Review of Transporter-Related Postmarketing Requirement or Postmarketing Commitment Studies

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1 Supplement Article Review of Transporter-Related Postmarketing Requirement or Postmarketing Commitment Studies The Journal of Clinical Pharmacology (2016), 56(S7) S193 S204 C 2016, The American College of Clinical Pharmacology DOI: /jcph.770 Ying Fan, PhD 1,2, Bo Sun, PhD 1,3,4, Sheetal Agarwal, PhD, RAC 1, and Lei Zhang, PhD 1 Abstract The objectives of this report are to summarize the content and status of transporter-related postmarketing requirement (PMR)/postmarketing commitment (PMC) studies in new drug applications (NDAs) approved by the U.S. Food and Drug Administration (FDA) and to discuss the reasons for requesting such studies and the impact of PMR/PMC study results on labeling to guide the optimal use of the drugs.multiple data sources were searched to collect information on transporter-related PMR/PMC studies between January 1999 and May A total of 40 transporter-related PMR/PMC study requests were issued for 35 NDAs. Among these PMR/PMC studies, 27 requested studies related to P-glycoprotein. As of May 31, 2015, 34 transporter-related PMR/PMC studies (85%) are considered fulfilled (per the FDA s PMR/PMC website), and 22 (65%) resulted in labeling updates. The majority of the PMR/PMC studies are for drugs in the therapeutic areas of anti-infectives, oncology, and neurology. The results from PMR/PMC studies are important for dosing optimization and are often included in the updated labeling. Because a significant lag time is anticipated between drug approval and PMR/PMC fulfillment, NDA applicants are encouraged to include transporter-related assessments in clinical drug development programs for drug products. Keywords transporters, new molecular entity (NME), postmarketing requirement (PMR), postmarketing commitment (PMC), drug drug interaction (DDI), regulatory, labeling Membrane transporters, especially those expressed in epithelia of the intestine, liver, and kidney and in the endothelium of the blood brain barrier can have clinically relevant effects on the pharmacokinetics and exposure of a drug in various organs and tissues by controlling its absorption, distribution (eg, tissue-specific drug targeting), and elimination. 1 3 In turn, they may affect a drug s safety and efficacy. 4 6 In the past few decades, general scientific consensus has implicated several transporters in drug interactions for commonly used drugs; these transporters include P-glycoprotein (P-gp; or multidrug resistance 1 [MDR1]), breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1/1B3 (OATP1B1/1B3), organic anion transporter 1 and 3 (OAT1/OAT3), multidrug and toxin extrusion proteins (MATEs), and organic cation transporter 2 (OCT2) The importance of evaluating transporter-mediated drug drug interactions (DDIs) during drug development and regulatory review has been highlighted in several publications and scientific meetings, such as the U.S. Food and Drug Administration s (FDA s) draft DDI guidance in 2006, the International Transporter Consortium (ITC) white paper in 2010, the Clinical Pharmacology Advisory Committee Meeting in 2010, the FDA s revised draft DDI guidance in 2012, the European Medicines Agency s Scientific Guideline on the Investigation of Drug Interactions in 2012, the Pharmaceuticals Medical Devices Agency s draft drug interaction guideline in 2013, and the recently published ITC white papers in ,10 22 The FDA also periodically updates information on its Drug Development and Drug Interaction website 23 to provide decision frameworks that outline thought processes to determine if in vivo transporter-based DDI studies should be conducted for an investigational drug based on in vitro assessment. Examples of probe substrates 1 Office of Clinical Pharmacology,Office of Translational Sciences,Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA 2 Current Affiliation: Office of Bioequivalence, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA 3 Oak Ridge Institution for Science and Education (ORISE) Fellow, Oak Ridge, TN, USA 4 Current Affiliation: Department of Pharmacy, Shanghai General Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,P.R.China Submitted for publication 24 January 2016; accepted 11 May Corresponding Author: Lei Zhang, PhD, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration New Hampshire Avenue, Silver Spring, MD leik.zhang@fda.hhs.gov Ying Fan and Bo Sun contributed equally to this work.

