key findings from preclinical and clinical drug...

1521-009X/44/1/83–101$25.00 http://dx.doi.org/10.1124/dmd.115.066720DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 44:83–101, January 2016Copyright ª 2015 by The American Society for Pharmacology and Experimental Therapeutics

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Key Findings from Preclinical and Clinical Drug Interaction StudiesPresented in New Drug and Biological License ApplicationsApproved by the Food and Drug Administration in 2014 s

Jingjing Yu, Tasha K. Ritchie, Zhu Zhou, and Isabelle Ragueneau-Majlessi

Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington

Received August 7, 2015; accepted September 25, 2015

ABSTRACT

Regulatory approval documents contain valuable information, oftennot published, to assess the drug–drug interaction (DDI) profile ofnewly marketed drugs. This analysis aimed to systematically reviewall drug metabolism, transport, pharmacokinetics, and DDI dataavailable in the new drug applications and biologic license applica-tions approved by the U.S. Food and Drug Administration in 2014,using the University of Washington Drug Interaction Database, and tohighlight the significant findings. Among the 30 new drug applicationsand 11 biologic license applications reviewed, 35 new molecularentities (NMEs) were well characterized with regard to drug metab-olism, transport, and/or organ impairment and were fully analyzed inthis review. In vitro, a majority of the NMEs were found to besubstrates or inhibitors/inducers of at least one drug metabolizingenzymeor transporter. In vivo, whenNMEswere considered as victimdrugs, 16 NMEs had at least one in vivo DDI study with a clinically

significant change in exposure (area under the time-plasma concen-tration curve or Cmax ratio ‡2 or £0.5), with 6 NMEs shown to besensitive substrates of cytochrome P450 enzymes (area under thetime-plasma concentration curve ratio ‡5 when coadministered withpotent inhibitors): paritaprevir and naloxegol (CYP3A), eliglustat(CYP2D6), dasabuvir (CYP2C8), and tasimelteon and pirfenidone(CYP1A2). As perpetrators, seven NMEs showed clinically significantinhibition involving both enzymes and transporters, although noclinically significant induction was observed. Physiologically basedpharmacokineticmodeling and pharmacogenetics studies were usedfor six and four NMEs, respectively, to optimize dosing recommen-dations in special populations and/or multiple impairment situations.In addition, the pharmacokinetic evaluations in patients with hepaticor renal impairment provided useful quantitative information tosupport drug administration in these fragile populations.

Introduction

The evaluation of pharmacokinetic drug–drug interactions (DDIs)during the development of a new molecular entity (NME) is based on asystematic and mechanistic approach that includes the assessment ofboth the possible effect of the NME on other drugs (NME as aperpetrator or precipitant) as well as the effect of other drugs on theNME (NME as a victim or object) (Zhang et al., 2009b). The results ofextensive in vitro and clinical evaluations using probe substrates andinhibitors of drug metabolizing enzymes (DMEs) and transporters areused to predict broader interactions with other drugs, herbs, and/or foodproducts that may be administered concomitantly (Zhang et al., 2009a,b; Lee et al., 2010; Tweedie et al., 2013). This knowledge is critical tosupport personalized dosing recommendations and to inform health

care providers of the potential risk for drug interactions through druglabeling (Zhang et al., 2010). The U.S. Food and Drug Administration(FDA) makes the entire new drug application (NDA) and biologiclicense application (BLA) approval packages, including several reviewdocuments as well as the product label, available online at its website,Drugs@FDA (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/)shortly after the approval of a new drug. However, only a small portionof this information becomes available in the scientific literature if andwhen the sponsor decides to publish, thus limiting the availability ofthese valuable research findings to the scientific community. As a follow-up to our 2014 review of the 2013 NDA approvals (Yu et al., 2014), thisreview includes a detailed analysis of the preclinical and clinical enzyme-and transporter-mediated DDIs observed for NDAs and BLAs approvedby the FDA in 2014, highlighting the main mechanistic findings anddiscussing their clinical relevance. As in the previous publication,the analysis was performed using the University of Washington DrugInteraction Database (DIDB) drug interactions, pharmacogenetics (PGx),

dx.doi.org/10.1124/dmd.115.066720.s This article has supplemental material available at dmd.aspetjournals.org.

ABBREVIATIONS: AUC, area under the time-plasma concentration curve; BCRP, breast cancer resistance protein; BLA, biologic licenseapplication; DDI, drug–drug interaction; DIDB, Drug Interaction Database; DME, drug metabolizing enzyme; EM, extensive metabolizer; FDA, Foodand Drug Administration; HI, hepatic impairment; HLM, human liver microsome; PXR, pregnane X receptor; IM, intermediate metabolizer; MATE,multidrug and toxin extrusion; MRP, multidrug resistance-associated protein; NDA, new drug application; NME, new molecular entity; OAT, organicanion transporter; OATP, organic anion-transporting polypeptide; OCT, organic cation transporter; P-gp, P-glycoprotein; P450, cytochrome P450;PBPK, physiologically based pharmacokinetic; PGx, pharmacogenetics; PK, pharmacokinetics; PM, poor metabolizer; PMR, postmarketingrequirement; RI, renal impairment; TDI, time-dependent inhibition; UGT, UDP-glucuronosyltransferase.

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and organ impairment modules (http://www.druginteractioninfo.org). Allof the parameters were directly extracted from the DIDB, where thechanges in mean area under the time-plasma concentration curve (AUC)and maximum plasma concentration (Cmax) values were calculated by theDIDB Editorial Team and are presented herein. The DIDB data werecurated from a thorough review of the NDA approval packages, including,but not limited to, the product label and clinical pharmacology andbiopharmaceutics review for each NDA. The analysis used a mechanisticapproach for evaluating DDIs reported for the individual NMEs, based onthe decision criteria recommended by the most recent FDA druginteraction guidance document (FDA, 2012). In addition to the individualenzyme and transporter preclinical and clinical studies reported in theNDAs, studies looking at mechanisms for enzyme-transporter interplay, aswell as those conducted in diseased populations [e.g., hepatic impairment(HI) or renal impairment (RI)] were also systematically analyzed. Themetric used for evaluation of clinical studies are the AUC and Cmax ratios,defined as AUCinhibited or induced/AUCcontrol and Cmax, inhibited or induced/Cmax, control, respectively, with a clinically significant interaction resulting inan AUC or Cmax ratio$2 (inhibition) or #0.5 (induction). In accordance

with the FDA guidance, NMEs were considered weak, moderate, orstrong inhibitors or inducers of cytochrome P450 (P450) enzymes whenthe observed AUC or Cmax ratios were 1.25–2, 2–5, and $5 forinhibitors, respectively, and 0.5–0.8, 0.2–0.5, and #0.2 for inducers,respectively (FDA, 2012). In addition, important labeling modificationsor recommendations were also noted. In 2014, a total of 30 NDAs and11 BLAs were approved by the FDA. A summary of the NDA/BLAs,including DDIs, PGx, organ impairment studies, physiologically basedpharmacokinetic (PBPK) modeling and simulations, as well astherapeutic classes and approval dates, is presented in Table 1, withthe chemical structures presented in Supplemental Table 1. When allNDA/BLAs were considered (n = 41), the most represented therapeuticareas were anti-infective agents (29%), oncology drugs (20%), andtreatments for metabolic disorders/endocrinology (17%). All of theNDAs and 2 BLAs had drug metabolism and/or transporter dataavailable and therefore were fully analyzed in this review. Of note,four NDAs were related to combination drugs: Harvoni (a combina-tion of ledipasvir and sofosbuvir), Akynzeo (netupitant and palono-setron), Zerbaxa (ceftolozane and tazobactam), and Viekira Pak

TABLE 1

NDA/BLAs approved by the FDA in 2014 (ordered by approval date)

Compound Name DDI HI/RI PGx PBPK Therapeutic ClassApproval Date(Month/Day)

Reference

Dapagliflozin Y Y Y N Diabetes treatments 01/08 FDA, 2014jTasimelteon Y Y N N Central nervous system agents 01/31 FDA, 2014lElosulfase alfaa N N N N Metabolism disorder/endocrinology treatments 02/14 FDA, 2014ajDroxidopa Y N N N Cardiovascular drugs 02/18 FDA, 2014wMetreleptina N N N N Metabolism disorder/endocrinology treatments 02/24 FDA, 2014uFlorbetaben Yb N N N Diagnostic agents 03/19 FDA, 2014vMiltefosine Y N N N Anti-infective agents 03/19 FDA, 2014mApremilast Y Y N N Skin agents 03/21 FDA, 2014aaAlbiglutide Y Y (RI) N N Diabetes treatments 04/15 FDA, 2014agRamucirumaba N N N N Cancer treatments 04/21 FDA, 2014fSiltuximaba N N N N Cancer treatments 04/23 FDA, 2014afCeritinib Y Yb N Y Cancer treatments 04/29 FDA, 2014aoVorapaxar Y Y N N Cardiovascular drugs 05/08 FDA, 2014amVedolizumaba N N N N Gastrointestinal agents 05/20 FDA, 2014hDalbavancin Y Y N N Anti-infective agents 05/23 FDA, 2014gEfinaconazole Y N N N Anti-infective agents 06/06 FDA, 2014oTedizolid phosphate Y Y N N Anti-infective agents 06/20 FDA, 2014adBelinostat Y N N Y Anti-infective agents 07/03 FDA, 2014bTavaborole Y N N N Anti-infective agents 07/07 FDA, 2014pIdelalisib Y Y N N Cancer treatments 07/23 FDA, 2014anOlodaterol Y Y Y N Respiratory agents 07/31 FDA, 2014aeEmpagliflozin Y Y N N Diabetes treatments 08/01 FDA, 2014nOritavancin Y Y (HI)c N N Anti-infective agents 08/06 FDA, 2014zSuvorexant Y Y N N Central nervous system agents 08/13 FDA, 2014cPeginterferon b-1aa N N N N Central nervous system agents 08/15 FDA, 2014abEliglustat Y Yd Y Y Metabolism disorder/endocrinology treatments 08/19 FDA, 2014ePembrolizumaba N N N N Cancer treatments 09/04 FDA, 2014qNaloxegol Y Y N Y Gastrointestinal agents 09/06 FDA, 2014tDulaglutide Y Y N N Diabetes treatments 09/18 FDA, 2014ahLedipasvir and sofosbuvir Y Y N N Anti-infective agents 10/10 FDA, 2014kNetupitant and palonosetron Y Y (HI)c N N Gastrointestinal agents 10/10 FDA, 2014aSulfur hexafluoride lipid-type A microspheres Y N N N Diagnostic agents 10/10 FDA, 2014rNintedanib Y Yc Y N Respiratory agents 10/15 FDA, 2014xPirfenidone Y Y N N Respiratory agents 10/15 FDA, 2014iBlinatumomaba N N N Y Cancer treatments 12/03 FDA, 2014dFinafloxacin Y N N N Anti-infective agents 12/17 FDA, 2014akCeftolozane and tazobactam Y Y (RI) N N Anti-infective agents 12/19 FDA, 2014alOlaparib Y Y (RI) N Y Cancer treatments 12/19 FDA, 2014sOmbitasvir, paritaprevir, and ritonavir

copackaged with DasabuvirY Y N N Anti-infective agents 12/19 FDA, 2014ai

Peramivir Y Y (RI) N N Anti-infective agents 12/19 FDA, 2014acNivolumaba N N N N Cancer treatments 12/22 FDA, 2014y

N, studies not included in the NDA/BLA reviews; Y, studies included in the NDA/BLA reviews.aNot evaluated in this review.bNo in vivo data are presented, only in vitro.cPopulation PK data presented for RI only, not included.dPopulation PK data presented, not included.

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(paritaprevir, ritonavir, ombitasvir, and dasabuvir), in which sofosbu-vir, palonosetron, and ritonavir have been previously approved by theFDA. Considering these combinations, a total of 35 NMEs were fullyreviewed and are covered in this analysis. A detailed analysis of thepreclinical findings and their related clinical investigations is presentedin the next section on metabolism and enzyme-mediated DDIs, whereasfurther consideration regarding the clinical relevance of the DDI studyresults is addressed in the section on clinically significant DDIs.Twenty-four NMEs were also evaluated in patients with variousdegrees of organ impairment.

