Review Review of Drug Interactions with Telaprevir and Antiretrovirals

Antiviral Therapy 2013; 18:553–560 (doi: 10.3851/IMP2527)

Review Review of drug interactions with telaprevir and antiretrovirals

Rolf PG van Heeswijk1*, Maria Beumont1, Robert S Kauffman2, Varun Garg2

1Janssen Infectious Diseases BVBA, Beerse, Belgium 2Vertex Pharmaceuticals Incorporated, Cambridge, MA, USA

*Corresponding author e-mail: [email protected]

HCV infection is a major cause of mortality worldwide. and studies in HCV–HIV-coinfected patients are ongoing. HCV-related deaths also represent a leading cause of Drug–drug interactions of telaprevir with antiretroviral mortality in HIV-coinfected individuals. Telaprevir is an drugs were investigated in a series of studies in healthy NS3/4A protease inhibitor approved for the treatment of subjects. This review summarizes the results of interaction chronic HCV genotype 1 infection in adults in combination studies with low-dose ritonavir, ritonavir-boosted HIV with pegylated interferon and ribavirin. Telaprevir-based protease inhibitors (atazanavir, darunavir, fosamprenavir treatment has been shown to increase rates of sustained and lopinavir), efavirenz, etravirine, rilpivirine, tenofovir viral response in HCV genotype-1-monoinfected patients, disoproxil fumarate and raltegravir.

Introduction

HCV infection is a serious health challenge [1,2], HCV genotype-1-infected adult patients in combina- affecting 170 million people, which is approximately tion with PEG-IFN/RBV [12,13], and is being evalu- 3% of the global population [3,4]. Worldwide, approx- ated for use in coinfected patients. Telaprevir is an imately 4 to 5 million individuals are coinfected with inhibitor of the HCV NS3/4A protease. Telaprevir is HCV and HIV. HCV prevalence among HIV-infected orally bioavailable [14], is primarily metabolized by individuals is particularly high in injection drug users cytochrome P450 3A4 (CYP3A4) as well as by non- (72–95%), but is also found in heterosexuals (9–27%) CYP pathways [15] and is also a potent inhibitor and homosexual men (1–12%) [5]. A number of stud- of CYP3A4 [16]. Therefore, doses of drugs that are ies demonstrate increased mortality among coinfected substrates of CYP3A may need to be adjusted when individuals treated with HAART [6] and also empha- coadministered with telaprevir. Telaprevir can also size the need for earlier and more aggressive HIV and inhibit or saturate P-glycoprotein (P-gp) in the gut HCV treatment in coinfected individuals [7,8]. and doses of drugs that are P-gp substrates may have Liver-related deaths represent a leading cause of death to be reduced [16]. in patients with HIV, primarily due to HCV coinfection. Efficacy and safety of telaprevir administration in HCV-associated liver disease is accelerated in HIV- HCV-monoinfected patients was demonstrated in three infected individuals with a threefold higher progres- Phase III studies, which showed significantly improved sion to cirrhosis compared with individuals with HCV SVR rates with telaprevir-based regimens for both monoinfection [9,10]. Pegylated interferon plus ribavi- treatment-naive and -experienced patients [17–19]. The rin (PEG-IFN/RBV) has been the standard HCV treat- relationship between telaprevir exposure and antiviral ment in coinfected patients. However, sustained viral efficacy with the approved treatment regimen (750 mg response (SVR) is achieved in only approximately 33% telaprevir every 8 h plus PEG-IFN/RBV) was found to be of coinfected individuals across HCV genotypes, and the shallow and non-significant [20]. likelihood of SVR is significantly lower in HCV geno- To guide evaluation of telaprevir-based regimens in type 1/4 infection compared with other genotypes [11]. HIV–HCV-coinfected patients, a number of studies have Hepatitis C therapies that provide better efficacy been conducted to investigate the potential drug–drug are therefore widely requested for coinfected patients. interaction (DDI) between telaprevir and a range of anti- Telaprevir has been approved for treatment of chronic retroviral drugs in healthy subjects. The results of these

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studies are discussed in this review. The DDI data are Alternatively, telaprevir itself is a strong inhibitor of summarized in Table 1. CYP3A [15] and autoinhibition of CYP3A may also explain the lack of a significant effect of RTV on tel- HIV protease inhibitors aprevir exposure after multiple-dose administration of Ritonavir telaprevir when CYP3A is already maximally inhib- Telaprevir exposure (maximum plasma concentration ited. Thus, although RTV increased telaprevir expo-