2 S194 The Journal of Clinical Pharmacology / Vol 56 S7 (2016) and inhibitors for enzymes and transporters are also provided on the website as a reference tool. Drug interaction studies may be conducted prior to or after drug approval for proper recommendations in the labeling to guide health care providers and patients. Prior to 2007, the FDA used the term postmarketing commitment (PMC) to refer to the studies (including clinical trials), which are agreed/committed to be conducted by an applicant after the drug has been approved for marketing or licensing. These studies were intended to further refine the safety, efficacy, or optimal use of a product or to ensure consistency and reliability of product quality and performance. These PMCs were either agreed on by the FDA and the applicant or, under certain circumstances, required by the FDA. 24,25 Postmarketing studies may also include certain studies that had been initiated by the applicants prior to drug approval, and results are allowed to be submitted postapproval to ensure the FDA s timely approval of drugs in therapeutic areas with major unmet medical needs such as oncology. In 2007, the Food and Drug Administration Amendments Act of 2007 (FDAAA) authorized the FDA to require certain postmarketing studies and clinical trials for prescription drugs and biological products approved under section 505 of the FDAAA or section 351 of the Public Health Service Act. It also describes the types of postmarketing studies and clinical trials that: (1) will generally be required under the new legislation (postmarketing requirements (PMRs)), and (2) will generally be agreed-on commitments (postmarketing commitments (PMCs)) because they do not meet the new statutory criteria for required postmarketing studies and clinical trials. Further details of PMRs and PMCs can be found in the FDA s guidance titled Guidance for Industry: Postmarketing Studies and Clinical Trials Implementation of Section 505 (o) of the Federal Food, Drug, and Cosmetic Act. 24 As the knowledge of transporter science is evolving, tools to study transporters are being developed, and the emerging importance of transporters in drug interactions is being increasingly appreciated. 7 12,26 29 Clinical studies are recommended for drugs that are either inhibitors or substrates of transporters based on the drug s safety margin, therapeutic range, and likely comedications used in the intended patient populations that are known substrates or inhibitors of the same transporters. The objective of this report is to summarize the content and status of transporter-related PMR/PMC studies in new drug application (NDA) approvals from January1999 to May We also report the rationale for requesting such studies and the impact of study results on product labeling to guide the optimal use of the drugs. Methods We searched multiple data sources including the FDA s internal review database, Drugs@FDA, and the FDA s PMR/PMC website for reports, legislative background, Frequently Asked Questions (FAQs), downloadable database files, and status and fulfillment categories to collect information on transporter-related PMR/PMC studies between January 1, 1999, and May 31, ,31 We reviewed and summarized the current status, reasons, and content of transporter-related postmarketing studies for NDAs and the impact on drug labeling based on study results of these studies. Positive results and negative results are defined based on the conclusions stated in the respective FDA reviews. Postmarketing transporter-related studies conducted by applicants or academic groups that are not part of PMR/PMC stated in the approval letters are not included in our report. Results Summary of Transporter-Related Postmarketing Studies Our review of the information indicates that a total of 40 transporter-related postmarketing study requests were issued for 35 NDAs (Table 1, Figure 1) from January 1999 to May Among these 35 NDAs with transporter-related postmarketing studies, 30 NDAs requested transporter PMR/PMC studies during the initial approval, and the remaining 5 NDAs requested transporter PMR/PMC studies post initial approval (Table 1). All these 35 NDAs are for approval of new molecular entities (NMEs). Of note, a total of 385 NMEs were approved by the FDA from January 1999 to May Therefore, about 9% of NME NDAs (35 of 385) included a postmarketing study request related to transporters between 1999 and In addition, only 6 transporter-related postmarketing study requests were made between 1999 and 2006 (prior to 2007), and 34 postmarketing study requests were made between 2007 and 2015 (after 2007); see Figure 1. Among the 40 transporter-related postmarketing studies, 27 studies involved DDI assessment with P-gp (68%, 27 of 40), and 16 studies (40%, 16 of 40) involved DDI assessment with other transporters such as OATP, BCRP, and renal transporters (eg, OCT2, MATE1, OAT1, OAT3, MRP2, MRP4; see Tables 1 and 2). These postmarketing studies include studying NMEs as a substrate, inhibitor, or a mixture of both for various transporters. Since 2012, an increasing number of postmarketing studies have been requested for the assessment of interactions with transporters other than P-gp such as OATP, OCT, BCRP, and MRP. For example, between January 2012 and May 2015, 6 of 9

