43
`44
`45
`46
`47
`48
`49
`50
`51
`52
`53
`54
`55
`56
`57
`58
`59
`60
`61
`62
`63
`64
`65
`66
`67
`68
`69
`70
`71
`72
`73
`74
`75
`76
`77
`78
`79
`80
`81
`82
`83
`
`
`
`2
`
`
`PAR1011
`IPR of U.S. Patent No. 8,772,306
`Page 6 of 79
`
`

`
`Contains Nonbinding Recommendations
`
`Draft – Not for Implementation
`
`
`
`additional studies are needed to better quantify the effect and to examine the effects of
`weaker inhibitors (early studies usually examine strong inhibitors) on the investigational
`drugs as substrates and effects of investigational drugs (as inhibitors) on a range of
`substrates, and (2) whether dosage adjustments or other prescribing modifications (e.g.,
`additional safety monitoring or contraindications) are needed based on the identified
`
`interaction(s) to avoid undesired consequences.
`
`
`
` The potential for drug interactions with metabolites of investigational drugs (metabolites
`present at 25% of parent drug AUC) should be considered (see section IV.A.3).
`
`
`
` Metabolic drug-drug interactions should also be explored for investigational drugs that are
`not eliminated significantly by metabolism because such drugs can inhibit or induce a co­
`administered drug’s metabolic pathway (see section IV.A.1).
`
`
`
` When evaluating a new drug as a potential cytochrome P450 (CYP) enzyme inhibitor,
`sponsors should consider a stepwise, model-based evaluation of metabolism-based
`interactions (from basic model for initial assessment to more mechanistic models including
`physiologically-based pharmacokinetic (PBPK) modeling) (see section IV.A.1). The criteria
`used for assessing “equivalence” (e.g., predicted AUC ratio of 0.8-1.25 using population-
`based PBPK models) may be used as an initial cutoff in deciding whether in vivo studies are
`needed. The criteria discussed in this guidance document are suggested values. We are open
`to discussion based on sponsors’ interpretation.
`
`
`
`-
`
`
`
`PBPK is a useful tool that can help sponsors (1) better design drug-drug interaction
`studies, including dedicated trials and population pharmacokinetic studies, and (2)
`quantitatively predict the magnitude of drug-drug interactions in various clinical
`situations. PBPK models also may offer useful alternatives to dedicated clinical
`studies.
`
`
`
`- When submitting PBPK studies to CDER, sponsors should provide details of model
`assumptions, physiological and biological plausibility, the origin of the parameters,
`and information on uncertainty and variability.
`
`
`
` The evaluation of CYP enzyme induction should begin with studies of CYP1A2, CYP2B6,
`and CYP3A in vitro (Figure 4). If the in vitro induction results are positive according to
`predefined thresholds using basic models, the investigational drug is considered an enzyme
`
`inducer and further in vivo evaluation may be warranted. Alternatively, a sponsor can
`estimate the degree of drug-drug interactions using mechanistic models to determine the need
`for further in vivo evaluation (see section IV.A.1.b-3).
`
`
`
`-
`
`
`
`It should be noted that there may be mechanisms of induction that are presently
`unknown. Therefore, a potential human teratogen needs to be studied in vivo for
`effects on contraceptive steroids if the drug is intended for use in fertile women,
`regardless of in vitro induction study results.
`
`84
`85
`86
`87
`88
`89
`90
`91
`92
`93
`94
`95
`96
`97
`98
`99
`100
`101
`102
`103
`104
`105
`106
`107
`108
`109
`110
`111
`112
`113
`114
`115
`116
`117
`118
`119
`120
`121
`122
`123
`124
`125
`126
`127
`
`
`
`3
`
`
`PAR1011
`IPR of U.S. Patent No. 8,772,306
`Page 7 of 79
`
`

`
`Contains Nonbinding Recommendations
`
`Draft – Not for Implementation
`
`In addition to CYPs, other metabolizing enzymes (e.g., uridine diphosphate (UDP)­
`glucuronosyl transferases (UGTs)) that may be important for the drugs under evaluation
`should also be considered (see section IV.A.1).
`
`
`
` A number of transporter-based interactions have been documented in recent years (see Table
`1, section III.B.2).