[Cmax], predose plasma concentration and average sure when given as a single dose, this was not sustained plasma concentration) after a single oral dose appli- after repeated dosage of the combination of 750 mg cation of 750 mg in the fed state was approximately telaprevir every 12 h (1,500 mg per day) and 100 mg twice as high when combined with ritonavir (RTV) RTV every 12 h. 100 mg compared with 750 mg telaprevir only [21]. Coadministration of telaprevir with RTV was well In the multiple-dose administration part of the study, tolerated with generalized pruritus, headache, rash, healthy male subjects received adjusted lower doses of nausea and diarrhoea as the most frequent drug-related telaprevir (750 mg every 12 h) in combination with adverse events. No serious adverse events and no clini- low-dose RTV (100 mg every 12 h) which was com- cally significant changes in laboratory values or vital pared with telaprevir 750 mg every 8 h given alone. All signs were reported [21]. drugs were taken with food. A 2.5-fold increase in telaprevir exposure (area under Atazanavir/ritonavir the concentration time curve [AUC]) was observed on A combination of 300 mg atazanavir (ATV)/100 mg day 14 compared to day 1 in the 750 mg telaprevir alone RTV once daily and 750 mg telaprevir every 8 h every 8 h group but a 15% decrease in the 750 mg tel- were coadministered in healthy subjects [24]. ATV/ aprevir every 12 h/100 mg RTV every 12 h group. RTV RTV coadministration decreased telaprevir steady- has been reported to have a time-dependent inductive/ state plasma concentrations compared with telaprevir

inhibitory effect on P-gp in the intestinal cell lines [22]. alone. Telaprevir Cmax, minimum plasma concentra-

The reduction of telaprevir exposure after multiple dos- tion (Cmin) and AUC8 h were decreased by 21%, 15% ing seen in this study is possibly due to inductive effects and 20%, respectively (Figure 1). The effect of ATV of RTV on CYP3A4, P-gp or other transporters, which on telaprevir exposure is considered to be modest; the may play a role in telaprevir disposition [21–23]. relationship between telaprevir exposure and antiviral

Table 1. Summary of clinical drug interaction studies of telaprevir with antiretroviral agents

Dose and schedule Number of AUC, LS means ratio (90% CI) Coadministered drug Coadministered drug Telaprevir individualsa Coadministered drug Telaprevir

HIV protease inhibitors Lopinavir/ritonavir 400/100 mg twice daily 750 mg every 8 h 12  1.06 (0.96, 1.17)  0.46 (0.41, 0.52) Atazanavir/ritonavir 300/100 mg once daily 750 mg every 8 h 14  1.17 (0.97, 1.43)  0.80 (0.76, 0.85) Darunavir/ritonavir 600/100 mg twice daily 750 mg every 8 h 11  0.60 (0.57, 0.63)  0.65 (0.61, 0.69) Fosamprenavir/ritonavir 700/100 mg twice daily 750 mg every 8 h 20  0.53 (0.49, 0.58)  0.68 (0.63, 0.72) Reverse transcriptase inhibitors TDF 300 mg once daily 750 mg every 8 h 16  1.30 (1.22, 1.39)  1.00 (0.94, 1.07) EFV 600 mg once daily 750 mg every 8 h 21  0.93 (0.87, 0.98)  0.74 (0.65, 0.84) EFV and TDF 600 mg once daily EFV 1,125 mg every 8 h 15  0.82 (0.74, 0.90) for EFV  0.82 (0.73, 0.92)b and 300 mg once daily TDF and 1.10 (1.03, 1.18) for TDF EFV and TDF 600 mg once daily EFV 1,500 mg every 12 h 16  0.85 (0.79, 0.91) for EFV  0.80 (0.73, 0.88)c and 300 mg once daily TDF and 1.10 (1.03, 1.17) for TDF Etravirine 200 mg twice daily 750 mg every 8 h 15  0.94 (0.85, 1.04)  0.84 (0.71, 0.98) Rilpivirine 25 mg once daily 750 mg every 8 h 16  1.78 (1.44, 2.20)  0.95 (0.76, 1.18) HIV integrase inhibitors Raltegravir 400 mg twice daily 750 mg every 8 h 20  1.31 (1.03, 1.67)  1.07 (1.00, 1.15)