3 Fan et al S195 Table 1. Summary of Transporter-Related PMR/PMC Study Requests from January 1, 1999 to May 31, 2015 Original NDA Approval Date NDA Number Brand Name (Drug Name) Current Status Content Labeling Change Following PMR/PMC Study Review? (,, or N/A) 9/15/ Rapamune (sirolimus) Fulfilled PMC 15: (a) you will provide us with the data published in the literature and/or data generated from additional studies to better define the effect of the P-glycoprotein efflux system on sirolimus pharmacokinetics; (b) studies are going using a subclone of the human intestinal Caco-2 cell line with induced CYP3A4 activity to examine the combined effect of metabolism and efflux on sirolimus disposition. To gain a better understanding of the roles of intestinal metabolism and efflux, you agree to complete this in vitro study and submit the data for review. 10/26/ Viread (tenofovir disoproxil fumarate) 9/20/ Hepsera (adefovir/dipivoxil) t fulfilled PMC 8: characterization of the specific renal transport pathways of tenofovir in vivo (anionic vs cationic transport). Once determined, evaluate the potential DDI between VIREAD and drugs that are renally eliminated and frequently used by the HIV population. Specific examples may include acyclovir, valacyclovir, ganciclovir, valganciclovir, and cidofovir. The study design should mimic clinical conditions with regard to dosing with/without food. Fulfilled PMC 6: characterize the specific renal transport pathways of adefovir in vivo (anionic vs cationic transport); evaluate the potential for DDI between adefovir and drugs that are renally eliminated and may be coadministered in patients with coexisting diseases. 6/22/ Aptivus (tipranavir) Fulfilled PMC 17: conduct a CYP/P-gp mechanistic study to determine effect of tipranavir/ritonavir on individual CYPs. 10/6/ Zolinza (vorinostat) Fulfilled PMC 6: Merck commits to conduct 2 in vitro efflux studies; one to determine whether vorinostat is a substrate of P-glycoprotein and one to determine whether vorinostat is an inhibitor of P-gp. 10/25/ Tyzeka (telbivudine) Fulfilled PMC 8: conduct and submit a final study report(s) for in vitro studies to evaluate if telbivudine is a P-gp inhibitor. 3/13/ Tykerb (lapatinib ditosylate) Fulfilled PMC 3: based on the ability of lapatinib to act as a P-gp inhibitor in vitro, GSK agrees to perform an in vivo drug interaction study of the ability of steady-state lapatinib dosing to alter the pharmacokinetics of a single dose of digoxin. A positive finding in this study may initiate a need to further studies. 6/15/ Nuvigil (armodafinil) Fulfilled PMC 4: provide a thorough literature search to determine whether there is any information on the P-gp induction potential of armodafinil in vivo. 6/16/ Letairis (ambrisentan) Fulfilled PMC 3: Gilead further agrees to explore the interaction potential of cyclosporine (strong inhibitor of OATP and P-gp) and rifampin (inhibitor of OATP and inducer of P-gp, CYP3A, and 2C19) on ambrisentan pharmacokinetics in humans. 8/6/ Selzentry (maraviroc) Fulfilled PMC 12: conduct a study to evaluate the potential of maraviroc to inhibit P-gp. 10/16/ Ixempra Kit (ixabepilone) Fulfilled PMC 4: An in vitro assessment to determine whether ixabepilone is a P-gp substrate or inhibitor needs to be conducted. 3/20/ Treanda (bendamustine hydrochloride) 7/1/ Requip XL (ropinirole hydrochloride) 7/3/ Eovist (gadoxetate disodium) Fulfilled PMC 6: Cephalon commits to conducting in vitro screening to assess the role of P-gp in the disposition of bendamustine. Fulfilled PMC 3: evaluate whether ropinirole is a P-gp substrate and/or inducer for major CYP enzymes (eg, CYP3A4) and, if so, any drug drug interaction potential through either mechanism. This can be accomplished through a comprehensive literature review or by conducting an in vitro study. Fulfilled PMC 4: to conduct a single-center crossover study to evaluate the possible influence of erythromycin as an example of an inhibitor of the organic anion transporting peptide on the hepatocyte uptake of Eovist in liver MR imaging in healthy subjects. 11/14/ Banzel (rufinamide) Fulfilled PMR 2: conduct an in vitro metabolism study to characterize the potential serious safety risk of the inhibitory effect of Banzel (rufinamide) on P-gp. N/A (Continued)