Metabolism and Enzyme-Mediated DDIs

In accordance with the FDA (2012) guidance, 35 NMEs approved in2014 were evaluated in vitro as substrates, inhibitors, and/or inducers ofclinically important DMEs. As substrates, the metabolic profile of 32NMEs (91%; except 3 NMEs: namely, albiglutide, dulaglutide, and sulferhexafluoride lipid-type A microspheres) was well characterized from invitro studies using recombinant enzymes or human liver tissues such ashuman livermicrosomes (HLMs) or human hepatocytes. Among those, 29NMEs were shown to be metabolized by at least one enzyme, with themajority primarily metabolized by P450 enzymes (Fig. 1A; Table 2). Notsurprisingly, CYP3A4/5 was shown to metabolize the largest number ofNMEs in vitro (n = 18), although not necessarily as the major enzymecontributing to the drug’s disposition. In vivo studies further confirmedthat 13 of these NMEs were indeed CYP3A substrates, with systemicexposure increases$25%, when coadministered with the strong CYP3Ainhibitors ketoconazole (200 or 400mg orally once daily or twice daily for3–22 days) or itraconazole (200 mg orally once daily for 8 days), resulting

in the following maximum AUC and Cmax ratios, respectively:naloxegol, 12.42 and 9.12; eliglustat, 4.40 and 4.25 [CYP2D6extensive metabolizers (EMs)]; ceritinib, 2.88 and 1.23; suvorexant,2.79 and 1.24; olaparib, 2.59 and 1.36; netupitant, 2.42 and 1.19;vorapaxar, 1.96 and 1.93; paritaprevir, 1.84 and 1.21; idelalisib, 1.79and 1.25; nintedanib, 1.61 and 1.79; tasimelteon, 1.45 and 1.39;dasabuvir, 1.40 and 1.16; and apremilast, 1.32 and 0.95. Interestingly,10 of these NMEs are also substrates of P-glycoprotein (P-gp) and/orbreast cancer resistance protein (BCRP) (Table 2), and inhibition ofthose transporters might also contribute to the observed increasedexposure (details are reviewed in the following transporter section). Thehighest AUC and Cmax ratios related to CYP3A inhibition wereobserved for naloxegol with concurrent use of ketoconazole (400 mgorally once daily for 5 days), confirming the primary role of CYP3A inthe metabolism of the drug. In addition, coadministration of themoderate CYP3A inhibitor diltiazem increased the AUC and Cmax ofnaloxegol by 224% and 178%, respectively. Therefore, strong CYP3Ainhibitors are contraindicated with naloxegol, whereas concomitant useof moderate CYP3A inhibitors should be avoided; however, if it cannotbe avoided, reduction of the naloxegol dose should be considered asindicated in the labeling (FDA, 2014t). For four of the remaining drugswith AUC ratios $2 in the presence of strong CYP3A inhibitors(ceritinib, eliglustat, olaparib, and suvorexant), concomitant use ofstrong CYP3A inhibitors is either contraindicated [suvorexant andeliglustat in CYP2D6 intermediate metabolizers (IMs) and poormetabolizers (PMs)], to be avoided [ceritinib and olaparib], or toreduce the dose [eliglustat in CYP2D6 EMs], according to therespective product labels; however, there is no such recommendationfor netupitant (FDA, 2014a). As expected, all of these substrates ofCYP3A were also sensitive to induction. Coadministration of rifam-pin (600 mg orally once daily or twice daily for 5–22 days) orcarbamazepine (200 mg orally once daily or twice daily for 24 days),both strong inducers of CYP3A, significantly reduced the systemicexposure of these drugs with observed maximum AUC and Cmax ratios,respectively, as follows: eliglustat, 0.04 and 0.05 (in CYP2D6 PMs);olaparib, 0.10 and 0.30; naloxegol, 0.11 and 0.26; suvorexant, 0.12 and0.36; tasimelteon, 0.14 and 0.23; netupitant, 0.20 and 0.45; idelalisib,0.24 and 0.43; apremilast, 0.28 and 0.57; ceritinib, 0.30 and 0.56;paritaprevir, 0.30 and 0.44; dasabuvir, 0.30 and 0.46; vorapaxar, 0.45and 0.61; and nintedanib, 0.50 and 0.60. On the basis of these results,concomitant use of strongCYP3A inducers is contraindicated [apremilastand tasimelteon], to be avoided [ceritinib, idelalisib, nintedanib, andolaparib], not recommended [eliglustat (CY2D6 EMs, IMs, and PMs),ledipasvir, naloxegol, and netupitant], or expected to reduce efficacy[dasabuvir, paritaprevir, and suvorexant], according to the respec-tive product labels, whereas no specific recommendation was madefor vorapaxar.Other P450 isoforms, such as CYP2D6, CYP2C9, CYP2C19,

CYP2C8, and CYP1A2, were also involved in the metabolism ofseven, six, five, four, and four NMEs in vitro, respectively (Fig. 1A). Invivo, coadministration with specific inhibitors of CYP1A2 (fluvox-amine, 50–100 mg orally once daily for 10 days in smokers forpirfenidone or 500 mg orally once daily for 7 days for tasimelteon),CYP2C8 (gemfibrozil, 600 mg orally twice daily for 5 days), orCYP2D6 (paroxetine, 30 mg orally once daily for 10 days in CYP2D6EMs) further identified dasabuvir (CYP2C8), eliglustat (CYP2D6),pirfenidone (CYP1A2), and tasimelteon (CYP1A2) as sensitivesubstrates, with AUC and Cmax ratios of 9.90 and 1.91, 10.00 and8.20, 6.81 and 1.78, and 6.87 and 2.28, respectively. In addition, severalNMEs were found to be primarily metabolized by non-P450 enzymes:droxidopa, which is metabolized by the catecholamine pathway,including L-amino acid decarboxylase; tedizolid phosphate, a prodrug,

Fig. 1. Quantitation of compounds acting as substrates (NMEs) or inhibitors (NMEsand metabolites) of DMEs in vitro. (A) Phase I and II enzymes contributing to NMEmetabolism. (B) DMEs inhibited by NMEs (solid bars) and metabolites (stripedbars). *Other enzymes include amidase, catecholamine pathway enzymes, esterases,phospholipidase, phosphatase, and proteinase. MAO, monoamine oxidase.

A Review of Drug Disposition and DDIs in the 2014 NDAs 85

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TABLE 2

Enzymes and transporters involved in the NDA/BLA elimination pathways

Compound Name Main Elimination Route Enzymes Involved Transporters Involved Reference

Dapagliflozin Metabolism, renal (75% mainly asmetabolites), fecal (21% mainly asparent)

UGT1A9a P-gp, OAT3 FDA, 2014j

Tasimelteon Metabolism, renal (80% mainly asmetabolites), fecal (4% mainly asparent)

CYP1A2,a CYP3A4,a CYP1A1,CYP2D6, CYP2C19, CYP2C9

None FDA, 2014l

Elosulfase alfa Proteolytic degradation N/T, mostly by proteolytic enzymes N/T FDA, 2014ajDroxidopa Renal (parent and metabolites), no mass

balance studyCatecholamine pathwaya by

catechol-O-methyltransferase,dihydrophenylalanine decarboxylase,dihydroxyphenylserine aldolase,monoamine oxidase, and others;not by P450 enzymes

N/T FDA, 2014w

Metreleptin Not metabolized, renal (as parent) None N/T FDA, 2014uFlorbetaben Biliary excretion, renal (30% mainly as

metabolites)CYP2J2,a CYP4F2a N/T FDA, 2014v

Miltefosine Unknown, no mass balance study Phospholipase Da Noneb FDA, 2014mApremilast Metabolism, renal (58% mainly as

metabolites), fecal (39% mainly asmetabolites)

CYP3A4,a CYP1A2, CYP2A6 P-gp FDA, 2014aa

Albiglutide Proteolytic degradation N/T, mostly by proteolytic enzymes N/T FDA, 2014agRamucirumab Proteolytic degradation N/T, mostly by proteolytic enzymes N/T FDA, 2014fSiltuximab Proteolytic degradation N/T, mostly by proteolytic enzymes N/T FDA, 2014afCeritinib Metabolism, fecal (92.3% mainly as

parent)CYP3Aa P-gp, BCRP FDA, 2014ao

Vorapaxar Metabolism, fecal (58% mainly asmetabolites), renal (25% all asmetabolites)

CY3A4,a CYP2J2a Noneb FDA, 2014am

Vedolizumab Proteolytic degradation N/T, mostly by proteolytic enzymes N/T FDA, 2014hDalbavancin Minimal metabolism, urine (33% as

parent and 12% as metabolite), fecal(20%)

Unknown, not by P450 enzymes N/T FDA, 2014g

Efinaconazole Some metabolism, elimination notdetermined

CYP2C19, CYP3A4 N/T FDA, 2014o

Tedizolid (phosphate) Metabolism Prodrug by phosphatase, notmetabolized in HLMs

Nonec FDA, 2014ad

Belinostat Metabolism, renal (mainly asmetabolites)

UGT1A1 (80%–90%),a CYP2A6,CYP2C9, CYP3A4

Noneb FDA, 2014b

Tavaborole Metabolism, renal (mainly asmetabolites)

Not identified N/T FDA, 2014p

Idelalisib Metabolism, fecal (78% mainly asmetabolites), renal (14% mainly asmetabolites)

Aldehyde oxidase (approximately70%),a CYP3A4 (approximately30%),a UGT1A4

P-gp, BCRP FDA, 2014an

Olodaterol Metabolism, fecal (i.v. 53% mainly asmetabolites), renal (i.v. 38% mainlyas metabolites)

CYP2C9,a CYP2C8,a UGT2B7,UGT1A1, UGT1A7, UGT1A9,SULT1A1, SULT1A3

P-gpb FDA, 2014ae

Empagliflozin Metabolism, fecal (41% mainly asparent), renal (54% mainly as parent)

UGT2B7, UGT1A3, UGT1A8,UGT1A9

P-gp, BCRP,OAT3, OATP1B1,OATP1B3

FDA, 2014n

Oritavancin Not metabolized, no mass balance study(,1% in feces, ,5% in urineexcreted unchanged after 2 wk)

None Noneb FDA, 2014z

Suvorexant Metabolism, fecal (66% as metabolites),renal (23% mainly as metabolites)

CYP3A,a CYP2C19a Noneb FDA, 2014c

Peginterferon b-1a Proteolytic degradation N/T, mostly by proteolytic enzymes N/T FDA, 2014abEliglustat Metabolism, fecal (51.4% primarily as

metabolites), urine (41.8% primarilyas metabolites)

CYP2D6,a CYP3A4a P-gp FDA, 2014e

Pembrolizumab Proteolytic degradation N/T, mostly by proteolytic enzymes N/T FDA, 2014qNaloxegol Metabolism, fecal (68% mainly as

metabolites), urine (16% mainly asmetabolites)

CYP3A,a CYP2D6 P-gp FDA, 2014t

Dulaglutide Proteolytic degradation N/T, mostly by proteolytic enzymes N/T FDA, 2014ahLedipasvir (and sofosbuvir) Biliary excretion, fecal (99% as parent) Slow metabolism via unknown

mechanism, not by P450 enzymesP-gp, BCRP FDA, 2014k

Netupitant (and palonosetron) Metabolism, fecal (70.7% mainly asmetabolites), renal (3.95%)

CYP3A,a CYP2C9, CYP2D6 Noned FDA, 2014a

Sulfur hexafluoride lipid-typeA microspheres

Pulmonary (88% as unchanged parent) Little or no biotransformation N/T FDA, 2014r

Nintedanib Metabolism, fecal (93.4% mainly asmetabolites)

Esterases,a UGT1A1, UGT1A7,UGT1A8, UGT1A10, CYP3A4

P-gp, OCT1 FDA, 2014x

(continued )

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which is converted by nonspecific endogenous phosphatases totedizolid, the active moiety after oral or intravenous administration;and finally, dapagliflozin, which is primarily metabolized by UDP-glucuronosyltransferase (UGT) UGT1A9 in vitro and dapagliflozinAUC and Cmax were increased by 51% and 13%, respectively, whencoadministered with the strong UGT1A9 inhibitor mefenamic acid.When NMEs were considered as perpetrators, 32 (91%; except 3