aThe number of individuals differs depending on the respective calculated ratio. bRatio (telaprevir 1,125 mg every 8 h with tenofovir disoproxil fumarate [TDF] and c efavirenz [EFV])/(telaprevir 750 mg every 8 h alone). Least square (LS) mean ratio based on average concentration at steady-state (Css,av) instead of the area under the concentration–time curve (AUC), ratio (telaprevir 1,500 mg every 12 h with TDF and EFV)/(telaprevir 750 mg every 8 h alone). , upwards increase in exposure; , decrease in exposure;  , no change in exposure.

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efficacy has been shown to be shallow and non-signif- which is also a substrate and strong inhibitor of CYP3A icant [20]. [25]. Mean reductions in the AUC of ATV, LPV and Telaprevir increased the exposure to ATV, as DRV by 34–44% were observed during combination

expressed by AUC24 h, by 17% (Figure 2). This can be with boceprevir. Coadministration of RTV-boosted

explained by the ATV Cmin increase of 85%, which ATV with boceprevir did not alter the exposure of likely reflects reduced systemic elimination of ATV due boceprevir, but coadministration of boceprevir with to telaprevir inhibition of CYP3A. However, there was LPV/RTV or RTV-boosted DRV decreased the expo- no significant effect on ATV absorption, as indicated by sure of boceprevir by 45% and 32%, respectively [26].

the small change in ATV Cmax (15% decrease). These findings can possibly be explained by the com- plex interplay between metabolic interactions and com- Darunavir/ritonavir petition of telaprevir and the HIV protease inhibitors for To study interactions between darunavir (DRV)/ plasma protein binding sites. Telaprevir is only moder- RTV and telaprevir, healthy subjects received 600 mg ately (59–76%) bound to plasma proteins (to both albu- DRV/100 mg RTV twice daily and 750 mg telaprevir min and a-acid glycoprotein) and protein displacement every 8 h [24]. Steady-state concentrations of telaprevir has been shown to occur both in vitro and in vivo. An decreased after coadministration of DRV/RTV and tel- increase in the free fraction of R-methadone was observed

aprevir: telaprevir Cmin, Cmax and AUC8 h were decreased in an in vivo DDI study with telaprevir [27], and in an by 32%, 36% and 35%, respectively (Figure 1). DRV in vitro study, it was shown that warfarin increased the concentrations were decreased in the presence of tel- free fraction of telaprevir [28]. Since all of the HIV pro-

aprevir: Cmin decreased by 42%, Cmax decreased by 40% tease inhibitors are highly bound to plasma proteins (85–

and AUC12 h decreased by 40% (Figure 2). 99%), with varying contributions of albumin and a-acid glycoprotein, competition for binding sites could occur Fosamprenavir/ritonavir [29–32]. DRV and APV have been reported to primar- Interactions between fosamprenavir (fAPV)/RTV and ily bind to a-acid glycoprotein, while ATV and LPV are telaprevir were studied in healthy subjects receiving bound to both a-acid glycoprotein and albumin [30–32]. 700 mg fAPV/100 mg RTV twice daily and 750 mg Since a-acid glycoprotein is present in plasma at much telaprevir every 8 h [24]. Telaprevir concentrations at lower concentrations than albumin [32], the potential for

steady-state decreased by 30% for Cmin, by 33% for protein displacement may be higher for DRV and APV

Cmax and by 32% for AUC8 h (Figure 1). Amprenavir compared with ATV and LPV. This could explain the dif- (APV) concentrations were also lowered in the presence ferences in the magnitude of the observed interactions

of telaprevir: APV Cmin, Cmax, and AUC12 h decreased by with these drugs during coadministration of telaprevir. 56%, 35% and 47%, respectively (Figure 2). However, other mechanisms, such as the effect on drug transporters may also be involved. Based on the modest Lopinavir/ritonavir effect of ATV/RTV on telaprevir exposure (see above) and Coadministration of 400 mg lopinavir (LPV)/100 mg the limited effect on exposure to ATV, the combination of RTV twice daily and 750 mg telaprevir every 8 h in ATV/RTV with telaprevir was selected for further clinical healthy subjects [24] decreased steady-state plasma evaluation in patients with HIV–HCV-coinfection. concentrations of telaprevir relative to telaprevir

