Original Article Pharmacokinetics of Elvitegravir and Etravirine Following Coadministration of Ritonavir-Boosted Elvitegravir and Etravirine

Antiviral Therapy 13:1011–1017

Original article Pharmacokinetics of elvitegravir and etravirine following coadministration of ritonavir-boosted elvitegravir and etravirine

Srinivasan Ramanathan1*, Thomas N Kakuda2, Rebecca Mack2, Steve West1 and Brian P Kearney1

1Gilead Sciences, Inc., Foster City, CA, USA 2Tibotec Inc., Yardley, PA, USA

*Corresponding author: E-mail: [email protected]

Background: This crossover, open-label clinical study ritonavir pharmacokinetics (maximum concentration

evaluated the potential for clinically relevant drug [Cmax], concentration at the end of the dosing interval

interactions between ritonavir-boosted elvitegravir [Ctau] and area under the plasma concentration–time

(elvitegravir/r), an HIV integrase inhibitor, and etravirine, curve [AUCtau; 0–24 h] and 80–125% for etravirine

a non-nucleoside reverse transcriptase inhibitor. pharmacokinetics (AUCtau 0–12 h). Methods: Healthy volunteers were randomized into one Results: Of the 34 enrolled participants, 31 completed of two groups, each with two arms. Group 1 (n=20) the study. There were three discontinuations, but none followed a sequence of 10‑day dosing of elvitegravir/r were caused by adverse events (AEs). The most com- (150/100 mg once daily) and elvitegravir/r plus etra- mon treatment-emergent AE was headache. Elvitegra- virine (200 mg twice daily) or the reverse (n=10 per vir pharmacokinetic GMR was 6–7% higher following sequence). Group 2 (n=14) followed a sequence of 10‑day elvitegravir/r plus etravirine dosing versus elvitegravir/r.

dosing of etravirine and etravirine plus elvitegravir/r or The GMR for etravirine and ritonavir AUCtau were 2.4% the reverse (n=7 per sequence), all under fed condi- and 12.3% lower, respectively. Importantly, the 90% CI tions. Elvitegravir, ritonavir and etravirine pharmaco- for elvitegravir and etravirine pharmacokinetics and

kinetics were determined on days 10 and 20 using AUCtau and Cmax for ritonavir were within the lack of non-compartmental analyses. Lack of pharmacokinetic alteration bounds. alteration bounds for 90% confidence intervals (CI) Conclusions: Elvitegravir/r and etravirine do not undergo about the geometric mean ratio (GMR; coadministra- clinically relevant drug interactions and can be coadmin- tion versus alone) were 70–143% for elvitegravir and istered without dose adjustment.

Introduction

Integrase inhibitors are a novel class of antiretroviral monotherapy study and a 48‑week Phase II study, is agents for the treatment of HIV-infected patients, espe- approximately 10-fold above its in vitro protein binding

cially those harbouring multiclass-resistant virus [1,2]. adjusted 95% inhibition concentration (IC95) follow- Elvitegravir is a once-daily potent strand transfer inhibi- ing 150/100 mg elvitegravir/r administration [4–6]. In tor undergoing evaluation in Phase III clinical trials. the Phase II study of treatment-experienced HIV type-1 Elvitegravir is metabolized by the cytochrome P450 (HIV-1) patients, elvitegravir/r demonstrated a potent enzyme, CYP3A4, and also by glucuronidation via uri- and durable reduction in HIV-1 viral load when coad- dine glucuronosyl transferase (UGT) 1A1/3 [3]. Once- ministered with other active antiretroviral agents, and daily administration of elvitegravir boosted with rito- was well tolerated [7,8]. navir 100 mg (elvitegravir/r) causes a 20‑fold increase Etravirine (TMC125), a non-nucleoside reverse in elvitegravir plasma exposure over the dosing inter- transcriptase inhibitor (NNRTI) that was recently val via inhibition of CYP3A4-mediated metabolism. In approved by the US Food and Drug Administration (18 addition, mean elvitegravir trough concentration, which January 2008), is active against NNRTI-resistant virus was the best determinant of antiviral activity in a 10‑day in addition to wild-type virus [9,10]. In randomized,

Ramanathan.indd 1011 4/12/08 16:52:59 S Ramanathan et al.