NMEs namely albiglutide, dulaglutide, and sulfer hexafluoride lipid-type A microspheres) were investigated in vitro for the potential toinhibit DMEs using HLMs or cDNA-expressed enzymes to determinethe inhibitory mechanisms [e.g., reversible or time-dependent inhibition(TDI)] and inhibition potency. Twenty-four NMEs inhibited at least oneP450 enzyme or UGT (Table 3), with the most affected enzymes beingCYP3A4 (n = 15), CYP2C8 (n = 12), CYP2C9 (n = 11), CYP2C19 (n =9), CYP2D6 (n = 9), CYP2B6 (n = 8), CYP1A2 (n = 6), and UGT1A1(n = 6) (Fig. 1B). In addition, the inhibitory potential of 13 majormetabolites of 8 NMEs was evaluated, and inhibition of P450 enzymesand UGT1A1 was also observed by these compounds (Table 3). Withregard to the mechanism of inhibition, 10 NMEs and six metaboliteswere evaluated for TDI of P450 enzymes and a majority, comprisingseven NMEs and five metabolites, showed TDI of one or more P450enzyme, in particular, CYP3A4/5. In addition, both eliglustat and itsmetabolite Genz-120965 (N-oxide of eliglustat) inhibited CYP2D6 inHLMs in a time-dependent manner, withKI values of 1.05 and 8.44mMand kinact values of 0.0151 and 0.206 min21, respectively.Using the in vitro inhibition results, as well as plasma concentration

data, the in vivo DDI risk was predicted by the sponsors by estimatingintrinsic clearance values in the presence and absence of an inhibitor,and the R value was calculated utilizing a basic model according to theFDA drug interaction guidance (R1 = 1 + [I]/Ki, for reversibleinhibition) (FDA, 2012). More complex models were also used, suchas PBPK modeling, which is reviewed in a subsequent section. On the

basis of the R1 values, the majority of the in vitro inhibitory interactionswere not considered clinically relevant (R1 # 1.1). Among drugs withR1. 1.1, in vivo studies with sensitive P450 substrates found only nineNMEs with positive enzyme inhibition: idelalisib was a strong inhibitorof CYP3A (midazolam: AUC ratio = 5.15; Cmax ratio = 2.31),netupitant was a moderate inhibitor of CYP3A (midazolam: AUC ratio= 2.44; Cmax ratio = 1.40), eliglustat was a moderate inhibitor ofCYP2D6 (metoprolol: AUC ratio = 2.33; Cmax ratio = 1.72), and thecombination drug paritaprevir, ritonavir, ombitasvir, and dasabuviradministered as Viekira Pak was a moderate inhibitor of UGT1A1(raltegravir: AUC ratio = 2.26; Cmax ratio = 2.27). In addition,ledipasvir (in combination with sofosbuvir) and suvorexant were weakinhibitors of CYP3A (midazolam: AUC ratio = 1.47; Cmax ratio = 1.23;and atazanavir: AUC ratio = 1.33; Cmax ratio = 1.06, respectively) andoritavancin was a weak inhibitor of CYP2C9 (S-warfarin: AUC ratio =1.32;Cmax ratio not available). Several drugs with R1 values. 1.1 werenot evaluated for clinical inhibition. However, for ceritinib, forexample, which was shown in vitro to be a potent inhibitor of CYP2C9(Ki = 0.24mM; R1 = 8.5) and CYP3A4 (midazolam:Ki = 0.16mM; R1 =12.3; testosterone: IC50 = 0.2 mM; R1 = 19.0, assuming competitiveinhibition), the in vivo drug interaction evaluation with sensitive probesubstrates of these two enzymes was requested as a postmarketingrequirement (PMR).A significant number of NMEs (n = 12) showed some inhibition of

CYP2C8 in vitro; however, based on R1 values (R1 # 1.1), 10 of thesedrugs were not likely to show any clinically relevant inhibition [twoNMEs, tasimelteon and vorapaxar, were still evaluated in vivo and, notsurprisingly, did not affect the pharmacokinetics (PK) of the coad-ministered CYP2C8 substrate rosiglitazone]. For belinostat and idelalisib,R1 was greater than 1.1; however, the clinical relevance of theseinhibitory interactions was not investigated. Similarly, nine NMEsinhibited CYP2C19 in vitro, of which six had R1 values # 1.1. Of the

TABLE 2—Continued

Compound Name Main Elimination Route Enzymes Involved Transporters Involved Reference

Pirfenidone Metabolism, renal (80% mainly asmetabolites)

CYP1A2,a CYP2C9, CYP2C19,CYP2D6, CYP2E1, FMO

Unknowne FDA, 2014i

Blinatumomab Proteolytic degradation N/T, mostly by proteolytic enzymes N/T FDA, 2014dFinafloxacin Minimal metabolism, elimination not

elucidatedCYP1A2, CYP2B6, CYP2C9,

CYP2C19, CYP2D6, CYP3A4None FDA, 2014ak

Ceftolozane and tazobactam Ceftolozane: not metabolized, renal(as parent)

None None FDA, 2014al

Tazobactam: metabolism, renal(.80% as parent)

Non-P450 enzymes OAT1, OAT3

Olaparib Metabolism, renal and fecal(% unknown)

CYP3A4,a CYP2A6, CYP1A1 P-gp, OATf FDA, 2014s

Ombitasvir, paritaprevir, and ritonavircopackaged with dasabuvir

Ombitasvir: fecal (90.2% mainly asparent), renal (1.91%)

Amide hydrolysis,a CYP3A4, CYP2C8 P-gp, BCRPg FDA, 2014ai

Paritaprevir: metabolism, fecal(88% mainly as metabolites), renal(8.8% mainly as metabolites)

CYP3A4,a CYP3A5, CYP2C8 P-gp, BCRP,OATP1B1,OATP1B3

Dasabuvir: metabolism, fecal(94.4% mainly as metabolite), renal(approximately 2%)

CYP2C8 (60%),a CYP3A (30%),CYP2D6 (10%)

P-gp, BCRP

Peramivir Not significantly metabolized, renal(76%–97% at parent, no metabolite)

Unknown (one metabolite formed withS9 incubation)

Unknownh FDA, 2014ac

Nivolumab Proteolytic degradation N/T, mostly by proteolytic enzymes N/T FDA, 2014y

FMO, flavin-containing monooxygenase; N/T, not tested; SULT, sulfotransferase.aThe primary enzymes responsible for metabolism of the respective NME.bOnly P-gp tested.cOnly P-gp and BCRP tested.dThe interaction of P-gp with netupitant was not fully evaluated; more in vitro studies were requested as a PMR.eInvolvement of P-gp is unlikely due to high A to B permeability coefficient.fThe specific OAT isoform was not determined.gAlthough no active efflux was observed in cellular models, a triple mouse knockout model (Bcrp1, Abcb1a, and Abcb1b) indicated that ombitasvir is likely a substrate of both P-gp and

BCRP.hInvolvement of P-gp and/or MRPs is unlikely; indomethacin and cimetidine both inhibited transport of peramivir in Caco-2 cells; however, it is unclear which transporter is responsible for

transport.


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TABLE 3

Enzyme inhibition interactions, in vitro to in vivo translation

Perpetrator IC50a (mM) R1 AUC Ratio

Cmax

RatioIn Vivo Victim Reference

Apremilast 56.1 (CYP2C8); no TDI observed ,1.1d FDA, 2014aaBelinostat 61.8 (CYP2C9) 4.24e 1.11 0.90 (S)-warfarin FDA, 2014b

100 (CYP2C8) 3.00e N/TCeftolozane 29% at 6000 mg/ml (CYP1A2); no TDI observed N/A 1.07g 0.99g Caffeine FDA, 2014al

32% at 6000 mg/ml (CYP2B6); no TDI observed N/A32% at 6000 mg/ml (CYP2C19); no TDI observed N/A

Ceritinib .100 (CYP1A2); no TDI observed 1.0 FDA, 2014ao5, 0.03 (Ki) (CYP2A6); no TDI observed 61.0e N/T2, 5.3 (Ki) (CYP2B6); no TDI observed 1.3e

2, 16.7 (Ki) (CYP2C8)b; no TDI observed 1.1

2, 0.24 (Ki) (CYP2C9); no TDI observed 8.5e PMR70 (CYP2C19); no TDI observed 1.020 (CYP2D6); no TDI observed 1.2e

30 (CYP2E1); no TDI observed 1.10.2, 0.16 (Ki) (CYP3A4/5)

b; TDI observedc 19.0e PMRDasabuvir 29 (CYP2B6) 1.00 0.98–1.03g 1.03g (S)- and (R)-

methadoneFDA, 2014ai

16.5 (CYP2C8) 1.018.6 (CYP2C9) 1.02 0.88 0.96 (S)-warfarin17.5 (CYP2C19) 1.01 0.62g 0.62g Omeprazole42.5 (CYP2D6) 1.000.92 (UGT1A1) 1.16e 2.26 2.27 Raltegravir

Metabolite M1 6.5 (UGT1A1) 1.39e

Efinaconazole 0.26 (Ki) (CYP2C9) 1.01 FDA, 2014oInhibition (CYP2B6, CYP2C8,

CYP2C19, and CYP3A4/5)cN/A

Eliglustat 5.82 (Ki); KI = 1.05, Kinact = 0.0151 min21 (CYP2D6)b 1.07d 2.33h 1.72h Metoprolol FDA, 2014e27.0 (CYP3A4/5) 1.03d 0.93h 1.03h Norethindrone

MetaboliteGenz-256222

0.399 (Ki, competitive) (CYP2D6) ,1.1

8.51 (Ki, competitive) (CYP3A4/5) ,1.1MetaboliteGenz-120965

KI = 8.44, kinact = 0.206 min21 (CYP2D6)

Florbetaben 1.4 (coincubation), 0.7 (preincubation) (CYP3A4/5)b ,1.1d FDA, 2014vIdelalisib 13 (CYP2C8) 1.708e N/T FDA, 2014an

76 (CYP2C19) 1.209e N/T44 (CYP3A4/5)b 1.121e 5.15 2.31 Midazolam42 (UGT1A1) .1.1e N/T

Metabolite GS-563117

39.8 (CYP2C8) 1.472e

90.7 (CYP2C9) 1.207e

60.4 (CYP2C19) 1.311e

5.1; KI = 0.18, kinact = 0.033 min21 (CYP3A4/5)b 3.686e, f

22 (UGT1A1) ,1.1Ledipasvir 9.9 (CYP3A4/5)b ,1.1d 1.33g 1.06g Atazanavir FDA, 2014k

1.2 1.44 Ethinyl estradiol

7.95 (UGT1A1) ,1.1d

Naloxegol 38.2% at 100 mM (CYP2C9); no TDI observed N/A FDA, 2014t84.7 (CYP2D6); no TDI observed ,1.141.4% at 100 mM (coincubation), 24.3% at 50 mM

(preincubation) (CYP3A4/5)bN/A

Netupitant 1.7, 1.1 (Ki) (CYP3A4/5)b .1.1e 2.76 1.89 Dexamethasone FDA, 2014a

2.44 1.40 Midazolam1.42 1.49 Docetaxel1.41g 0.99g Levonorgestrel1.29 1.29 Erythromycin1.23 1.04 Etoposide

32.39 (CYP2B6) 1.0850.4 (CYP2C8) 1.0518.0, 25.0 (Ki) (CYP2C9) ,1.1d

Metabolite M1 39.39 (CYP1A2) 1.014.89 (CYP2B6) 1.044.74 (CYP2C8) 1.0426.41 (CYP2C9) 1.0133.26 (CYP2C19) 1.018.54 (CYP2D6) 1.020.51 (CYP3A4/5)b 1.42e

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TABLE 3—Continued


Cmax


Metabolite M2 23.72 (CYP2B6) 1.0357.45 (CYP2C19) 1.0158.12 (CYP2D6) 1.0138.84 (CYP3A4/5)b 1.02

Metabolite M3 23.62 (CYP2B6) 1.0126.95 (CYP2C8) 1.0177.03 (CYP2C19) 1.00474.97 (CYP2D6) 1.0049.45 (CYP3A4/5)b 1.03

Nintedanib 70.1 (CYP3A4/5) ,1.1d FDA, 2014x24.5 (UGT1A1) ,1.1d

77.6 (UGT2B7) ,1.1d

Metabolite M2 85.5 (CYP2C9) N/POlaparib 44% at 100 mM (CYP3A4/5)b; no TDI observed N/A FDA, 2014sOlodaterol 1.92 (Ki) (CYP2D6) ,1.1 FDA, 2014ae

Glucuronidemetabolite

KI = 99.0, kinact = 0.044 min21 (CYP2D6) N/P

Ombitasvir 7.4 (CYP2C8) 1.00 FDA, 2014ai2.12 (UGT1A1) 1.00 2.26g 2.27g Raltegravir

Oritavancin 40.5 (CYP1A2) 4.4d,e 1.18 (caffeine metabolitesin urine)

N/P Caffeine FDA, 2014z

16–40.5 (CYP2B6)c .4.4d,e N/T16–40.5 (CYP2C9)c .4.4d,e 1.32 N/P (S)-warfarin16–40.5 (CYP2C19)c .4.4d,e 1.16 (omeprazole/5-

hydroxyomeprazole)N/P Omeprazole

12.6 (Ki, hepatocytes) (CYP2D6) 6.5d,e 0.69 (dextromethorphan/dextrorphan in urine)

N/P Dextromethorphan

16 (CYP3A4/5) 9.7d,e 0.81 N/P MidazolamParitaprevir 13 (CYP2C8) 1.01 FDA, 2014ai

3.62 (UGT1A1) 1.05 2.26g 2.27g RaltegravirNo direct inhibition; weak TDI observed (CYP3A4/5)c N/A

Pirfenidone 34% at 1000 mM (CYP1A2) N/A FDA, 2014i27% at 1000 mM (CYP2A6) N/A30% at 1000 mM (CYP2C9) N/A27% at 1000 mM (CYP2C19) N/A21% at 1000 mM (CYP2D6) N/A27% at 1000 mM (CYP2E1) N/A