administered alone: Cmax was decreased by 53%, Cmin Safety of coadministration of telaprevir and

was decreased by 52% and AUC8 h was decreased by ritonavir-boosted HIV protease inhibitors 54% (Figure 1). Telaprevir did not affect the exposure The type of adverse events observed during coadministra-

to LPV (expressed by Cmax and AUC12 h; Figure 2); how- tion of telaprevir and HIV protease inhibitors ATV/RTV,

ever, the Cmin of LPV was increased by 14% after coad- LPV/RTV, DRV/RTV or fAPV/RTV in these healthy vol- ministration with telaprevir. unteer studies was consistent with the safety profile of the individual drugs. Events related to hyperbilirubinaemia Summary of telaprevir interactions with ritonavir- were observed during treatments including ATV/RTV boosted protease inhibitors (that is, increased blood bilirubin and ocular icterus). The variable degrees of reduction in exposure to telaprevir as well as to some of the HIV protease inhibi- Pharmacokinetic interactions between telaprevir and tors administered together with RTV during coadmin- reverse transcriptase inhibitors istration were unexpected as all of these agents are both DDIs between telaprevir and the nucleotide reverse substrates and inhibitors of CYP3A, although various transcriptase inhibitor tenofovir disoproxil fumarate non-overlapping metabolic pathways are involved (TDF), and the non-nucleoside reverse transcriptase as well. Similar unexpected findings were recently inhibitors (NNRTIs) efavirenz (EFV), etravirine (ETR) reported for the HCV protease inhibitor boceprevir, and rilpivirine (RPV) were investigated.

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Figure 1. Pharmacokinetic profiles of telaprevir alone and in combination with HIV protease inhibitors

LPV ATVDRV fAPV n=14 n=17 n=16 n=20 3,000

TVR alone

2,000

TVR + ARV

1,000 TVR concentration, ng/ml n=12 n=14 n=11 n=18

AUC 54% AUC 20% AUC 35% AUC 32% 0 024 6 8 024 6 8 024 6 8 024 6 8 Time, h

ARV, antiretroviral; ATV, atazanavir; AUC, area under the curve; DRV, darunavir; fAPV, fosamprenavir; LPV, lopinavir; TVR, telaprevir.

Figure 2. Pharmacokinetic profiles of HIV protease inhibitors alone and in combination with telaprevir

LPV/r ATV/r 12,000 4,000

3,000 8,000 n=19

n=12 2,000 n=7 4,000 1,000 n=11 ATV concentration, ng/ml ATV LPV concentration, ng/ml AUC AUC 17% 0 0 0 246810 12 0 6 12 18 24 Time, h Time, h

DRV/r fAPV/r 6,000 4,000

4,000 3,000 n=16 n=20

2,000 2,000 n=11 1,000 n=18 APV concentration, ng/ml DRV concentration, ng/ml DRV AUC 40% AUC 47% 0 0 0 246810 12 0 246810 12 Time, h Time, h PI alone PI plus TVR

APV, amprenavir; ATV, atazanavir; AUC, area under the curve; DRV, darunavir; fAPV, fosamprenavir; LPV, lopinavir; PI, protease inhibitor; /r, ritonavir-boosted; TVR, telaprevir.

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Tenofovir disoproxil fumarate telaprevir can inhibit CYP3A4, it was hypothesized that TDF is a widely used nucleotide reverse transcriptase coadministration of telaprevir and EFV could result in inhibitor for the treatment of HIV infections, in com- changed exposure of both telaprevir and EFV. bination with other antiretroviral agents. TDF is a Pharmacokinetic interactions between EFV and prodrug of tenofovir and is administered at 300 mg telaprevir were investigated in healthy subjects [38]. once daily, which is equivalent to 136 mg of tenofo- Subjects received 600 mg EFV once daily and 750 mg vir. Although tenofovir is largely excreted unchanged telaprevir every 8 h. Coadministration of EFV with

into the urine, previous trials [33,34] have shown drug telaprevir decreased the Cmin of telaprevir by 47% and

interactions with CYP3A4 substrates and/or inhibi- the telaprevir exposure (AUC0–8) by 26%. The Cmax of tors such as HIV protease inhibitors. As telaprevir is telaprevir was unaffected. The pharmacokinetic param- a CYP3A4 substrate and inhibitor, interaction with eters of EFV were similar in the presence or absence of tenofovir was studied in healthy subjects [35]. Subjects telaprevir [38]. received 300 mg TDF once daily and 750 mg telaprevir Overall, this study demonstrates that there was a every 8 h. The exposure to telaprevir, as expressed by significant effect of the CYP3A4 inducer EFV on the