4 S196 The Journal of Clinical Pharmacology / Vol 56 S7 (2016) Table 1. Continued Original NDA Approval Date NDA Number Brand Name (Drug Name) Current Status Content Labeling Change Following PMR/PMC Study Review? (,, or N/A) 12/15/ Mozobil (plerixafor) Fulfilled PMR 1: screen plerixafor in vitro to assess whether it is a substrate and inhibitor of P-glycoprotein. Depending on the results of this study, an in vivo drug drug interaction trial may be needed. 5/6/ Fanapt (iloperidone) Fulfilled PMR 4: conduct a study investigating the possible in vitro interaction of iloperidone and P-glycoprotein (P-gp). 9/24/ Folotyn (pralatrexate) Fulfilled PMC 5: perform in vitro study to determine if transporters are involved in the elimination of pralatrexate. Description of study: This will be an in vitro study to determine whether pralatrexate is a substrate for the organic anion transporter (OAT) family, including but not limited to OAT1 and OAT3 and whether drugs that interfere with or compete for these transporters (eg, acyclovir, probenecid, NSAIDS) have an effect on pralatrexate transport. 3/24/ Xifaxan (rifaximin) Fulfilled PMC : an in vivo drug interaction study to evaluate the effect of P-glycoprotein inhibitor(s) of 7/23/ Aricept (donepezil hydrochloride) 10/19/ Pradaxa (dabigatran etexilatemesylate) 01/27/ Viibryd (vilazodone hydrochloride) rifaximin pharmacokinetics in healthy subjects.pmc : an in vitro study to evaluate the potential for rifaximin to inhibit P-gp transporter. Fulfilled PMR : An in vitro study to evaluate whether donepezil is a P-glycoprotein substrate. Fulfilled PMR : an in vitro study profiling of dabigatran as a substrate or inhibitor of a panel of drug solute carrier (SLC) transporters (OATPs, OATs, and OCTs) that are proposed as being relevant by the recently published ITC white paper (Giacomini M, Huang S-M, Tweedie D, et al. Membrane transporters in drug development. Nature Review Drug Discovery, 2010;9: )PMR : an in vitro study of the effects of amiodarone and dronedarone on active transport of dabigatran. Fulfilled PMC : information on the effect of P-gp on the pharmacokinetics of vilazodone and the effect of vilazodone on P-gp was not submitted. We request that you conduct an in vitro study to evaluate whether vilazodone is a substrate or inhibitor of P-gp. 05/13/ Victrelis (boceprevir) Fulfilled PMR : conduct an in vivo drug drug interaction trial between boceprevir and a sensitive substrate of p-glycoprotein (eg, digoxin). 05/20/ Edurant (rilpivirine) Fulfilled PMR : conduct a clinical trial in healthy subjects to evaluate the effect of rilpivirine at steady state 6/10/ Potiga (ezogabine) : t fulfilled; : fulfilled on the single-dose pharmacokinetics of digoxin. The pharmacokinetics of digoxin when coadministered with rilpivirine (test arm) will be compared with the pharmacokinetics of digoxin by itself (reference arm). The primary digoxin pharmacokinetic parameters that will be evaluated are AUC0, AUC0 ),and Cmax. PMR : an in vitro study to evaluate whether ezogabine is a substrate for major transporters in the kidney. Refer to the agency s guidance ( RegulatoryInformati on/guidances/ucm pdf) for more detailed recommendations regarding transporter-based drug drug interactions.pmr : a clinical trial to evaluate the acetyl metabolite of ezogabine (NAMR) as an inhibitor of P-glycoprotein using digoxin as a probe substrate. Refer to the agency s guidance ( on/guidances/ucm pdf) for more detailed recommendations regarding transporter-based drug drug interactions. a N/A (PMR1781-4) (PMR ) (Continued)

5 Fan et al S197 Table 1. Continued Original NDA Approval Date NDA Number Brand Name (Drug Name) Current Status Content Labeling Change Following PMR/PMC Study Review? (,, or N/A) 7/1/ Xarelto (rivaroxaban) Fulfilled PMR : perform a clinical trial to evaluate the effect of renal impairment (ie, mild, moderate, severe) plus the concurrent use of P-gp and moderate inhibitors of CYP3A4 on the pharmacokinetics, pharmacodynamics, and safety of rivaroxaban in volunteers so that appropriate dosing recommendations can be developed in these populations. 1/31/ Kalydeco (ivacaftor) Fulfilled PMR : assess the impact of Kalydeco (ivacaftor) administration on exposure of coadministered P-gp substrates in an in vivo trial with a sensitive P-gp substrate, such as digoxin. 8/27/ Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) Fulfilled PMR : evaluate inhibition by the components of Stribild of the hepatic transporters OATP1B1, OATP1B3, OCT1, and BSEP and evaluate transport of the hepatically eliminated components of Stribild (EVG and COBI) by the hepatic transporters OATP1B1, OATP1B3, and OCT1.PMR : evaluate inhibition by the components of Stribild of the renal transporters OCT2,MATE1, OAT1, OAT3, MRP2, and MRP4 and evaluate transport of the renally eliminated components of Stribild (FTC and TFV) by renal transporters OCT2,OAT1, OAT3, and MRP2.PMR : evaluate whether components of Stribild are transported by or inhibit P-gp and breast cancer resistance protein (BCRP). 09/12/ Aubagio (teriflunomide) Fulfilled PMR : a clinical trial to evaluate the effects of teriflunomide on plasma concentrations of rosuvastatin, a substrate of both OATP1B1 and BCRP. Refer to the agency s guidance fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm pdf for more detailed recommendations regarding transporter-based drug drug interactions. 