Suvorexant 74 (CYP1A2) 1.03d FDA, 2014c64 (CYP2B6) 1.03d

15 (CYP2C8) 1.13d,e

15 (CYP2C9) 1.13d,e

5.3 (CYP2C19) 1.36d,e N/T17 (CYP2D6) 1.11d,e

4, KI = 11.6, kinact = 0.136 min21 (CYP3A4/5) 1.48d,e 1.47 1.23 MidazolamMetabolite M9 .100 (CYP1A2) N/A

44 (CYP2B6) N/P37 (CYP2C8) N/P47 (CYP2C9) N/P35 (CYP2C19) N/P39 (CYP2D6) N/P11; kobs = 0.078 min21 at 50 mM (CYP3A4/5)b N/P

Metabolite M17 .50 (CYP2C9) N/A.50 (CYP2D6) N/A28 (CYP3A4/5) N/P

Tasimelteon 29% (co- and preincubation) at 100 mM (CYP1A2) N/A FDA, 2014l28% (coincubation) and 13% (preincubation) at

100 mM (CYP2C8)N/A 1.03 1.01 Rosiglitazone

80 (coincubation) and 68 (preincubation) (CYP2C19) N/A17% (coincubation) and 1.2% (preincubation) at

100 mM (CYP2D6)N/A

34% (coincubation) and 38% (preincubation) at100 mM (CYP3A4/5)b

N/A 0.9 0.94 Midazolam

550 (coincubation) and 150 (preincubation) (CYP2B6) N/A12% (coincubation) and 26% (preincubation) at

100 mM (CYP2C9)N/A

Metabolite M12 ,50% at 100 mM (CYP2C8) N/A.100 (coincubation) and 92 (preincubation) (CYP2C19) N/P84 (coincubation) and 61 (preincubation) (CYP3A4/5) 1.01

Metabolite M13 31.2% (coincubation) and 34.7% (preincubation) at100 mM (CYP3A/5)

N/A

Tavaborole 4.3% (coincubation) and 41% (preincubation) at100 mM (CYP2A6)

,1.1 FDA, 2014p

42% (coincubation) at 100 mM, 57 (preincubation)(CYP2E1)

,1.1

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three NMEswith R1. 1.1, oritavancin did not significantly increase theexposure of the CYP2C19 substrate omeprazole, whereas idelalisib andsuvorexant were not evaluated.In terms of enzyme induction potential, 29 NMEs were evaluated

using human hepatocytes, and 10 were found to induce DMEexpression or activity as well as activate human pregnane X receptor(PXR) to some extent in vitro (Table 4): apremilast (CYP3A4),belinostat (CYP1A2), ceritinib (CYP2C9 and CYP3A4), idelalisib(CYP2B6, CYP2C8, CYP2C9, CYP3A4, UGT1A1, and UGT1A4),ledipasvir (CYP2B6, CYP3A4, and PXR), olaparib (CYP2B6),pirfenidone (CYP2C19 and CYP3A4), suvorexant (CYP1A2,CYP2B6, CYP3A4, and PXR), tasimelteon (CYP2B6, CYP2C8, andCYP3A4), and vorapaxar (CYP1A2 and CYP2B6). Nuclear receptorswere not commonly investigated; only four NMEs (dapagliflozin,ceritinib, ledipasvir, and suvorexant) were evaluated for PXR activationand one (ledipasvir) for aryl hydrocarbon receptor activation togetherwith P450 enzyme induction. As a result, ledipasvir and suvorexantshowed positive PXR activation. One of the metabolites of tasimelteon,M12, also showed some induction of CYP1A2 and CYP2B6. Inaddition, activation of CYP2E1 was observed for vorapaxar, with a300% increase in activity at 30 mM in HLMs. For most of the drugs,however, the in vitro induction results were observed at concentrationsmuch higher than the expected clinically relevant concentrations (Cmax

values are presented in Table 4). Therefore, considering their lowsystemic exposure and high protein binding, these interactions areunlikely to have any clinical relevance. Indeed, in vivo, only thecombination drug ledipasvir and sofosbuvir was found to be a weakCYP2B6 inducer, decreasing the AUC and Cmax of the coadministeredprobe substrate efavirenz by 21%. Interestingly, the majority of the invitro inducers also showed inhibition of the same P450 enzyme(Table 3). For example, suvorexant was found to increase CYP3A4mRNA by 22.0-fold at 20 mM (42.7% of positive control rifampin) aswell as activate PXR (33% of rifampin) at 10 mM in human hepatocytes(suvorexant Cmax = 1.0 mM); however, it also inhibited CYP3A4 bothdirectly (IC50 = 4 mM) and in a time-dependent manner (KI = 11.6 mM;kinact = 0.136 min21) in HLMs. In vivo, overall inhibition of CYP3Awas observed, with 47% and 23% respective increases in AUC andCmax of the coadministered CYP3A probe substrate midazolam.Similarly, ceftolozane and tazobactam, coadministered as a combina-tion drug, as well as the tazobactam metabolite M1, were all found toreduce the expression and activity of CYP1A2, CYP2B6, and CYP3A4in vitro, and they also inhibited these enzymes. However, when testedwith in vivo probe substrates for CYP1A2 (caffeine) and CYP3A(midazolam), no significant effect was observed (the clinical impact onCYP2B6 was not evaluated).

In summary, regardingDMEs, CYP3Awas involved in themetabolismof the most NMEs in vitro (17 of 35), 14 of which were further confirmedto be substrates of CYP3A in vivo. As perpetrators, 24 drugs showedpositive inhibition and/or induction toward at least one enzyme in vitro;however, only one-third were found to affect the exposure of a clinicalprobe (AUC or Cmax ratio $1.25 or#0.8), highlighting the challenge oftranslating inhibition and induction data from in vitro to in vivo.

Transport and Transporter-Mediated DDIs

Of the 30 NDA approval packages released by the FDA in 2014, 22(73%) contained in vitro transporter data, either substrate assays,inhibition assays, or both. Although this is a lower percentage of overallapprovals than was seen in the previous year (20 of 25 NDA approvalpackages from 2013 contained transporter data), the overall number ofcompounds (drugs and metabolites) tested against transporters in-creased. As a result of multiple combination drugs, there were 25 NMEsrepresented in the 22 NDA approval packages containing transporterassays. In addition, 17 individual metabolites were also evaluated;therefore, 42 new compounds were screened for in vitro transporterinteractions in the approvals from 2014 (also screened was a pool of 10metabolites of eliglustat). To follow up the in vitro findings, nine drugs(a total of 10 NMEs) were studied in vivo as substrates for P-gp, organicanion-transporting polypeptides OATP1B1/3, and organic anion trans-porter OAT3 using clinical inhibitors and/or inducers. A total of 23clinical studies were performed, with 20 showing positive results (AUCor Cmax ratio $1.25 or #0.8). As perpetrators, 10 drugs (a total of 13NMEs) were evaluated clinically for the inhibition of P-gp, OATP1B1/3,OAT1/3, organic cation transporter OCT2, and BCRP. Of the 14 clinicalstudies conducted, one-half showed positive results.In addition to an increase in the number of compounds screened in

the 2014 approval packages, the number of total assays described alsojumped from just over 120 assays in 2013 to over 450 assays in 2014,with more than two-thirds of the assays using the new compound as aprospective inhibitor. This was a result of not only more compoundsbeing tested but also more transporters tested, as well as moretransporters screened per compound. In the 2013 approvals, 16transporters were evaluated, whereas experiments involving 19 trans-porters were described in the 2014 documentation. In addition to theseven transporters explicitly mentioned in the 2012 FDA guidancedocuments (P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, andOCT2; FDA, 2012), assays involving the following transporters werealso described: OATP2B1, OAT2, OCT1, multidrug and toxinextrusion proteins MATE1 and MATE2-K, bile salt export pump,and multidrug resistance-associated proteins MRP1–MRP5 andMRP8.

TABLE 3—Continued


Cmax


Tazobactam 59% at 1000 mg/ml (CYP3A4/5)b ,1.1 1.23g 1.14g Midazolam FDA, 2014alTedizolid

(phosphate)8.7 (MAO-A) .1.1 FDA, 2014ad

5.7 (MAO-B) .1.1Vorapaxar 1.5, 0.86 (Ki) (CYP2C8) ,1.1 1.03 0.95 Rosiglitazone FDA, 2014am

30 (CYP2C9) ,1.1 1.05 1.05 (S)-warfarin

MAO, monoamine oxidase; N/A, not applicable; N/P, not provided; N/T, not tested; PMR, study has been requested as a PMR; some of the metabolite structures are available in the NDA reviews.aIf not specified, the inhibition studies were performed using HLMs.bMultiple IC50 or Ki values are provided in the NDA reviews using different testing systems or substrates, although only the most potent results is presented.cSpecific value is not provided in the NDA reviews.dR1 value calculated by the DIDB Editorial Team using Ki or assuming Ki = IC50/2.eValues exceed the FDA cut-off value of 1.1.fR2 . 1.1 assuming kdeg of 0.000825 min21.gPerpetrator was administered as the combination drug.hResults from CYP2D6 EMs.

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TABLE 4

Enzyme induction interactions, in vitro to in vivo translation

Perpetrator Induction Effect Cmax (mM)AUCRatio

Cmax


Apremilast Approximately 0.65-fold in activity at 10 mM (CYP1A2) 0.8 FDA, 2014aa0.30-fold in activity at 100 mM (CYP2C9)3.7-fold, approximately50% of rifampin in activity at

100 mM (CYP3A4)0.84 0.90 Norgestimateb

Belinostat 2.3-fold and 14% of omeprazole in activity at 15 mM(CYP1A2)

100 FDA, 2014b

Ceftolozane 0.27-fold in mRNA and 0.39-fold in activity at1000 mg/ml (CYP1A2a)

97.3 1.07 0.99 Caffeinec FDA, 2014al

0.36-fold in mRNA and 0.60-fold in activity at1000 mg/ml (CYP2B6a)

0.26-fold in mRNA and 0.70-fold in activity at1000 mg/ml (CYP3A4)

1.23 1.14 Midazolamc

Ceritinib 6.03-fold in mRNA and 2.06-fold in activity (1 donor) at2.5 mM (CYP3A4a)

1.8 FDA, 2014ao

1.18-fold in mRNA and 2.31-fold in activity (1 donor)at 1 mM (CYP2C9)

Idelalisib 46% of positive control in mRNA at 10 mM (CYP2B6) 4.6 FDA, 2014an3.9-fold in mRNA at 10 mM (CYP2C8a)3.1-fold in mRNA at 10 mM (CYP2C9)54% of positive control in mRNA at 10 mM (CYP3A4)2.4-fold in mRNA at 10 mM (UGT1A1a)2.1-fold in mRNA at 10 mM (UGT1A4)

Ledipasvir 4.08-fold at 10 mM and 71% of weak activator androstanol(PXR)

0.4 FDA, 2014k

2.0-fold at 1 mM in mRNA, 2-fold at 10 mM in activity(CYP2B6)

0.79 0.79 Efavirenzc

1.06 0.93 Efavirenz2.6-fold at 1 mM and .10-fold at 10 mM in mRNA, 1.32-fold

at 1 mM and .5-fold at 10 mM in activity (CYP3A4a)1.33 1.06 Atazanavirc

1.2 1.44 Ethinyl estradiolOlaparib 3.2-fold and 40% of phenobarbital in activity at 30 mM

(CYP2B6)18.2 FDA, 2014s

Pirfenidone 2.20-fold in activity at 250 mM (CYP2C19) 48.8 FDA, 2014i1.87-fold in activity at 250 mM (CYP3A4a)

Suvorexant 4.8-fold and 20.4% of omeprazole in mRNA at 5 mM, 2.7-foldand 10.7% of omeprazole in activity at 20 mM (CYP1A2a)

1.0 FDA, 2014c

2.4-fold and 18.6% of phenobarbital in mRNA at 5 mM,2.3-fold and 23.1% of phenobarbital in activity at20 mM (CYP2B6a)

22.0-fold and 42.7% of rifampin in mRNA at 5 mM, 0.4-foldin activity at 20 mM (CYP3A4a)

1.47 1.23 Midazolam

33% of rifampin at 10 mM (PXR)Tasimelteon 16.5-fold in mRNA and 5-fold in activity at 100 mM (CYP2B6) 0.8 FDA, 2014l

4.43-fold and 60.3% of rifampin in activity at 100 mM(CYP2C8)

1.03 1.01 Rosiglitazone

2.27-fold and 83.2% of rifampin in activity at 100 mM(CYP3A4a)

0.9 0.94 Midazolam

Metabolite M12 4.64-fold in mRNA and 2.71-fold (1 donor) in activity at100 mM (CYP1A2a)

12-fold in mRNA and 8-fold in activity at 100 mM (CYP2B6)Tazobactam 0.46-fold in mRNA and 0.63-fold in activity at 1250 mg/ml

(CYP1A2)55.9 1.07 0.99 Caffeinec FDA, 2014al

0.60-fold in mRNA and 0.65-fold in activity at 1250 mg/ml(CYP2B6)

0.44-fold in mRNA and 2.9-fold (12% of rifampin) in activityat 1250 mg/ml (CYP3A4a)

1.23 1.14 Midazolamc

Metabolite M1 0.15-fold in mRNA and 0.16-fold in activity at 75 mg/ml(CYP1A2)

0.062-fold in mRNA and 0.11-fold in activity at 75 mg/ml(CYP2B6)

0.47-fold in mRNA and 0.67-fold in activityat 75 mg/ml mRNA 3/3 donors (CYP3A4)

Vorapaxar 2.97-fold in activity at 30 mM (CYP1A2) 0.05 FDA, 2014am4.66-fold in activity at 30 mM (CYP2B6)300% activation at 30 mM (CYP2E1)

R3 values were not provided for any of the compounds listed.aInhibition was also observed of the same enzyme.bMetabolite norelgestromin was measured.cPerpetrator was administered as the combination drug.