Cmin, Cmax and AUC8 h, was not affected by coadminis- pharmacokinetics of telaprevir, and therefore dosage tration of TDF. Steady-state plasma concentrations of adjustment strategies of telaprevir were evaluated in a tenofovir were higher after coadministration of TDF subsequent study. with telaprevir than after intake of TDF alone: tenofo-

vir Cmin, Cmax and AUC24 h increased by 41%, 30% and Tenofovir disoproxil fumarate and efavirenz 30%, respectively. Renal clearance of tenofovir (total coadministration amount of tenofovir excreted in urine over 24 h divided Based on the previously described findings with TDF

by the plasma AUC24 h) was decreased by 36% when and EFV, a follow-up study examined the effect of EFV TDF was administered in combination with telaprevir, on telaprevir pharmacokinetics with the dosing sched- compared with TDF administration alone [35]. ule of telaprevir changed to either 1,125 mg every 8 h Increased exposure to tenofovir during coadmin- or 1,500 mg every 12 h to compensate for the decreased istration of telaprevir may be explained by the effect telaprevir concentrations seen with EFV coadministra- of telaprevir on uptake and efflux transporters, which tion [24]. Because EFV and TDF are frequently coad- have been shown to play a role in the pharmacokinet- ministered in HIV-infected subjects, and because of the ics of tenofovir. TDF (but not tenofovir) is a substrate previously observed 30% increase in tenofovir exposure of P-gp and inhibition of intestinal P-gp has been pro- when coadministered with telaprevir, this study was posed as a mechanism for increased tenofovir exposure designed to investigate the effect of coadministration during combination with HIV protease inhibitors [33]. of all three drugs on their pharmacokinetic parameters. Telaprevir has been shown to increase the exposure to Healthy subjects received a telaprevir dosage of orally administered digoxin (a P-gp probe substrate), 1,125 mg every 8 h or 1,500 mg every 12 h coadmin- and reduced efflux of TDF during absorption may con- istered with EFV (600 mg once daily) and TDF (300 tribute to increase exposure to tenofovir during combi- mg once daily). Telaprevir plasma concentrations nation with telaprevir. Based on in vitro studies, several at steady-state were compared with those achieved drug transporters have been shown to play a role in with telaprevir alone at 750 mg every 8 h and were the active renal tubular secretion of tenofovir. Teno- decreased in both combination dosage regimens. fovir is transported from the blood into the proximal- When telaprevir was given at 1,125 mg every 8 h in

tubule cells by the human organic anion transporters addition to EFV plus TDF, Cmin, Cmax and AUC8 h of tel- hOAT1 and hOAT3, and subsequently eliminated from aprevir were 25%, 14% and 18% lower, respectively. these cells into urine by the MRP4 efflux pump. Neither When telaprevir was given at 1,500 mg every 12 h

hOCT1, hOCT2, MRP2 nor P-gp are involved in active in addition to EFV plus TDF, Cmin and average con- tubular secretion of tenofovir [36]. centration at steady state of telaprevir were 48% and

These results suggest that TDF and telaprevir can 20% lower, respectively, while Cmax was not changed be coadministered without dose adjustments but with significantly. increased clinical and/or laboratory monitoring for Telaprevir coadministration decreased EFV plasma adverse events related to increased tenofovir exposure. concentrations at steady-state in a similar amount in

both combination-dosing regimens: EFV Cmax was

Efavirenz decreased by 24%, Cmin by 10% and AUC24 h by 18%, EFV is an HIV-1-specific NNRTI indicated to treat respectively, when EFV and TDF were administered in HIV-1 infection. EFV is metabolized by CYP3A4 and the presence of telaprevir 1,125 mg every 8 h, and by is also an inducer of CYP3A4 [37]. Therefore, it has the 20%, 11% and 15%, respectively, in the presence of potential to decrease concentrations of telaprevir. As telaprevir 1,500 mg every 12 h.