12/28/ Sirturo (bedaquiline) Fulfilled PMR : conduct an in vitro study to characterize the potential of bedaquiline and M2 as a substrate, inhibitor, or inducer of the OATP1B1 and OATP1B3 drug transporters. 12/31/ Fulyzaq (crofelemer) Fulfilled PMC : an in vitro study to determine whether crofelemer is an inhibitor of the transporters P-glycoprotein and BCRP. 09/30/ Brintellix (vortioxetine) t PMR : in vitro determination of vortioxetine and its major metabolites as potential inhibitors of fulfilled major transporters as recommended by the drug drug interaction guidance. 10/10/ Akynzeo (netupitant and palonosetron) 09/10/ Contrave (naltrexone hydrochloride/bupropion hydrochloride) t fulfilled t fulfilled 05/27/ Viberzi (eluxadoline) t fulfilled PMR : in vitro study to evaluate the potential of netupitant to act as a substrate for P-gp transporter in a bidirectional transport assay system. PMR : conduct a drug drug interaction clinical trial with organic cation transporter 2 (OCT2) substrate, such as metformin, to evaluate the in vivo potential of Contrave constituents (bupropion and naltrexone) to inhibit OCT2. The trial should test the single-dose pharmacokinetics of the OCT2 substrate with and without coadministration of Contrave (preferably at steady state after multiple doses). PMC : conduct an in vitro study to estimate the IC50 (or Ki) value of eluxadoline with respect to P-gp and predict the in vivo relevance of this interaction. N/A N/A N/A N/A Fulfilled, the applicant has submitted the final study report for the commitment, and on review of the final study report, FDA is satisfied that the applicant has met the terms of the commitment (including PMR/PMC status categories of fulfilled or released as defined in the FDA s PMR/PMC website 31 ). t fulfilled, for the purpose of this articlet, all PMR/PMC requirements that are not deemed fulfilled by the FDA are listed as not fulfilled (including PMR/PMC status categories of pending, ongoing, delayed, or submitted as defined in the FDA s PMR/PMC website 30,31 ). N/A, not applicable. a Labeling revision was made under NDA

6 S198 The Journal of Clinical Pharmacology / Vol 56 S7 (2016) Figure 1. Number of transporter-related PMR/PMC studies and number of respective NDAs containing transporter-related PMR/PMC studies (from January 1999 to May 2015). PMR, postmarketing requirement; PMC, postmarketing commitment; NDA, new drug application. Table 2. Numbers of PMR/PMC Studies or NDAs Related to Transporters and CYP450 (January 1999 May 2015) Before 2007 ( ) Number of PMR/PMC Studies After 2007 (January 2007 May 2015) Total (January 1999 May 2015) Transporter related P-gp Other transporters (OAT, OCT, OATP, BCRP) Number of NDAs Transporter related CYP450 related PMR/PMC studies including both P-gp and other transporters are counted twice (once under P-gp and once under Other transporters ). NDAs (67%) included transporter-related postmarketing study requests for non-p-gp transporters (Table 1). Among the 40 transporter-related postmarketing studies, 34 (85%) were considered fulfilled (per the FDA s PMR/PMC website), and the remaining 6 studies were not fulfilled as of May 31, 2015 (Table 1). The 6 not fulfilled postmarketing studies had the status of either pending, ongoing, delayed, or submitted, as defined in the FDA s PMR/PMC website. 31 We also compared the number of NDAs that include postmarketing study requests made for the assessment of cytochrome P450 enzymes (CYP450)- related interactions with the number of NDAs that included postmarketing study requests made for the transporter-related interactions to determine whether assessment of transporter-based DDIs has gained increasing significance. Prior to 2007, the total number of NDAs with transporter-related postmarketing studies was about 26% of that for NDAs with CYP-related postmarketing studies (6 NDAs having transporterrelated postmarketing studies versus 23 NDAs having CYP-related postmarketing studies). However, between January 2007 and May 2015, this number increased to 64% (29 NDAs with transporter-related postmarketing studies vs 45 NDAs with CYP-related postmarketing studies; Table 2). With respect to therapeutic areas, the following 3 therapeutic areas contained the most transporterrelated postmarketing studies: (1) anti-infectives (29%), (2) oncology (20%), and (3) neurology (20%). Labeling Impact of Transporter-Related Postmarketing Studies We reviewed drug product labeling pre- and postcompletion of these transporter-related postmarketing studies to evaluate the possible impact of data obtained from postmarketing studies. The data showed that among the 34 fulfilled transporter-related PMR/PMC studies, 22 (65%, 22 of 34) resulted in a labeling update, and 12 (35%, 12 of 34) did not (Table 1). To determine the relationship between the outcome of study results (positive, negative, or mixed) and the likelihood of a labeling update (yes or no), we divided these 34 fulfilled postmarketing