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Not surprisingly, P-gp was once again the most represented trans-porter with regard to substrate assays screened as well as positivesubstrate interactions identified (Fig. 2A). A total of 33 compoundswere tested, with 19 positive interactions (i.e., efflux ratio $2),comprising 15 NMEs and four metabolites. Interestingly, for onlyone of the metabolites shown to be a substrate of P-gp was the parentcompound also a P-gp substrate (dasabuvir and the metabolite M1);however, in the case of netupitant (in which the metabolite M2 was asubstrate of P-gp), the potential for the parent compound to be asubstrate was not fully examined and further in vitro experiments havebeen requested as a PMR (FDA, 2014a). Of the 15 NMEs identified asP-gp substrates (apremilast, belinostat, ceritinib, dapagliflozin,dasabuvir, eliglustat, empagliflozin, idelalisib, ledipasvir, naloxegol,nintedanib, olaparib, olodaterol, ombitasvir, and paritaprevir), 10 NMEswere tested in vivo as P-gp substrates, and nine positive interactionswere identified, with the largest interaction observed when ledipasvirwas coadministered with simeprevir (ledipasvir: AUC ratio = 1.88;Cmax ratio = 1.78). Coadministration with the P-gp inhibitor verapamilalso resulted in a ledipasvir AUC ratio of 1.66 and a Cmax ratio of 1.21,although no effect was observed with cyclosporine, also a P-gpinhibitor. Similarly, verapamil had no effect on the AUC of empagli-flozin. Interactions of a comparable magnitude (1.25 # AUC ratio , 2)were observed with coadministration of ketoconazole (also a CYP3Ainhibitor) with apremilast, dasabuvir, idelalisib, nintedanib, olodaterol,and paritaprevir (all of which, with the exception of olodaterol, are alsoCYP3A substrates); therefore, these interactions are likely mediated byP450 enzymes in addition to possible transporter influence. In addition,the P-gp inhibitor quinidine had an effect on the PK of naloxegol (AUC

ratio = 1.39; Cmax ratio = 2.43). Regarding induction of P-gp, bothrifampin (idelalisib: AUC ratio = 0.24;Cmax ratio = 0.43; ledipasvir: AUCratio = 0.40; Cmax ratio = 0.69; and nintedanib: AUC ratio = 0.50; Cmax

ratio = 0.60) and carbamazepine (dasabuvir: AUC ratio = 0.30;Cmax ratio= 0.46; and paritaprevir: AUC ratio = 0.30;Cmax ratio = 0.44) were tested.However, because both of these compounds also induce P450 enzymes,the effects observed are likely due to the combination of transporter andP450 enzyme induction.For inhibition assays, although P-gp was also the most commonly

screened transporter, OATP1B1 had more positive inhibitory interac-tions (14 parents and seven metabolites; Fig. 2B), whereas OATP1B3(13 parents and six metabolites), P-gp, and BCRP all had 19 positiveinhibitory interactions. However, of the 16 NMEs showing positiveinteractions with OATP1B1 and/or OATP1B3, only five NMEs(dasabuvir, idelalisib, ledipasvir, olaparib, and paritaprevir) hadCmax/IC50 values greater than the FDA guidance cut-off of 0.1. Twoof those NMEs (ledipasvir and olaparib) had subsequent R values lessthan the FDA guidance cut-off value of 1.25 and therefore did notnecessitate an in vivo DDI study. For the remaining NMEs, in vivostudies with various statins, which are known substrates of OATP1B1/3,were performed (Table 5). No effect of idelalisib was observed onrosuvastatin PK, nor did empagliflozin affect the PK of simvastatin.However, the combination drug, Viekira Pak (containing paritaprevir,ritonavir, ombitasvir, and dasabuvir), did significantly affect pravastatinand rosuvastatin exposure (AUC ratio = 1.82 and 2.59, respectively;Cmax

ratio = 1.36 and 7.15, respectively), although the rosuvastatin interactionmay be partially mediated by BCRP, because paritaprevir, ritonavir, anddasabuvir were all shown to inhibit BCRP, as well as OATP1B1 andOATP1B3, in vitro.Nineteen compounds, comprising 13 NMEs and six metabolites,

were shown to be inhibitors of P-gp in vitro. With respect tometabolites, in contrast with the substrate assays, the parent compoundsfor all metabolites showing inhibition of P-gp were also inhibitors(dasabuvir and metabolite M1, netupitant and metabolites M1–M3,nintedanib and metabolite M2, and suvorexant and metabolite M9). Forsix NMEs, in vitro inhibition was minimal and therefore no in vivostudy was triggered (apremilast, netupitant, nintedanib, olodaterol,pirfenidone, and tedizolid; Table 6); however, a clinical study was stillperformed with netupitant and the P-gp probe substrate digoxin, but noin vivo effect was observed (digoxin: AUC ratio = 1.04; Cmax ratio =1.10). Four of the remaining compounds showed no potential systemicinteractions ([I]1/IC50 was below the regulatory cut-off value of 0.1);however, the intestinal interaction potential was greater than the cut-offvalue ([I]2/IC50 . 10, where [I]2 is the maximal therapeutic dose, inmoles, divided by 250 milliliters). Therefore, in vivo DDI studies withdigoxin were performed. Both paritaprevir and dasabuvir wereinhibitors of P-gp in vitro; however, the combination drug ViekiraPak containing both compounds (as well as ritonavir, which alsoshowed in vitro inhibition of P-gp, and ombitasvir, which did not) hadno significant effect on digoxin AUC or Cmax (AUC ratio = 1.16; Cmax

ratio = 1.14), whereas eliglustat and suvorexant increased digoxinexposure (AUC ratio = 1.49 and 1.27; Cmax ratio = 1.71 and 1.21,respectively). Finally, two NMEs, idelalisib and vorapaxar, showedpossible clinically relevant inhibition potential at both the systemic andintestinal levels, although neither showed a significant effect on digoxinAUC in vivo (AUC ratio = 1.00 and 1.05, respectively). However,significant effects on digoxin Cmax were observed with both com-pounds (Cmax ratio = 1.25 and 1.54, respectively). The largest in vivoeffect observed was with ledipasvir and simeprevir, in which co-administration resulted in the simeprevir AUC and Cmax ratios of 2.84and 2.56, respectively; however, this interaction may be partiallymediated by BCRP as well, because ledipasvir has been shown to be an

Fig. 2. Quantitation of compounds acting as substrates (NMEs) or inhibitors (NMEsand metabolites) of transporters in vitro. (A) Transporters involved in transport ofNMEs. (B) Transporters inhibited by NMEs (solid bars) and metabolites (stripedbars). *The specific OAT isoform was not determined.

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inhibitor of BCRP in vitro and simeprevir is a substrate of at least themouse homolog of BCRP (Bcrp1) (FDA, 2013a). This interaction isalso particularly of interest, because both simeprevir and ledipasvir(combined with sofosbuvir) are indicated for the treatment of hepatitisC; however, based on this interaction, coadministration is not recom-mended (FDA, 2014k). One NME, dapagliflozin, showed no inhibitorypotential of P-gp in vitro; however, the sponsor still performed an invivo DDI study with the P-gp substrate digoxin, although no effect wasobserved (digoxin AUC ratio = 1.00).

In terms of BCRP inhibition, a total of 19 compounds, comprising 11NMEs and eight metabolites, were shown to be inhibitors in vitro(Table 7). Similar to P-gp, the parent compounds for all of themetabolites showing inhibition of BCRP were also BCRP inhibitors,with the exception of tasimelteon and its M9 metabolite. Five NMEs(dasabuvir, netupitant, paritaprevir, suvorexant, and tedizolid) werepredicted to be involved in possible clinical DDIs, based on both the[I]1/IC50 and [I]2/IC50 values; however, in the case of suvorexant, bothvalues only slightly exceed the cut-off values of 0.1 (0.117) and 10 (28),

TABLE 5

Hepatic OATP inhibition interactions, in vitro to in vivo translation

Perpetrator OATP In Vitro Substrate IC50 (mM) Cmax/IC50 AUC Ratio Cmax Ratio In Vivo Victim Reference

Ceftolozane 1B3 Fluo-3 25% at 1500 mM FDA, 2014alCeritinib 1B1 Estradiol 17-b-glucuronide 31.8% at 5 mM FDA, 2014ao

1B3 Estradiol 17-b-glucuronide 24.1% at 5 mMDapagliflozin 1B1 Estradiol 17-b-glucuronide 69.3 0.005b FDA, 2014j

1B3 Cholecystokinin octapeptide 8 0.044b

Dasabuvir 1B1 N/S 0.9 2.32b,c 1.82 1.36 Pravastatind FDA, 2014ai1B3 N/S 6.6 0.32b,c 2.59 7.15 Rosuvatstatind

Eliglustat 1B1 Estrone-3-sulfate 150 0.003b FDA, 2014e1B3 Fluo-3 100 0.004b

Empagliflozin 1B1 N/S 71.8 0.009 1.00 0.95 Simvastatin FDA, 2014n1B3 N/S 58.6 0.012

Idelalisib 1B1 N/S 10 0.46b,c 1.11 1.21 Rosuvastatin FDA, 2014an1B3 N/S 7 0.66b,c

Ledipasvir 1B1 Fluo-3 3.5 0.29c N/T; Re , 1.25 FDA, 2014k1B3 Fluo-3 6.5 0.15c N/T; Re , 1.25

Netupitant 1B1 Estrone-3-sulfate 22% at 30 mM FDA, 2014a1B3 Fluo-3 44% at 30 mM

Olaparib 1B1 N/S 20.3 0.9c N/T; Re = 1.16 FDA, 2014s1B3 N/S 25% at 100 mM

Paritaprevir 1B1 N/S 0.031 61.9b,c 1.82 1.36 Pravastatind FDA, 2014ai1B3 N/S 0.017 112.9b,c 2.59 7.15 Rosuvatstatind

Suvorexant 1B1 Pitavastatin 48% at 10 mM FDA, 2014cTazobactam 1B3 Fluo-3 32.3% at 500 mg/ml FDA, 2014alTedizolid (phosphate) 1B1 Estradiol 17-b-glucuronide 29% at 30 mMa FDA, 2014adVorapaxar 1B1 Pitavastatin 31% at 10 mM FDA, 2014am

1B3 Bromsulphthalein 45% at 10 mM

N/S, not specified; N/T, not tested.aFollow-up experiments showed no inhibition.bRatio was calculated by the DIDB Editorial Team.cValues exceed the FDA cut-off value of 0.1.dPerpetrator was administered as the combination drug.eR = 1 + (fu � Iin,max/IC50).