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By contrast, telaprevir coadministration increased evaluated by comparing telaprevir 750 mg every 8 h plasma concentrations of tenofovir at steady state with as reference to telaprevir 750 mg every 8 h plus 25 mg both combination-dosing regimens showing a similar once daily RPV as test treatment. Telaprevir exposure

effect: tenofovir Cmin was increased by 17%, Cmax by was not affected by concomitant application of RPV at

22% and AUC24 h by 10% when EFV and TDF were steady state [40]. administered in the presence of telaprevir 1,125 mg No new or clinically significant safety issues were every 8 h, and by 6%, 24% and 10%, respectively, in identified for ETR, RPV or telaprevir in this study. the presence of telaprevir at 1,500 mg every 12 h. RPV has been shown to prolong the QTc interval at Telaprevir alone or in combinations with TDF and supratherapeutic doses (≥75 mg once daily), but not EFV, was generally safe and well tolerated in this study at the recommended therapeutic dose of 25 mg once in healthy subjects [24]. These results suggested that daily [42], and the observed increased exposure to during coadministration of telaprevir, EFV and TDF, the RPV during combination with telaprevir is not consid- dosage of telaprevir should be increased from 750 mg ered to be clinically relevant. The results of this study every 8 h to 1,125 mg every 8 h. EFV and TDF can be suggest that RPV and telaprevir can be administered administered without dose adjustment. The combina- together without dose adjustment [40]. tion of EFV and TDF with the 1,125 every 8 h dose of telaprevir is being tested in ongoing studies in patients HIV integrase inhibitor: raltegravir with HIV–HCV coinfection. The HIV integrase inhibitor raltegravir (RAL) is glucuronidated via UGT1A1 and is a substrate of P-gp and Etravirine therefore had the potential to interact with telaprevir. ETR is a substrate and weak inducer of CYP3A, a sub- This was investigated in a study in healthy subjects strate and weak inhibitor of CYP2C9 and CYP2C19, receiving telaprevir 750 mg every 8 h alone for 6 days and a weak inhibitor of P-glycoprotein [39]. Therefore, and RAL 400 mg twice daily alone for 4 days followed a study was designed to determine the pharmocokinetic by coadministration of telaprevir 750 mg every 8 h and effects of ETR and telaprevir on each other at steady- RAL 400 mg twice daily [43]. state under fed conditions [40]. This study had separate Coadministration of RAL did not influence the expo- study panels addressing the DDIs with ETR or RPV sure to telaprevir. Coadministration of telaprevir did (see below) and telaprevir in a crossover design. moderately increase the exposure to RAL. The RAL

Subjects received ETR 200 mg twice daily as refer- Cmin, Cmax and AUC8 h increased by 78%, 26% and 31%, ence and ETR 200 mg twice daily plus telaprevir 750 respectively. Exposure to glucuronidated RAL was sim- mg every 8 h as test treatment to evaluate ETR expo- ilarly increased with a least square mean ratio (90% CI) sure. Exposure to ETR was not affected by concomitant for the AUC of RAL versus glucuronidated RAL of 1.05 application of telaprevir at steady-state. Exposure to (0.95, 1.15). The increase in exposure to RAL was pos- telaprevir was evaluated by comparing telaprevir 750 sibly due to inhibition of intestinal P-gp by telaprevir as mg every 8 h as reference to telaprevir 750 mg every 8 no influence on UGT1A1 glucuronidation activity was h plus 200 mg ETR twice daily given as test treatment. found based on the parent/metabolite ratio. Telaprevir concentrations decreased with concomitant The effect of telaprevir on RAL was not considered

application of ETR by 25% for Cmin, 10% for Cmax and clinically relevant and both drugs can be administered