7 Fan et al S199 Table 3. Number of PMR/PMC Studies Under Each Group a Positive Study Results Negative Study Results Mixed Study Results b Total Labeling updated 13 (group 1) 7 (group 3) 2 (group 5) 22 Labeling not updated 0 (group 2) 12 (group 4) 0 (group 6) 12 Total a Group 1, result posivtive with labeling update; group 2, results positive with no labeling update; group 3, results negative with labeling update; group 4, results negative with no labeling update; group 5, mixed results (some transporter positive/some transporter negative) with labeling update; group 6, mixed results (some transporter positve/some transporter negative) with no labeling update. b More than 1 transporter is involved in PMR/PMC studies; some results were positive, some results were negative. Positive study results and negative study results are defined based on the FDA review comments. studies into 6 groups. As shown in Table 3, groups 1 and 2 represent fulfilled postmarketing studies with positive DDI results (as defined under the Methods section) with or without a labeling update, respectively (there were a total of 13 studies); groups 3 and 4 represent fulfilled postmarketing studies with negative DDI results (as defined under the Methods section) with or without a labeling update, respectively (there were a total of 19 studies); and groups 5 and 6 represent fulfilled postmarketing studies with mixed results (some transporter positive/some transporter negative) with or without a labeling update, respectively (there were a total of 2 studies).the data showed that among the 22 postmarketing studies that resulted in labeling updates, 13 had positive DDI results, 7 had negative DDI results, and 2 had mixed results in which multiple transporters were studied in the same study (Tables 1 and 3). Among 12 postmarketing studies that did not result in labeling updates, all showed negative results. Table 4 lists 4 examples to illustrate what labeling changes (impact) have been made based on study results of transporter-related PMR/PMC studies. The first example is Tykerb (lapatinib), which was originally approved on March 13, 2007, and only in vitro P- gp information was included in the original labeling. After the PMC study (an in vivo DDI study with digoxin) was conducted, the positive in vivo study results were included in the updated labeling with a more specific dosing recommendation for coadministration of lapatinib and digoxin. The second example is Folotyn (pralatrexate injection), which was approved on September 24, 2009, and only negative in vitro P- gp study results were included in the original labeling. After the PMC study was conducted for studying additional transporters (ie, BCRP, MRP2, MRP3, OAT1/3, OCT2, and OATP1B1/1B3) in vitro, both negative and positive results were included in the updated labeling. The third example is Mozobil (plerixafor), for which the PMR study showed negative results, and the negative results have been updated in the labeling. The last example is Selzentry (maraviroc), for which no information related to transporters was included in the labeling originally. The PMC study for P-gp showed positive in vitro results that triggered further in vivo DDI study with digoxin. However, the in vivo study result with digoxin was negative. Therefore, the updated labeling included positive in vitro study results and negative in vivo study results. Discussion Transporters play an important role in drug safety, efficacy, and DDIs. In recent years, increasing numbers of transporter-based DDIs have been evaluated during drug development When transporter-based DDI potentials were not comprehensively evaluated in drug development, the lack of information, although it may not impact approvability of the drug, may pose a safety risk based on comedications and indicated patient populations of the drug. For optimal use of the drug and proper drug interaction management postapproval, postmarketing studies may be requested to address drug interaction potentials. Our survey showed that the number of transporterrelated PMR/PMC studies was very limited before 2007 (n = 6) and that the number of such studies increased from 2007 to 2012 (n = 34). The number of transporter-related PMR/PMC decreased from 2012 to 2015 (Figure 1). The increase in transporter-related postmarketing study requests coincides with the time when the FDA published the draft DDI guidance in 2006, which for the first time included recommendations to evaluate potential transporter-mediated drug interactions during drug development, in particular, P- gp. The recommendation in the 2006 guidance may have stimulated more transporter-related PMR/PMC studies being requested. Of note, the proportion of NMEs with transporter-related PMR/PMC studies in the total number of NMEs approved per year was the highest (31%) in 2007.The decreased number of transporter-related PMR/PMC studies after 2012 may suggest that needed transporter studies were conducted during drug development, leading to fewer transporterrelated postmarketing studies being requested.