TABLE 6

P-gp inhibition interactions, in vitro to in vivo translation

PerpetratorIn VitroSubstrate

IC50 (mM) [I]1/IC50 [I]2/IC50AUCRatio

Cmax

RatioIn VivoVictim

Reference

Apremilast Digoxin 31% at 50 mM FDA, 2014aaDapagliflozin Digoxin None 1.00 N/P Digoxin FDA, 2014jDasabuvir N/S 16.7 0.12c 121c 1.16 1.14 Digoxine FDA, 2014aiEliglustat Digoxin 22 0.018b 37.8b,c 1.49 1.71 Digoxin FDA, 2014eIdelalisib N/S 8 0.575b,c 180.5b,c 1.00 1.25 Digoxin FDA, 2014anLedipasvir Calcein AM 46.3% at 1 mM 2.84 2.56 Simeprevir FDA, 2014kNetupitant Digoxin a 1.04 1.10 Digoxin FDA, 2014aNintedanib N/S 27.1% at 3 mM FDA, 2014xOlodaterol Digoxin 365 2.8 � 1028b d FDA, 2014aeParitaprevir N/S 38.1 0.05 20.6c 1.16 1.14 Digoxine FDA, 2014aiPirfenidone Digoxin 29% at 1000 mM FDA, 2014iSuvorexant Digoxin 18.7 0.05b 18.9b,c 1.27 1.21 Digoxin FDA, 2014cTedizolid

(phosphate)Digoxin 15.5% at 60 mM FDA, 2014ad

Vorapaxar Digoxin 1.2 0.13c 14.1c 1.05 1.54 Digoxin FDA, 2014am

N/P, not provided; N/S, not specified.aER reduced from 29 to 4.7 at 5 mM.bRatio was calculated by the DIDB Editorial Team.cValues exceed the FDA cut-off value of 0.1 ([I]1/IC50) or 10 ([I]2/IC50).dRoute of administration is inhalation, therefore no potential intestinal effect.ePerpetrator was administered as the combination drug.


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respectively, and thus the sponsor did not expect clinically relevantinhibition, especially because the [I]2/IC50 value drops to 10.6 at thetherapeutic dose of 15 mg (FDA, 2014c). Regarding the four remainingNMEs (dasabuvir, netupitant, paritaprevir, and tedizolid), only one invivo study was performed using rosuvastatin and the combination drugViekira Pak (paritaprevir, ritonavir, ombitasvir, and dasabuvir), whichresulted in a rosuvastatin AUC ratio of 2.59 and a Cmax ratio of 7.15,although as mentioned previously, this interaction is likely at leastpartially mediated by OATP1B1 and/or OATP1B3 as well. In the caseof tedizolid, an in vivo drug interaction study with a BCRP substratewas recommended (FDA, 2014ad). For netupitant, although not a PMR,the reviewers noted that “since total Cmax/IC50 is greater than 0.1 forparent drug netupitant, a follow-up in vivo study may be recom-mended” (FDA, 2014a).In summary, 15 NMEs were shown to be substrates of P-gp in

vitro, nine of which were tested in in vivo DDI studies, resulting ineight NMEs showing a positive interaction (AUC ratio of the NME$1.25 when administered with a P-gp inhibitor). However, most ofthese NMEs are also CYP3A substrates, and the DDI studies wereperformed with the strong CYP3A inhibitor ketoconazole; therefore,the interactions observed are likely mediated by P450 enzymes aswell as P-gp. Regarding inhibition, three NMEs (namely, ledipasvir,eliglustat, and suvorexant) showed inhibition of P-gp in vivo, withAUC ratios of 2.84 (substrate: simeprevir), 1.49 (substrate: digoxin),and 1.27 (substrate: digoxin), respectively, whereas dasabuvir andparitaprevir were shown to be moderate OATP inhibitors in vivo (aswell as likely inhibitors of BCRP). These data are in contrast with invitro data, where of the 25 NMEs tested, 21 had positive inhibitoryinteractions with one or more transporter. Of the four compoundswith no positive inhibitory interactions, three (belinostat, oritavancin,and peramivir) were only tested against P-gp, whereas naloxegolwas screened against multiple transporters and no interaction wasobserved. The same trend was observed in the 2013 NDA approvalpackages, in which a majority of the compounds tested wereinhibitors of transporters in vitro; however, most of these interactionswere not clinically relevant, indicating that further research in thetransporter field is required to improve the predictive value of in vitroexperiments.

Pharmacogenetic Studies

For four NMEs (dapagliflozin, eliglustat, nintedanib, and olodaterol),the effects of genetic variants of the primary enzymes for metabolicclearance (namely UGT1A9, CYP2D6, UGT1A1, UGT1A1, UGT1A7,

UGT1A9, and UGT2B7, respectively) on the PK of each drug wereevaluated. Eliglustat, which is primarily metabolized by CYP2D6 andCYP3A4, displayed a significant effect of CYP2D6 polymorphisms onits disposition. When eliglustat was administered at the dose regimenof 84 mg orally twice daily for 10 days, its AUC and Cmax weresignificantly reduced by 91% and 88%, respectively in CYP2D6 ultra-rapid metabolizers (CYP2D6*1/*2 dup), and increased by 7.39- and5.48-fold in PMs (CYP2D6*4/*4, CYP2D6*4/*5, and CYP2D6*4/*6),compared with CYP2D6 EMs (CYP2D6*1/*1 and CYP2D6*2/*2). Bycontrast, the PK of eliglustat was not significantly affected in CYP2D6IMs compared with EMswhen dosed at 84 mg twice daily for 52 weeks;hence, no dose adjustment is required for CYP2D6 IMs. Since eliglustathas the potential to prolong the QT interval, CYP2D6 PMs are at risk ofcardiac toxicity due to the expected elevated plasma exposure;therefore, the recommended dose is reduced to 84 mg once daily inCYP2D6 PMs. On the other hand, in CYP2D6 ultra-rapid metabolizers,eliglustat may not achieve adequate concentrations for the therapeuticeffect and its use is limited in this patient population. On the basis ofthese results, it is necessary to determine each patient’s CYP2D6genotype prior to the administration of eliglustat to define a properdosage regimen (FDA, 2014e).In the case of nintedanib, which is metabolized by esterases to M1

and then subsequently glucuronidated by UGT enzymes to M2, therewas no significant effect of the UGT1A1*28 allele on the exposure tonintedanib; by contrast, there was a significant decrease in both theAUC and Cmax (62% and 63%, respectively) of the glucuronidemetabolite M2 in individuals homozygous for the variant. However,since M2 does not appear to be biologically active, no dosingrecommendations based on UGT1A1 genotype have been made.As for dapagliflozin and olodaterol, none of the tested UGTpolymorphisms (UGT1A9*2 and UGT1A9*3 for dapagliflozin, andUGT1A1*28/36/37, UGT1A1*60, UGT1A1*93, UGT1A7*2,UGT1A7*3, UGT1A7*4, UGT1A7*12, UGT1A9*3, and UGT2B7*2for olodaterol) affected the systemic exposure of the respective NME.

PBPK Modeling and Simulations

In recent years, PBPK modeling has become an important tool indrug development and is increasingly accepted by regulatory agenciesin lieu of clinical studies in certain circumstances (Rowland et al., 2011;Zhao et al., 2012; Huang et al., 2013; Wagner et al., 2015). Indeed,PBPK approaches have been included in the recent regulatory guidancedocuments on DDIs (European Medicines Agency, 2012; FDA, 2012;Pharmaceuticals Medical Devices Agency, 2014), PGx (European

TABLE 7

BCRP inhibition interactions, in vitro to in vivo translation

Perpetrator In Vitro Substrate IC50 (mM) [I]1/IC50 [I]2/IC50 AUC Ratio Cmax Ratio In Vivo Victim Reference

Dasabuvir N/S 15.6 0.13a 130a 2.59 7.15 Rosuvastatinb FDA, 2014aiEmpagliflozin N/S 114 0.006 1.90 FDA, 2014nLedipasvir Hoechst 33342 38.1% at 1 mM FDA, 2014kNetupitant Estrone-3-sulfate 6 0.25a 346a,c e FDA, 2014aOlodaterol Estrone-3-sulfate 10–100 1.04 � 1026c FDA, 2014aeParitaprevir N/S 0.59 3.25a 1328a 2.59 7.15 Rosuvastatinb FDA, 2014aiSuvorexant Methotrexate 10–15 (62% at 15 mM) 0.117a,c 28a,d FDA, 2014cTedizolid

(phosphate)Genistein 51.1 0.16a 31.7a,c PMR FDA, 2014ad

Vorapaxar Methotrexate 2.5 0.064 6.8 FDA, 2014am

N/S, not specified; PMR, study has been requested as a PMR.aValues exceed the FDA cut-off value of 0.1 ([I]1/IC50) or 10 ([I]2/IC50).bPerpetrator was administered as the combination drug.cRatio was calculated by the DIDB Editorial Team.dValue is 10.6 at therapeutic dose of 15 mg.eRecommended by reviewers, although not a PMR.

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TABLE 8

Clinically significant inhibition interactions, NMEs as victims or perpetrators

Victim Drug (Dose) Inhibitor (Dose)

Enzymes/TransportersPossiblyInvolved

Max AUC Ratio Max Cmax Ratio Study Design/PopulationbLabelingImpact

Reference

Tacrolimus (2 mg aloneand 0.5 mg withperpetrators SD)

Ombitasvir,a paritaprevir,a

dasabuvir,a and ritonavir(paritaprevir/ritonavir150/100 once daily +ombitasvir 25 mg oncedaily + dasabuvir 400 mgtwice daily for 28 d)

CYP3A,P-gp

57.07 16.48 One-sequence/12 healthysubjects

Y FDA, 2014ai

Paritaprevir (300 mg SD)a Ritonavir (100 mg SD) CYP3A,OATP1B1

47.43 28.07 Parallel/6 healthy subjectsper group

Y FDA, 2014ai

Naloxegol (25 mg SD)a Ketoconazole (400 mg oncedaily for 5 d)

CYP3A,P-gp


Y FDA, 2014t

Eliglustat (100 mg twicedaily for 14–17 d)a

Paroxetine (30 mg oncedaily for 10 d)

CYP2D6 10.00 8.20 One-sequence/24 healthysubjects (CYP2D6 EMs)

Y FDA, 2014e

Dasabuvir (400 mg SD)a Gemfibrozil (600 mg twicedaily for 5 d)

CYP2C8 9.90 1.91 One-sequence/11 healthysubjects

Y FDA, 2014ai

Tasimelteon (5 mg SD)a Fluvoxamine (50 mg oncedaily for 7 d)

CYP1A2(3A, 2C9,2C19)


Y FDA, 2014l

Pirfenidone (801 mg SD)a Fluvoxamine (50–100 mgonce daily or twice dailyfor 10 d)

CYP1A2 6.81 (smokers),3.97(nonsmokers)

2.24 (smokers),1.69(nonsmokers)

One-sequence/healthysubjects (26 smokers and25 nonsmokers)

Y FDA, 2014i

Cyclosporine (100 mg SDalone, 10 mg SD withinhibitors)



CYP3A,P-gp


Y FDA, 2014ai

Midazolam (5 mg SD) Idelalisib (150 mg twicedaily for 8 d)a

CYP3A 5.15 2.31 One-sequence/11 healthysubjects

Y FDA, 2014an

Eliglustat (100 mg twicedaily for 14 d)a

Ketoconazole (400 mg oncedaily for 7 d)

CYP3A 4.40 4.25 One-sequence/24 healthysubjects (CYP2D6 EMs)

Y FDA, 2014e

Ceritinib (450 mg SD)a Ketoconazole (200 mgtwice daily for 14 d)


Y FDA, 2014ao

Simeprevir (150 mg oncedaily for 10 d)

Ledipasvir (30 mg oncedaily for 10 d)a

P-gp 2.84 2.56 Random Crossover/28healthy subjects

Y FDA, 2014k

Suvorexant (4 mg SD)a Ketoconazole (400 mg oncedaily for 11 d)

CYP3A 2.79 1.23 One-sequence/11 healthymales

Y FDA, 2014c

Ritonavir (100 mg oncedaily for 28 d)



CYP3A,P-gp


Y FDA, 2014ai

Norgestimate (250 mgonce daily for 21 d)


dasabuvir,a and ritonavir(paritaprevir/ritonavir150/100 once daily +ombitasvir 25 mg oncedaily + dasabuvir 250 mgtwice daily for19 d)

CYP3A,UGT

Norelgestromin:2.75; norgestrel:

2.64

Norelgestromin:2.30; norgestrel:

2.46

One-sequence/3 healthyfemales

Nc FDA, 2014ai

Rosuvastatin (5 mg oncedaily for 21 d)



OATP1B1/3,BCRP


Y FDA, 2014ai

Rilpivirine (25 mg oncedaily for 28 d)




Y FDA, 2014ai

Olaparib (100 mg SD)a Itraconazole (200 mg oncedaily for 8 d)