`
`
`
`
`
`
`
`
`
`
`
`- All investigational drugs should be evaluated in vitro to determine whether they are a
`potential substrate of P-glycoprotein (P-gp) or Breast Cancer Resistance Protein
`(BCRP) (see Figure 6, left panel, section IV.A.2). Investigational drugs should be
`evaluated in vitro to determine whether they are a substrate of hepatic uptake
`transporters Organic Anion Transporting Polypeptide 1B1(OATP1B1) or OATP1B3
`when their hepatic pathway is significant (see Figure 6, middle panel, section
`IV.A.2). Similarly, investigational drugs should be evaluated in vitro to determine
`whether they are a substrate of Organic Aniton Transporter 1 (OAT1) or OAT3 or
`Organic Cation Transporter 2 (OCT2) when renal active secretion is important
`(Figure 6, right panel, section IV.A.2).
`
`
`
`- Because there have been clinically significant interactions demonstrated for critical
`drugs that are known substrates for P-gp (e.g., digoxin), BCRP (e.g., rosuvastatin),
`OATP1B1/OATP1B3 (e.g., statin drugs), OAT1/OAT3 (e.g., methotrexate, tenofovir)
`and OCT2 (e.g., metformin), evaluation of investigational drugs as inhibitors for
`these transporters should be conducted (see section IV.A.2).
`
`
`- The need for further in vivo drug interaction studies based on in vitro evaluation will
`be based on the criteria described in the decision trees in Figures A1-A6 in the
`Appendix.
`
`
`
` Because of the lack of a validated in vitro system to study transporter induction, the
`definitive determination of induction potential of an investigational drug on transporters is
`based on in vivo induction studies. The sponsor should consult with CDER about studying
`induction of transporters in vivo.
`
`
`
` Human clinical studies to assess drug-drug interactions may include simultaneous
`administration of a mixture of substrates of multiple CYP enzymes and transporters in one
`study (i.e., a “cocktail approach”) to evaluate a drug’s inhibition or induction potential (see
`section V.C.3). Negative results from a well-conducted cocktail study may eliminate the
`need for further evaluation of particular CYP enzymes and transporters. However, positive
`results may indicate that further in vivo evaluation should be conducted.
`
`
`
`
` The potential for interactions with drug products should be considered for certain classes of
`therapeutic proteins (TPs) (see Figure 7, section IV.B.2).
`
`
`
`128
`129
`130
`131
`132
`133
`134
`135
`136
`137
`138
`139
`140
`141
`142
`143
`144
`145
`146
`147
`148
`149
`150
`151
`152
`153
`154
`155
`156
`157
`158
`159
`160
`161
`162
`163
`164
`165
`166
`167
`168
`169
`170
`171
`
`
`
`4
`
`
`PAR1011
`IPR of U.S. Patent No. 8,772,306
`Page 8 of 79
`
`

`
`
`
`-
`
`
`
`
`-
`
`
`
`Contains Nonbinding Recommendations
`
`Draft – Not for Implementation
`
`If an investigational TP is a cytokine or cytokine modulator, studies should be
`conducted to determine the TP’s effects on CYP enzymes or transporters. The in
`vivo evaluations of TPs in targeted patient populations can be conducted with
`
`individual substrates for specific CYP enzymes and transporters, or studies can be
`
`conducted using a “cocktail approach” (see section V.C.3).
`
`For TPs that will be used in combination with other drug products (small molecule or
`TP) as a combination therapy, studies should evaluate the effect of each product on
`the other. This evaluation is particularly important when the drug used in
`combination has a narrow therapeutic range.
`
`
`
`
`- When there are known mechanisms or prior experience with certain PK or PD
`interactions for other similar TPs, appropriate in vitro or in vivo assessments for
`possible interactions should be conducted.
`
`
`
`
` Refer to section V for information regarding in vivo drug interaction study design. The
`section also contains tables on classification of in vivo inhibitors (Table 3) or inducers for
`CYP enzymes (Table 4), examples of sensitive in vivo CYP substrates and CYP substrates
`with narrow therapeutic ranges (Table 5), examples of in vivo inhibitors and inducers of
`selected transporters (Table 6), examples of in vivo substrates of selected transporters (Table
`7) and examples of in vivo CYP3A and P-gp inhibitors and their relative potency (Table 8).
`
`
`
`
`
`-
`
`
`
`Simulations (e.g., by population-based PBPK models) can provide valuable insight
`into optimizing the study design (see section IV.A.1).
`
`
`
`- Detailed information on the dose given and time of administration should be
`documented for the co-administered drugs. When relevant for the specific drug, the
`time of food consumption should be documented.