16% for AUC8 h, respectively, at steady state. without dose adjustment [43]. No new or clinically significant safety issues were identified for ETR and telaprevir coadministration in Conclusions this study. Results suggest that ETR and telaprevir can be administered together without dose adjustment [40]. Pharmacokinetics and safety of coadministration of telaprevir and respective anti-HIV treatment were investi- Rilpivirine gated in healthy subjects. Mutual DDIs were observed. RPV is a substrate of CYP3A (major pathway) [41]. As Coadministration of telaprevir and the RTV- telaprevir is a substrate and strong inhibitor of CYP3A, boosted protease inhibitors ATV, DRV, fAPV or LPV it was hypothesized that a DDI could occur between reduced the exposure to telaprevir after repeated RPV and telaprevir. The study subjects received RPV 25 doses to some degree, with the least effect on tel- mg once daily as reference and RPV 25 mg once daily aprevir observed during combination with ATV/RTV. plus telaprevir 750 mg every 8 h as test treatment to Telaprevir did not significantly influence exposure evaluate RPV exposure. RPV concentrations increased to ATV or LPV but decreased the exposure to DRV with concomitant application of telaprevir, that is, by and APV. Given these data, the combination of tel-

93% for Cmin, 49% for Cmax and 78% for AUC24 h, aprevir-based treatment and ATV/RTV therapy was respectively, at steady-state. Exposure to telaprevir was investigated in a pilot study in HIV–HCV-coinfected

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patients [44]. Interim data from this study suggest journal reviewer comments, and Janssen for providing that telaprevir and ATV/RTV can be coadministered funding for the medical writing support. without dose modification [44], but larger confirma- This study was supported by Janssen Infectious Dis- tory studies in this population are necessary. Appro- eases BVBA and Vertex Pharmaceuticals Incorporated. priate doses for combination treatment with the other studied RTV-boosted HIV protease inhibitors have Disclosure statement not yet been established. Further studies to investigate the mechanism of these interactions are ongoing. RPGvH and MB are employees of Janssen Infectious Exposure to telaprevir was not affected during Diseases BVBA. VG and RSK are employees of Vertex coadministration with the reverse transcriptase inhibi- Pharmaceuticals Incorporated. tor TDF, and exposure to tenofovir was only modestly increased similar to the effect seen with HIV pro- References tease inhibitors. No dose adjustment is necessary, but 1. De Francesco R, Migliaccio G. Challenges and successes increased monitoring is warranted. Coadministration in developing new therapies for hepatitis C. Nature 2005; of EFV resulted in reduced exposure to telaprevir, but 436:953–960. higher telaprevir doses (1,125 mg every 8 h) were able 2. Brown RS, Jr., Gaglio PJ. Scope of worldwide hepatitis C problem. Liver Transpl 2003; 9:S10–S13. to largely offset the interaction with EFV. Therefore, 3. Wasley A, Alter MJ. Epidemiology of hepatitis C: the combination of telaprevir (1,125 mg every 8 h) geographic differences and temporal trends. 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Risk of developing specific AIDS defining illnesses in patients The effect of telaprevir on RAL was not considered co-infected with HIV and hepatitis C virus with or without clinically relevant and both drugs can be administered liver cirrhosis. Clin Infect Dis 2009; 49:612–622. without dose adjustment. Administration of telaprevir 8. Kovacz A, Karim R, Mack WJ, et al. Activation of CD8 T cells predicts progression of HIV infection in women and coadministration of telaprevir with antiretroviral coinfected with hepatitis C virus. J Infect Dis 2010; medications was generally well tolerated in healthy 201:823–834. subjects. 9. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents In conclusion, a number of DDI studies of telaprevir in HIV-1-infected adults and adolescents. 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Accessed 21 May investigating the involvement of drug transporters and 2012.) Available from http://www.ema.europa.eu/ protein-binding displacement as possible mechanisms. ema/pages/includes/document/open_document. jsp?webContentId=WC500115529 Further clinical evaluation is warranted to establish 13. Incivek™ (telaprevir). FDA prescribing information. the safety and efficacy of telaprevir-based therapy in (Updated April 2013. Accessed 1 November 2012.) this population. Available from http://pi.vrtx.com/files/uspi_telaprevir.pdf 14. Lin C, Kwong AD, Perni RB. Discovery and development of VX-950, a novel, covalent, and reversible inhibitor of Acknowledgements hepatitis C virus NS3.4A serine protease. Infect Disord Drug Targets 2006; 6:3–16. The authors wish to thank Thomas Wagner from 15. Garg V, Kauffman RS, Beaumont M, van Heeswijk RPG. Telaprevir: pharmacokinetics and drug interactions. Antivir Trilogy Writing & Consulting for editorial support, Ther; 2012; 17:1211–1221. 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Accepted 5 December 2012; published online 23 January 2013

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