CYP3A 2.59 1.36 One-sequence/56 patientswith advanced solidtumors

Y FDA, 2014s

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Medicines Agency, 2011; FDA, 2013b), pediatrics (FDA, 2014ap), andHI (EuropeanMedicines Agency, 2005) as a tool to guide clinical studydesign and labeling decisions. Among the drugs approved in 2014,PBPKmodeling was used in at least one clinical situation for six NMEs:belinostat, PGx; blinatumomab, DDIs; ceritinib, DDIs and absorption;eliglustat, DDIs and complex drug–gene interactions; naloxegol, DDIs;and olaparib, DDIs. The modeling results for four of these drugs(namely, ceritinib, eliglustat, naloxegol, and olaparib) were useddirectly to inform dose recommendations with moderate inhibitorsand inducers. For ceritinib, PBPK modeling predicted that fluconazole,a moderate inhibitor of CYP3A, may increase ceritinib exposure by37%, whereas efavirenz, a moderate CYP3A inducer, may decreaseceritinib exposure by 43%; therefore, it is not recommended to restrictconcomitant use of these drugs with ceritinib. In the case of eliglustat,complex drug–PGx interaction scenarios were simulated with co-administration of moderate or strong CYP2D6 and/or CYP3A inhib-itors in subjects with different CYP2D6metabolizing status (EMs, IMs,and PMs). Alteration in the daily dose is recommended based on thepredicted interaction results (FDA, 2014e). For example, PBPK

simulations showed that if eliglustat (84 mg twice daily) wascoadministered with paroxetine (a strong CYP2D6 inhibitor) togetherwith ketoconazole (a strong CYP3A4 inhibitor), or terbinafine (amoderate CYP2D6 inhibitor) together with fluconazole (a moderateCYP3A4 inhibitor), its exposure would increase by 24.16- and 13.58-fold in CYP2D6 EMs, respectively, and 9.81- and 4.99-fold inCYP2D6 IMs, respectively. Therefore, administration of eliglustatwith strong or moderate CYP2D6 inhibitors concomitantly with strongor moderate CYP3A4 inhibitors is contraindicated in CYP2D6 EMsand IMs. Considering the safety margins of eliglustat, performing suchclinical studies may have resulted in unsafe overexposure to eliglustat,leading to possible adverse events and/or toxicities, highlighting theutility of using PBPK modeling in place of clinical evaluations inspecific situations. In the case of naloxegol, PBPK simulations withmoderate CYP3A4/P-gp inhibitors (erythromycin, fluconazole, andverapamil) predicted increases in naloxegol exposure of 2.21- to 4.63-fold (minimal PBPK model). Therefore, the concomitant use ofnaloxegol with moderate CYP3A4/P-gp inhibitors should be avoidedor, if unavoidable, the dose of naloxegol should be reduced (note that

TABLE 8—Continued

Victim Drug (Dose) Inhibitor (Dose)

Enzymes/TransportersPossiblyInvolved

Max AUC Ratio Max Cmax Ratio Study Design/PopulationbLabelingImpact

Reference

Amlodipine (5 mg SD) Ombitasvir,a paritaprevir,a



Y FDA, 2014ai

Midazolam (7.5 mg SD) Netupitant (300 mg SD)a CYP3A 2.44 1.40 Random crossover/20healthy subjects

Y FDA, 2014a

Netupitant (300 mg SD)a Ketoconazole (400 mg oncedaily for 12 d)

CYP3A 2.42 1.19 Random crossover/18healthy subjects

Y FDA, 2014a

Metoprolol (50 mg SD) Eliglustat (150 mg twicedaily for 5 d)a

CYP2D6 2.33 1.72 One-sequence/8 healthysubjects (CYP2D6 EMs)

Y FDA, 2014e

Raltegravir (400 mg twicedaily for 17 d)



UGT1A1 2.26 2.27 One-sequence/12 healthysubjects

N FDA, 2014ai

Ketoconazole (400 mgonce daily for 6 d)


dasabuvir,a and ritonavir(paritaprevir/ritonavir/ombitasvir 150/100/25mg + dasabuvir250 mg SD)


Y FDA, 2014ai

Buprenorphine (median 16mg once daily for 25 d)



CYP3A 2.05 2.00 One-sequence/10 patients Y FDA, 2014ai

Ledipasvir (90 mg oncedaily for 10 d)a

Atazanavir/ritonavir(atazanavir/ritonavir300/100 mg once dailyfor 10 d)

P-gp 2.05 1.93 Random crossover/30healthy subjects

N FDA, 2014k

Droxidopa (not provided)a DOPA decarboxylaseinhibitors (not specified)

Catechol-O-methyltransferase

2.00 NA Not provided Y FDA, 2014w

Maximum AUC and Cmax ratios of the victim drug are presented.SD, single dose.a2014 NMEs.bThe number of subjects listed represents the number of subjects who completed the study, as described in the DIDB.cAlthough there is no labeling recommendation specific to norgestimate, ethinyl estradiol–containing oral contraceptives are contraindicated with Viekira Pak due to potential alanine

aminotransferase elevation.

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the use of naloxegol with strong CYP3A4/P-gp inhibitors is contra-indicated). Similarly, olaparib, which is primarily metabolized byCYP3A, was evaluated in clinical studies with the strong CYP3Ainhibitor itraconazole and the strong inducer rifampin, whereas the DDIrisk with concomitant use of moderate CYP3A inhibitors or inducerswas predicted through PBPK modeling. It was predicted that flucona-zole would likely increase olaparib AUC by 2.26-fold and efavirenzwould likely decrease olaparib AUC by 59%. Therefore, a dosereduction to 200 mg twice daily (original dose of 750 mg once daily)is recommended for concomitant use of a moderate CYP3A inhibitor.On the other hand, because increasing the dose could be impracticalgiven the number of capsules to be administered, it is recommended thatconcomitant use of a moderate CYP3A inducer should be avoided. If amoderate CYP3A inducer must be coadministered, it may result inreduced efficacy (FDA, 2014s).

Clinically Significant DDIs

As in our prior publication (Yu et al., 2014), the measure of theexposure to the victim drug (AUC and Cmax) with and withoutcoadministration of the perpetrator (AUC and Cmax ratios) was usedto evaluate the clinical significance of the DDI study results. Asdiscussed previously, even though the concentration ratio representsonly one of the factors to consider when analyzing the possible clinicalimpact of a drug interaction, this is a simple metric that can be appliedacross all studies, irrespective of the substrate evaluated. Since a 2-foldchange in drug exposure will often trigger dosing recommendations, an

AUC or Cmax ratio $2 for inhibition and #0.5 for induction wasconsidered in this analysis as a cut-off for further consideration.However, for completeness and to take into account the varioussubstrates’ therapeutic ranges, drugs with changes in exposure smallerthan 2-fold (1.25# AUC ratio, 2 for inhibition, and 0.5, AUC ratio# 0.8 for induction) but still triggering dosing recommendations orspecific monitoring are presented in Supplemental Table 2. Overall, itwas found that 17 of the 35 NMEs analyzed (46%) had at least one invivo DDI study with a change in exposure of clinical significance, withNMEs being mainly victim drugs. Maximum clinically significantinhibition and induction results observed with NMEs as victims orperpetrators are presented in Table 8 (inhibition) and Table 9(induction). For inhibition studies, alteration of CYP3A activity wasthe most common underlying mechanism, explaining one-half of theresults. A majority of the NMEs (n = 12) were affected by theinteraction as victims, whereas seven NMEs were perpetrators (fivebeing both victims and perpetrators). On the other hand, inductionstudies were all related to NMEs as victim drugs and, in most cases,involved induction of CYP3A by the known inducers rifampin orcarbamazepine.The largest change in exposure was observed with the combination

drug Viekira Pak (paritaprevir, ritonavir, ombitasvir, and dasabuvir) asa perpetrator, which drastically increased the exposure of the CYP3Aand P-gp substrate tacrolimus upon coadministration (AUC ratio =57.07; Cmax ratio = 16.48). Consequently, dose reduction of tacrolimusand close monitoring of its blood concentrations are recommendedwhen coadministered with Viekira Pak (FDA, 2014ai). On the other

TABLE 9

Clinically significant induction interactions, all 2014 NMEs as victims

Victim Drug (Dose) Inducer (Dose)Enzymes /TransportersPossibly Involved

MaxAUCRatio

MaxCmax

RatioStudy Design/Populationa

LabelingImpact

Reference

Eliglustat (100 mgtwice dailyfor 6 d)

Rifampin (600 mg oncedaily for 6 d)

CYP3A 0.04 0.05 One-sequence/6 healthy subjects(CYP2D6 PMs)

Y FDA, 2014e

Naloxegol(25 mg SD)


CYP3A, P-gp 0.11 0.26 One-sequence/22 healthy subjects Y FDA, 2014t

Olaparib(300 mg SD)


CYP3A 0.11 0.30 One-sequence/17 patients withadvanced solid tumors

Y FDA, 2014s

Suvorexant(40 mg SD)


CYP3A 0.12 0.36 One-sequence/10 healthy subjects Y FDA, 2014c

Tasimelteon(20 mg SD)


CYP1A2, CYP3A,CYP2C9, CYP2C19

0.14 0.23 One-sequence/24 healthy subjects Y FDA, 2014l

Netupitant(300 mg SD)


CYP3A 0.20 0.45 Random Crossover/18 healthysubjects

Y FDA, 2014a

Idelalisib(150 mg SD)


CYP3A, P-gp 0.24 0.43 One-sequence/11 healthy subjects Y FDA, 2014an

Apremilast(30 mg SD)


CYP3A, P-gp 0.28 0.57 One-sequence/21 healthy subjects Y FDA, 2014aa

Paritaprevir(150 mg SD)

Carbamazepine (200 mg oncedaily for 3 d, twice daily for 21 d)

CYP3A, P-gp 0.30 0.44 One-sequence/12 healthy subjects Y FDA, 2014ai

Dasabuvir(250 mg SD)

Carbamazepine (200 mgonce daily for 3 d,twice daily for 21 d)

CYP3A, P-gp 0.30 0.46 One-sequence/12 healthy subjects Y FDA, 2014ai

Ceritinib(750 mg SD)


CYP3A 0.30 0.56 One-sequence/19 healthy subjects Y FDA, 2014ao

Ledipasvir(90 mg SD)


P-gp 0.40 0.69 One-sequence/31 healthy subjects Y FDA, 2014k

Vorapaxar (2.5mg once dailyfor 22 d)


CYP3A 0.45 0.61 Parallel, placebo-controlled/12healthy subjects

Y FDA, 2014am

Pirfenidone(801 mg SD)

Cigarette smoking(dose not provided)

CYP1A2 0.49 0.71 Parallel/healthy subjects (26smokers and 25 nonsmokers)

Y FDA, 2014i

Nintedanib(150 mg SD)


CYP3A, P-gp 0.50 0.60 One-sequence/25 healthy males Y FDA, 2014x

Maximum AUC and Cmax ratios of the victim drugs are presented.aThe number of subjects listed represents the number of subjects who completed the study, as described in the DIDB.


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hand, the exposure of one of the constituents of Viekira Pak(paritaprevir), a substrate of CYP3A and of various transporters(OATPs, BCRP, and P-gp), was increased 47.43-fold when coadminis-tered with the potent inhibitor ritonavir. Indeed, ritonavir is used in thecombination drug for its boosting effect on paritaprevir concentrations(FDA, 2014ai). Paritaprevir was also sensitive to induction bycarbamazepine, with decreases in AUC and Cmax of 70% and 56%,respectively. Both interactions are highlighted in Viekira Pak pre-scribing information (FDA, 2014ai). Dasabuvir, another component ofViekira Pak, was also found to be sensitive to inhibition of CYP2C8 bygemfibrozil, with a change in AUC of almost 10-fold (interestingly, theeffect of gemfibrozil on dasabuvir Cmax was limited, with a change ofonly 1.91-fold). In addition, when the full drug combination (paritaprevir,ritonavir, ombitasvir, and dasabuvir) was tested as a perpetrator, aseries of substrates were significantly inhibited: namely, amlodipine(CYP3A), buprenorphine (CYP3A), cyclosporine (CYP3A/P-gp),ketoconazole (CYP3A), norgestimate (CYP3A and UGT), raltegravir(UGT1A1), rilpivirine (CYP3A), ritonavir (CYP3A/P-gp), androsuvastatin (OATP1B1/3 and BCRP), with AUC and Cmax ratios of2.57 and 1.26, 2.05 and 2.00, 5.80 and 15.73, 2.15 and 1.13, 2.64 and2.46 (for the metabolite norgestrel), 2.26 and 2.27, 3.40 and 2.93, 2.78 and2.54, and 2.60 and 7.15, respectively. Themultitude of interactions observedwith Viekira Pak—which mechanistically involve the constituents as bothvictims and perpetrators, including both inhibition and induction of severalenzymes and transporters—highlight the challenges of managing druginteractions in the clinic with such complex combination drugs.Another NME particularly sensitive to both inhibition and in-

duction of its metabolism was eliglustat. As mentioned above,eliglustat is metabolized by CYP2D6 and to a lesser extent CYP3A4.Coadministration of the strong CYP2D6 inhibitor paroxetine or thestrong CYP3A4 inhibitor ketoconazole in healthy CYP2D6 EMsincreased eliglustat AUC by 10.00- and 4.40-fold, respectively, andCmax by 8.20- and 4.25-fold, respectively, whereas the strong inducerrifampin significantly decreased eliglustat plasma levels, especially inCYP2D6 PMs (AUC ratio = 0.04; Cmax ratio = 0.05). On the otherhand, eliglustat was also found to be an inhibitor of CYP2D6,

increasing the AUC of the probe substrate metoprolol 2.33-fold andCmax 1.72-fold in CYP2D6 EMs. As previously discussed, results ofextensive PBPK modeling were used to guide eliglustat dosingrecommendations in complex situations of multiple impairment and/or in patients with various degrees of CYP2D6 expression (FDA,2014e). In addition, two NMEs were found to be sensitive substratesof CYP1A2: tasimelteon and pirfenidone, with AUC ratios of 6.87and 6.81, respectively, when coadministered with the strong CYP1A2inhibitor fluvoxamine. Of note, fluvoxamine also inhibits CYP3A,CYP2C9, and CYP2C19, which are also involved to some extent inthe metabolism of tasimelteon. Both the tasimelteon and pirfenidonelabels include dosing recommendations related to cigarette smoking,which is known to induce CYP1A2 activity (FDA, 2014i,l).Regarding transporter-based clinical interactions, there were only a

few drug interactions with over 2-fold changes in substrate exposure,which could be explained purely by alteration of transport. Theinteractions involving ledipasvir as a victim (2.05-fold increase inAUC when coadministered with atazanavir boosted with ritonavir, and60% decrease in AUC with rifampin coadministration) and as aperpetrator (increase in simeprevir AUC by 2.84-fold) involved mainlyinhibition and induction of P-gp. Also, as discussed above, the effect ofViekira Pak on rosuvastatin disposition can be mainly explained byinhibition of OATP1B1/3 and BCRP.In conclusion, when a cut-off of 2-fold change in drug exposure was

considered for clinical relevance, approximately one-half of the drugsanalyzed had clinically significant DDIs, most of which related to theNMEs as victim drugs. Not surprisingly, the underlying mechanism for alarge number of these interactions was inhibition or induction of CYP3A.