`
`-
`
`
`
`Population pharmacokinetic (PopPK) analyses of data obtained from large-scale
`clinical studies that include sparse or intensive blood sampling can help characterize
`the clinical impact of known or newly identified interactions and determine
`recommendations for dosage modifications for the investigational drug as a substrate
`(section V.B). DDI analyses using a population PK approach should focus on
`excluding a specific clinically meaningful PK change. Because exposure of co­
`administered drugs is not monitored in most PopPK studies, the PopPK approach may
`not be useful to assess the effect of the investigational drugs on other drugs.
`
`
`
` The likelihood of drug interactions in specific populations (e.g., patients with organ
`impairment, and pediatric and geriatric patients) should be considered on a case-by-case
`basis. PBPK modeling (if well verified for intended purposes) can be helpful to guide the
`determination of the need to conduct population-specific studies (see “Populations” in
`section V.B and “Complex Drug Interactions” section V.C.4).
`
`
`
`172
`173
`174
`175
`176
`177
`178
`179
`180
`181
`182
`183
`184
`185
`186
`187
`188
`189
`190
`191
`192
`193
`194
`195
`196
`197
`198
`199
`200
`201
`202
`203
`204
`205
`206
`207
`208
`209
`210
`211
`212
`213
`214
`215
`
`
`
`5
`
`
`PAR1011
`IPR of U.S. Patent No. 8,772,306
`Page 9 of 79
`
`

`
`Contains Nonbinding Recommendations
`
`Draft – Not for Implementation
`
`
`
` Additional study design issues are discussed throughout the guidance (e.g., route of
`administration (section V.D), dose selection (section V.E), defining endpoints (section V.F),
`and statistical considerations (section V.G)).
`
`
`
` Labeling recommendations with regard to drug interactions are described in section VI.
`
`
`
`- A forest plot is considered a useful tool for presenting changes in pharmacokinetic
`exposure measures by various intrinsic and extrinsic factors including drug
`interactions in the PHARMACOKINETIC subsection of the labeling (see Figure 8,
`section VI).
`
`
`
`-
`
`
`
`216
`217
`218
`219
`220
`221
`222
`223
`224
`225
`226
`227
`228
`229
`230
`231
`232
`233
`234
`235
`236
`237
`238
`239
`240
`241
`242
`243
`244
`245
`246
`
`III. BACKGROUND
`247
`
`248
`
`249 A.
`
`250
`The desirable and undesirable effects of a drug are related to its concentration at various sites of
`251
`action, which is usually related to the blood or tissue concentration of the drug. The blood or
`252
`tissue concentrations resulting from a dose are determined by the drug’s absorption, distribution,
`253
`254 metabolism, and excretion (ADME). Elimination of a drug or its active metabolites occurs either
`by metabolism to an inactive metabolite that is excreted, or by direct excretion of the drug or
`255
`active metabolites. The kidneys and liver are responsible for most drug excretion. Drug
`256
`interactions related to metabolism and excretion are well-recognized, but effects related to
`257
`transporters are being documented with increasing frequency and are, therefore, important to
`258
`consider in drug development. Therapeutic proteins may be eliminated through a specific
`259
`
`If the sponsor wishes to include a statement in the labeling that no known drug-drug
`interaction of clinical significance exists, the sponsor should recommend specific no
`effect boundaries, or clinical equivalence intervals, for a drug-drug interaction and
`should provide the scientific justification for the recommendations. No effect
`boundaries represent the interval within which a change in a systemic exposure
`measure is considered not clinically meaningful. These conclusions can be based on
`exposure-response or dose-response data.
`
`
`
` Sponsors are encouraged to communicate with the Office of Clinical Pharmacology or the
`appropriate clinical review divisions within CDER regarding questions about drug
`interactions, in particular when
`
`
`
`- Using mechanistic or PBPK models for the prediction of drug-drug interactions
`including evaluation of complex drug-drug interactions
`- Determining the need to evaluate drug interactions with non-CYP enzymes or
`additional transporters that are not included in the decision trees
`- Determining drug-drug interaction studies involving TPs.
`
`Relevance of Drug Interactions
`
`
`
`
`
`
`
`6
`
`
`PAR1011
`IPR of U.S. Patent No. 8,772,306
`Page 10 of 79
`
`

`
`Contains Nonbinding Recommendations
`
`Draft – Not for Implementation
`
`The overall objective of interaction studies for a new drug is to determine:
`
`
`interaction with cell surface receptors, followed by internalization and lysosomal degradation
`260
`261 within the target cell.