8 S200 The Journal of Clinical Pharmacology / Vol 56 S7 (2016) Table 4. Examples of Transporter-Related Labeling Changes Based on PMR or PMC Study Results Brand Name (Drug Name) Transporter-Related Labeling (Before PMR/PMC Studies) Transporter-Related Labeling Changes (After PMR/PMC Studies) Tykerb (lapatinib) Folotyn (pralatrexate) 7. Drug interactions Lapatinib inhibits human P-glycoprotein. If Tykerb is administered with drugs that are substrates of P-gp, increased concentrations of the substrate drug are likely, and caution should be exercised Pharmacokinetics/Distribution In in vitro studies using MDR1-MDCK and Caco-2 cell systems, pralatrexate was not a substrate for P-glycoprotein (P-gp) mediated transport, nor did it inhibit P-gp-mediated transport. Highlight section: Tykerb is likely to increase exposure to concomitantly administered drugs which are substrates of CYP3A4, CYP2C8, or P-glycoprotein (ABCB1). 7. Drug interactions: 7.1 Effects of lapatinib on drug metabolizing enzymes and drug transport systems Lapatinib inhibits CYP3A4, CYP2C8, and P-glycoprotein (P-gp, ABCB1) in vitro at clinically relevant concentrations and is a weak inhibitor of CYP3A4 in vivo. Caution should be exercised and dose reduction of the concomitant substrate drug should be considered when doing Tykerb concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4, CYP2C8, or P-gp... Digoxin: following coadministration of Tykerb and digoxin (P-gp substrate), systemic AUC of an oral digoxin dose increased approximately 2.8-fold. Serum digoxin concentrations should be monitored prior to initiation of Tykerb and throughout coadministration. If digoxin serum concentration is >1.2 ng/ml, the digoxin dose should be reduced by half. 7.3 Drugs that inhibit drug transport systems Lapatinib is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If Tykerb is administrated with drugs that inhibit P-gp, increased concentrations of lapatinib are likely, and caution should be exercised Pharmacokinetics Drug Interactions: In vitro, pralatrexate is a substrate for the breast cancer resistance protein (BCRP), MRP2, multidrug resistance-associated protein 3 (MRP3), and organic anion transport protein 1B3 (OATP1B3) transporter systems at concentrations of pralatrexate that can be reasonably expected clinically. Pralatrexate is not a substrate of the P glycoprotein (P-gp), organic anion transport protein 1B1 (OATP1B1), organic cation transporter 2 (OCT2), organic anion transporter 1 (OAT1), and organic anion transporter 3 (OAT3) transporter systems. In vitro, pralatrexate inhibits MRP2 and MRP3 transporter systems ([I]/IC50 > 0.1) at concentrations of pralatrexate that can be reasonably expected clinically. MRP3 is a transporter that may affect the transport of etoposide and teniposide. In vitro, pralatrexate did not significantly inhibit the P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B1, and OATP1B3 transporter systems at concentrations of pralatrexate that can be reasonably expected clinically. (Continued)

9 Fan et al S201 Table 4. Continued Brand Name (Drug Name) Mozobil (plerixafor) Selzentry (maraviroc) Transporter-Related Labeling (Before PMR/PMC Studies) Transporter-Related Labeling Changes (After PMR/PMC Studies) 12.3 Pharmacokinetics Elimination: the ability of plerixafor to act as a substrate or as an inhibitor of P-glycoprotein has not been investigated Pharmacokinetics Elimination At concentrations similar to what are seen clinically, plerixafor did not act as a substrate or inhibitor of P-glycoprotein in an in vitro study with MDCKII and MDCKII-MDR1 cell models. language related to P-gp inhibition by maraviroc. Based on the in vitro results (updated on 10/21/2011): 12.3 Pharmacokinetics Effect of maraviroc on the pharmacokinetics of concomitant drugs In vitro results indicate that maraviroc could inhibit P-glycoprotein in the gut and may thus affect bioavailability of certain drugs. Based on the in vivo results (updated on 2/1/2013, this part is also the same as the label updated on 3/27/14): 12.3 Pharmacokinetics In vitro results suggest that maraviroc could inhibit P-gp in the gut. However, maraviroc did not significantly affect the pharmacokinetics of digoxin in vivo, indicating maraviroc may not significantly inhibit or induce P-gp clinically.