Hepatic and Renal Impairment Studies

It is well recognized that organ impairment can significantly affecta drug’s plasma exposure, and, in some situations, may affect itssafety and efficacy. The probability and extent of these effects in agiven patient population will significantly differ depending on theseverity of impairment of these eliminating organs. Therefore, the

TABLE 10

NMEs with HI-related labeling impact

Compound Name Max AUC Ratio Cmax Ratioc Labeling Impact Reference

AUC $2Dasabuvira 3.51 (severe) 1.09 (severe) Not recommended (moderate);

contraindicated (severe)FDA, 2014ai

Netupitant 4.18 (severe) 3.13 (severe) Avoid use (severe) FDA, 2014aParitaprevirb 5.25 (severe) 2.21 (severe) Not recommended (moderate);

contraindicated (severe)FDA, 2014ai

Tasimelteon 2.67 (moderate); M14: 3.43(moderate)

1.34 (moderate); M14: 0.79(moderate)

Not recommended (severe) FDA, 2014l

AUC ratio ,2, withdosing informationDalbavancin 0.64 (severe) 0.71 (severe) Exercise caution

(moderate and severe)FDA, 2014g

Idelalisib 1.66 (moderate) 0.95 (moderate) Monitor for toxicity FDA, 2014anNaloxegol 0.82 (moderate) 1.15 (moderate) Avoid use (severe) FDA, 2014tPirfenidone 1.61 (moderate) 1.41 (moderate) Not recommended (severe) FDA, 2014iSuvorexant 1.03 (moderate) 0.94 (moderate) Not recommended (severe) FDA, 2014cVorapaxar 0.77 (severe) 0.74 (severe) Not recommended (severe) FDA, 2014am

No dedicated HI study,with dosing informationEliglustat Not evaluated Not evaluated Not recommended (any HI) FDA, 2014eNintedanib Not evaluated, HI requested

as PMRNot evaluated Not recommended

(moderate and severe)FDA, 2014x

AUC and Cmax values presented have been calculated by the DIDB Editorial Team using mean values available from the NDA review documents and may differ from those presented in the product label.aThe AUC ratio presented in the product label is 4.25.bThe AUC ratio presented in the product label is 10.45.cThe Cmax ratios presented are for the same impairment state as the maximal AUC ratio; however, they may not be the Cmax ratios observed when considering other impairment states.

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FDA recommends that sponsors conduct organ impairment studies ifHI and/or RI might affect a drug and/or its active metabolites’ PK, orif the drug might be used in these respective populations (Yeunget al., 2015). For the purpose of this review, the AUC and Cmax ratios(impaired/control) were considered as a standard outcome measure-ment of the effect of various degrees of organ impairment on theNMEs, using values observed in patients with HI or RI versus thoseobserved in control healthy populations. Similar to the in vivoclinical significance evaluation presented in the previous section, anAUC ratio $2 was considered as a cut-off to systematically evaluatethe NDAs for any dosing and labeling recommendations.Overall, 24 NMEs were assessed for the effect of HI and/or RI on

the drug’s PK. Among the 19 NMEs evaluated for HI studies, fourdemonstrated an AUC ratio $2 in patients with HI (mild, moderate,and severe, Child-Pugh score A, B, and C, respectively) versushealthy controls, resulting in dosing recommendations, whereas sixNMEs had AUC ratios,2 but still reported dosing recommendationsin these populations. In addition, dosing recommendations were givenfor two NMEs for which the sponsor did not conduct dedicated HIstudies (Table 10). Among the four NMEs for which systemicexposure was increased by $2-fold, all are extensively metabolizedby the liver. Three (dasabuvir, netupitant, and paritaprevir) are mainlyeliminated via biliary excretion, whereas tasimelteon is primarilyeliminated by renal excretion as metabolites. The highest change inexposure was observed for paritaprevir (a constituent of the combi-nation drug Viekira Pak) in patients with severe HI, showing a 5.25-fold increase in AUC and a 2.21-fold increase in Cmax, whereas theAUC and Cmax ratios were 1.68 and 1.17, respectively, in patientswith moderate HI. Dasabuvir, another NME in the same combinationdrug, demonstrated a 3.51-fold increase in AUC (Cmax ratio = 1.09) inpatients with severe HI and no increase in patients with mild ormoderate HI. On the basis of these results, Viekira Pak is contra-indicated in patients with severe HI and is not recommended in

patients with moderate HI (FDA, 2014ai). The next largest change inexposure was observed for netupitant (AUC ratio = 4.18) in thepopulation with severe HI. Of note, PK data were only available fortwo patients with severe HI, with individual AUC ratios of 6.06 and2.29. The use of netupitant in patients with severe HI is to be avoided,with no dose recommendation in patients with moderate impairment(FDA, 2014a). Finally, tasimelteon showed AUC and Cmax ratios of2.67 and 1.34, respectively, in patients with moderate HI. Doseadjustment is not necessary in patients with mild or moderate HI;however, the product label states that “[tasimelteon] has not beenstudied in patients with severe hepatic impairment and is notrecommended in these patients” (FDA, 2014l).With regard to RI studies, six of the 22 NMEs evaluated in patients

with RI demonstrated AUC ratios $2 in patients versus healthycontrols, resulting in specific dosing recommendations; however,five NMEs (apremilast, dalbavancin, empagliflozin, olaparib, andpirfenidone) had AUC ratios ,2 but still reported dosing recom-mendations. For two NMEs (eliglustat and netupitant), dedicated RIstudies were not performed; however, dosing recommendationswere provided (Table 11). Among the six NMEs for which sys-temic exposure was increased by $2-fold (albiglutide, ceftolozane,dapagliflozin, peramivir, naloxegol, and tazobactam), four are mainlyeliminated via renal excretion, whereas naloxegol is mainly elimi-nated via biliary excretion, and albiglutide, a therapeutic protein, iseliminated via proteolysis. Peramivir showed the largest effect inpatients with RI, with 4.15-, 5.27-, and 18.08-fold increases in AUCin patients with moderate, severe, and end-stage renal disease,respectively, with dose adjustment recommendations noted in theproduct label for these patients (FDA, 2014ac). Other changes inexposure ranged from a 2.00-fold change in tazobactam AUC whenadministered in patients with moderate HI to a 3.19-fold increase inAUC for naloxegol in patients with moderate RI, yielding specificlabeling recommendations in all cases (Table 11). In addition, for

TABLE 11

NMEs with RI-related labeling impact

Compound Name Max AUC Ratio Cmax Ratiob Labeling Impact Reference

AUC $2Albiglutidea 2.82 (severe) 2.61 (severe) Monitor renal function FDA, 2014agCeftolozane 2.55 (moderate) 1.04 (moderate) Monitor CrCL and adjust dose if

necessaryFDA, 2014al

Dapagliflozin 2.31 (severe); dapagliflozin-3-O-glucorunide: 3.22 (severe)

1.34 (severe); dapagliflozin-3-O-glucorunide: 1.38 (severe)

Contraindicated (severe, ESRD,dialysis)

FDA, 2014j

Naloxegol 3.19 (severe) 2.24 (severe) Reduce dose (CrCL ,60 ml/min) FDA, 2014tPeramivir 18.08 (ESRD) 1.21 (ESRD) Reduce dose (CrCL ,50 ml/min),

administer after dialysisFDA, 2014ac

Tazobactam 2.00 (moderate) 1.28 (moderate) Monitor CrCL and adjust dose ifnecessary

FDA, 2014al

AUC ratio ,2, withdosing informationApremilast 1.89 (severe); M12: 2.92 (severe) 1.43 (severe); M12: 1.43 (severe) Reduce dose (severe) FDA, 2014aaDalbavancin 1.97 (severe) 0.99 (severe) Adjust dose (CrCL ,30 ml/min,

without dialysis)FDA, 2014g

Empagliflozin 1.67 (severe) 1.23 (severe) Contraindicated (severe, ESRD,dialysis)

FDA, 2014n

Olaparib 1.66 (mild) 1.27 (mild) Monitor for toxicity FDA, 2014sPirfenidone 1.09 (severe); 5-carboxy: 5.88

(severe)1.13 (severe); 5-carboxy: 2.97

(severe)Not recommended (ESRD on dialysis),

monitor for adverse reactionsFDA, 2014i

No dedicated RI study, withdosing informationEliglustat Not evaluated Not evaluated Not recommended (moderate, severe) FDA, 2014eNetupitant Not evaluated Not evaluated Avoid use (severe, ESRD) FDA, 2014a

AUC and Cmax values presented have been calculated by the DIDB Editorial Team using mean values available from the NDA review documents and may differ from those presented in the productlabel. CrCL, creatinine clearance; ESRD, end-stage renal disease.

aNo exact AUC ratio for severe RI is provided in the product label; however, according to the sponsor, albiglutide exposure was increased by approximately 30%–40% in patients with RI (all stages).bThe Cmax ratios presented are for the same impairment state as the maximal AUC ratio; however, they may not be the Cmax ratio observed when considering other impairment states.


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dapagliflozin, a 2.31-fold increase in AUC was observed in patientswith severe RI, whereas the AUC of the main circulating (inactive)metabolite, dapagliflozin 3-O-glucuronide, was found to increase by3.22-fold and 1.99-fold in patients with severe and moderate RI,respectively, although the parent drug AUC was only increased by1.60-fold in patients with moderate RI. Hence, dapagliflozin iscontraindicated in patients with severe RI or ESRD, or in patientsrequiring dialysis (FDA, 2014j). Taken together, these data indicatethe importance of assessing the PK of NMEs in impaired populationsbecause AUC ratios reported in patients with HI or RI may be on thesame order of magnitude as those observed in clinical drug interactionstudies.

Conclusions

The systematic and detailed evaluation of the DDI data available inthe 2014 NDAs and BLAs (covering 35 NMEs) provides valuableinsights regarding the potential risk of these drugs to interact withalready marketed drugs. Overall, the NMEs were extensively studiedboth in vitro and in vivo and their drug interaction profiles were wellcharacterized. Similar to drugs approved in recent years, there was aclear focus on the preclinical assessment of transporters in the drugdisposition and interaction profiles, with most of the NMEs beingthoroughly evaluated for transporter-based DDIs. However, becauseof the intricacy of transporter system functions, the lack of selectiveand specific probe substrates and inhibitors in vivo, and thesometimes complex overlap with metabolic enzymes, translatingthese research findings into definitive clinical recommendationsremains challenging. In addition, tools such as PBPK modeling arenow commonly used to evaluate complex scenarios involvingmultiple impairment situations and to support optimized dosingrecommendations.

Acknowledgments

The authors thank Dr. Sophie Argon, Dr. Catherine K. Yeung, MarjorieImperial, and Dr. Katie Owens for their contributions to the NDA/BLA datacuration.

Authorship ContributionsParticipated in research design: Yu, Ritchie, Zhou, Ragueneau-Majlessi.Performed data analysis: Yu, Ritchie, Zhou, Ragueneau-Majlessi.Wrote or contributed to the writing of the manuscript: Yu, Ritchie, Zhou,

Ragueneau-Majlessi.

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