`262
`263
`264
`265
`266
`267
`268
`269
`270
`In some instances, understanding how to adjust a dose or dosage regimen in the presence of an
`271
`interacting drug, or how to avoid drug-drug interactions, may allow marketing of a drug that
`272
`273 would otherwise have an unacceptable level of risk. In a few cases, consequences of an
`interaction have led to the conclusion that the drug could not be marketed safely. In almost all of
`274
`these cases, that conclusion was strengthened by the availability of alternative drugs with lower
`275
`risks for interactions. Several drugs have been withdrawn from the market because of significant
`276
`drug interactions that led to QT prolongation and Torsades de Pointes (TdP) arrhythmias, after
`277
`278 warnings in drug labels did not adequately manage the risk of drug interactions. For example,
`terfenadine and astemizole, two early nonsedating antihistamines metabolized by CYP3A, were
`279
`280 withdrawn after labeling failed to reduce cases of TdP sufficiently, because fexofenadine and
`loratadine fulfilled the need for nonsedating antihistamines that had no risk of TdP. Cisapride, a
`281
`282 CYP3A metabolized drug, was withdrawn because its gastrointestinal benefits were not felt to
`outweigh its TdP risk. A fourth drug, mibefradil (a calcium channel blocker similar to verapamil
`283
`and diltiazem) was a strong CYP3A inhibitor and, when used with simvastatin, caused
`284
`rhabdomyolysis because of markedly increased simvastatin exposure.
`285
`286
`287
`
`288 B.
`Drug Interaction Considerations for Small Molecule Drugs
`
`289
`The main focus of this guidance is pharmacokinetic drug interactions. The drug development
`290
`process should include evaluation of a new drug’s potential to affect the metabolism or transport
`291
`of other drugs and the potential for the new drug’s metabolism or transport to be affected by
`292
`other drugs. Use of in vitro tools to determine whether a drug is a substrate, inhibitor, or inducer
`293
`of metabolizing enzymes, followed by in vivo interaction studies to assess potential interactions,
`294
`has become an integral part of drug development and regulatory review. In addition to the
`295
`evaluation of metabolic drug interactions, the role of transporters in drug interactions should be
`296
`evaluated. This section will separately discuss drug-drug interactions at the levels of
`
`297
`298 metabolizing enzymes and transporters, and also consider situations when multiple drug-drug
`interaction mechanisms are present.
`299
`
`300
`1.
`301
`302
`
`
`
` whether any interactions are sufficiently large to necessitate a dosage adjustment of the
`drug itself or of the drugs with which it might be used,
` whether any interactions calls for additional therapeutic monitoring, or
` whether there should be a contraindication to concomitant use when lesser measures
`cannot mitigate risk.
`
`Metabolism-Based Drug-Drug Interactions
`
`
`
`
`
`
`
`
`
`
`
`
`7
`
`
`PAR1011
`IPR of U.S. Patent No. 8,772,306
`Page 11 of 79
`
`

`
`Contains Nonbinding Recommendations
`
`Draft – Not for Implementation
`
`Hepatic metabolism occurs primarily through the cytochrome P450 family (CYP) of
`enzymes located in the hepatic endoplasmic reticulum, but may also occur through non­
`CYP enzyme systems, such as glucuronosyl- and sulfo-transferases, which can, in
`general, inactivate a drug and increase its renal elimination. Some drug metabolizing
`enzymes are present in the gut wall and other extrahepatic tissues, in addition to the liver.
`
`Many metabolic routes of elimination can be inhibited or induced by concomitant drug
`treatment. Metabolic drug-drug interactions can cause substantial changes — an order of
`magnitude or more decrease or increase in the blood and tissue concentrations of a drug
`or metabolite — and can affect the extent to which toxic or active metabolites are
`formed. These large changes in exposure can alter the safety and efficacy profile of a
`drug and its active metabolites, regardless of whether the drug has a narrow therapeutic
`range (NTR). For example, certain HMG-CoA reductase inhibitors (e.g., lovastatin,
`simvastatin) that are extensively metabolized by CYP3A can have a 10-fold or more
`increase in blood levels when their metabolism is inhibited by co-administration with
`strong CYP3A inhibitors such as mibefradil or ketoconazole, or even moderate inhibitors
`such as erythromycin. Although the HMG-CoA reductase inhibitors are not NTR drugs,
`the blood level increases caused by interactions between HMG-CoA reductase inhibitors
`and CYP3A inhibitors can cause myopathy and in some cases rare and life-threatening
`
`rhabdomyolysis.
`
`In addition to evaluating a drug as a substrate of an enzyme that another drug may inhibit
`or induce, it is important to determine whether an investigational drug significantly
`affects the metabolic elimination of