10 S202 The Journal of Clinical Pharmacology / Vol 56 S7 (2016) Overall, P-gp was the most frequently studied transporter in the transporter-related PMR/PMC studies to date (Table 2). Explicit recommendations on additional transporters (eg, BCRP, OATP1B1/1B3, OAT1/OAT3, and OCT2) were included in the FDA s 2012 revised draft DDI guidance. 20 The updated recommendations may have impacted the number of PMR/PMC studies associated with transporters other than P-gp. For example, all 4 drugs (Stribild, Aubagio, Sirturo, and Fulyzaq) approved in 2012 that have transporter-related PMR/PMC studies included transporter postmarketing studies involving BCRP, OATP1B1/1B3, OAT1/3, or OCT2 in addition to P-gp (Tables 1 and 2). These transporters are also among the primary transporters recommended for studying during drug development by other regulatory agencies and the ITC. 7,14,20 22 The need for transporter-related PMR/PMC studies can be determined by multiple factors including: (1) therapeutic areas, (2) likely comedications in patients, (3) the importance of transporter information in managing drug interactions or toxicity, and (4) whether applicants had collected such information during drug development. Below are the 3 main reasons for the agency to issue transporter-related PMR/PMC studies with respective examples: 1. To comply with the FDA DDI guidance recommendations (2006 or 2012 draft DDI guidance). The agency issued a PMR in 2008 to study whether plerixafor is a substrate or inhibitor of P-gp in vitro because the applicant did not conduct such studies during drug development. Depending on the results of the in vitro studies, in vivo DDI trials may be needed. 2. To understand in vivo DDI potential following positive in vitro study results. Lapatinib was shown to be a P-gp substrate and inhibitor in vitro during drug development. However, no in vivo DDI study was conducted by the applicant to understand how P-gp inhibitors may affect lapatinib pharmacokinetics (PK) and how lapatinib may affect the PK of P-gp substrates (eg, digoxin) in vivo. The agency issued a PMR in 2007 to conduct clinical DDI studies to evaluate P-gp-mediated DDI potentials. 3. To address safety concerns raised during drug development. Pralatrexate is not a substrate, inhibitor, or inducer of CYP enzymes, nor is it a substrate or inhibitor of P-gp. At the drug development stage, it was found that urinary excretion of pralatrexate was virtually absent in 3 of the 41 subjects with urine data, and these subjects experienced severe adverse events. Therefore, the agency recommended a PMC in 2009 to perform in vitro experiments to determine if transporters (in particular renal organic cation and organic anion transporters) are involved in the elimination of pralatrexate. The above 3 reasons are not mutually exclusive. Multiple reasons may have contributed to PMR/PMC studies in some cases. For example, Aubagio (teriflunomide) is used for the treatment of multiple sclerosis, and the reason for requesting the PMR is related to a combination of the second and third reasons as stated above (ie, to understand in vivo DDI potential following positive in vitro study results and to address safety concerns). Teriflunomide was identified as an in vitro inhibitor of both OATP1B1 and BCRP. Rosuvastatin (a substrate of both OATP1B1 and BCRP) was chosen to be studied for in vivo DDI potential as a worst-case scenario because of inhibition of both transporters. Results from the DDI study could also be clinically relevant because statins can be coadministered with teriflunomide in the indicated patient population, and an increase in statin exposure could lead to safety concerns such as myopathy or more serious rhabdomyolysis. The postmarketing DDI study showed an increase in mean rosuvastatin C max and AUC (2.65- and 2.51-fold, respectively) following repeated doses of teriflunomide. The labeling was updated to provide a recommendation on rosuvastatin dosing adjustment, that is, the dose of rosuvastatin should not exceed 10 mg once daily in patients taking Aubagio. Labeling is an important communication tool for health care providers and patients to understand the risk benefit profile of a drug. The results from PMR/PMC studies are important to inform dosing and are often included in the updated labeling (Tables 1 and 3). As shown in Table 3, in general, positive results were more likely to result in a labeling change. In contrast, for NDAs with postmarketing studies that showed negative results (n = 19), only 7 (37%) had a labeling update, and 12 (63%) did not. Conclusion Previous publications and this survey showed an increasing trend in the evaluation of transportermediated DDIs either during drug development or postapproval. This observation may be a reflection of recent interest in the area of drug transporters encompassing the evaluation of all factors that may impact the safe and effective use of drug products. The information obtained from transporter-related postmarketing studies could be critical for dosing optimization in the labeling related to coadministration of the drug product in the presence of other drugs that may modify transporter function. Because a significant lag time is anticipated between drug approval and PMR/PMC

11 Fan et al S203 fulfillment, it is detrimental to include transporter assessments as part of the drug development strategy in the clinical drug development programs so that knowledge gained can be used for proper management of therapy at the drug approval and not wait until postmarketing. Acknowledgments The authors thank Shiew-Mei Huang PhD for her comments and critical review of this article, the review staff of the Office of Clinical Pharmacology in the Office of Translational Sciences, the Center for Drug Evaluation and Research (CDER), the FDA, and members of the Office of Clinical Pharmacology Transporter Scientific Interest Group (SIG), in particular Drs. Vikram Arya, Sue-Chih Lee, Xinning Yang, Huixia Zhang, and Jenney H. Zheng, for their input on the review examples. Part of this report has been presented as an oral presentation at the American Society for Clinical Pharmacology and Therapeutics (ASCPT) Annual Meeting in Dallas, Texas, in March Funding Dr. Bo Sun was supported in part by an appointment to the research participation program at the CDER administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U.S. Dept. of Energy and the U.S. FDA. She was also supported by the National Key Clinical Specialty Construction Project of China. Disclaimer The views expressed in this article are those of the authors and do not necessarily reflect the official views of the FDA. References 1. Sai Y. Biochemical and molecular pharmacological aspects of transporters as determinants of drug disposition. Drug Metab Pharmacokinet. 2005;20(2): Choudhuri S, Klaassen CD. 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