Figure 1. Study design

Group 1

Days 1–10 Days 11–20

EVG/r 150/100 mg n=10 EVG/r 150/100 mg once daily once daily + ETR 200 mg twice daily Baseline 7-Day (day 0) follow-up EVG/r 150/100 mg once daily EVG/r 150/100 mg + once daily n=10 ETR 200 mg twice daily

Group 2

Days 1–10 Days 11–20

EVG/r 150/100 mg n=7 ETR 200 mg once daily twice daily + ETR 200 mg twice daily Baseline 7-Day (day 0) follow-up EVG/r 150/100 mg once daily ETR 200 mg twice daily + n=7 ETR 200 mg twice daily

Pharmacokinetic sampling was performed following study drug dosing on days 10 and 20. ETR, etravirine; EVG/r, ritonavir-boosted elvitegravir.

double-blind, placebo-controlled Phase III studies (150/100 mg once daily) and etravirine (200 mg twice (DUET-1 and DUET-2), significantly more treatment- daily) alone and in combination. experienced adult HIV-1 patients with documented resistance to NNRTIs had an undetectable viral load (<50 copies/ml) with etravirine plus a background Methods regimen compared with placebo and a background regimen [11,12]. Etravirine is metabolized primarily Participants and study design by CYP3A4 and the CYP2C subfamily (2C8, 2C9 and This was a Phase I, single-centre, open-label, crossover 2C19). Etravirine has been shown to induce CYP3A4 study in healthy male and female (non-pregnant and and its clinical coadministration has resulted in lower non-lactating) volunteers (aged 18–45 years, inclu- plasma exposures of CYP3A4 substrates (for example, sive) performed at Seaview Research, Inc. (Miami, atorvastatin, clarithromycin, maraviroc and sildenafil). FL, USA). Eligible participants were administered the Etravirine also mildly inhibits CYP2C9, CYP2C19 and assigned study treatments as shown in Figure 1. The the transporter, P‑glycoprotein (Pgp) [13]. study protocol and informed consent document were Given the antiviral activity of etravirine and reviewed and approved by the Independent Institu- elvitegravir/r against multiclass-resistant HIV-1 virus, tional Review Board Inc. (Plantation, FL, USA) and their coadministration is desirable as there remains an participants provided written informed consent before unmet medical need for combinations of newer agents; study participation. The major eligibility criteria were however, their overlapping metabolic pathways first good health (based on medical history, physical exams necessitate evaluation of clinically relevant drug interac- and laboratory evaluations), non-smoking, normal tions. The pharmacokinetics and safety of elvitegravir, 12‑lead electrocardiogram, haemoglobin ≥12.0 g/dl, ritonavir and etravirine were determined in this study creatinine clearance ≥80 ml/min, no evidence of HIV, following multiple dose administration of elvitegravir/r hepatitis B virus or hepatitis C virus infection and

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use of at least two forms of contraception, including elsewhere [14,15]. In brief, assay conditions for rito- an effective barrier method. Exclusion criteria were navir samples involved processing using solid-phase plasma and blood donation within 7 and 56 days of extraction and MS/MS detection using electrospray ion- study entry, respectively, history of significant sensitiv- ization. The assay calibration curve was linear between ity or allergy to drugs, history of alcohol abuse and 5–5,000 ng/ml. Accuracy, expressed as percentage bias, use of prescription drugs within 30 days of study drug ranged from -8 to 13.9% (intraassay) and -2.0 to 9.4% dosing (with the exception of vitamins, acetamino- (interassay). Corresponding estimates for precision were phen, ibuprofen and/or hormonal contraceptive). 3.3–11.3% and 8.0–11.6%, respectively. The precursor In two groups, participants were randomized to the to product ion transition was 721 m/z→268 m/z. sequence of receiving elvitegravir/r 150/100 mg once daily and elvitegravir/r 150/100 mg once daily plus etra- Pharmacokinetic analyses virine 200 mg twice daily (Group 1, n=10 per sequence) Pharmacokinetic parameters of elvitegravir, ritonavir or etravirine 200 mg twice daily and elvitegravir/r and etravirine were estimated by application of a non- 150/100 mg once daily plus etravirine 200 mg twice linear curve-fitting software package (WinNonlin® daily (Group 2, n=7 per sequence). Each study treat- software, Professional Edition, Version 5.0.1; Phar- ment was administered for 10 days. On days 10 and sight Corporation, Mountain View, CA, USA) using 20, following elvitegravir/r dosing and/or the morning non-compartmental methods. Parameters included

dose of etravirine, the pharmacokinetics of elvitegravir maximum observed plasma concentration (Cmax), time

and ritonavir were evaluated in Group 1 and that of to reach maximum concentration (Tmax), area under etravirine evaluated in Group 2. The sampling scheme the plasma concentration–time curve over the dosing

for Group 1 was pre-dose (0) and 1, 2, 3, 3.5, 4, 4.5, interval (AUCtau; calculated using the linear up‑log 5, 6, 8, 10, 12, 18 and 24 h after dosing. The sampling down trapezoidal method; 0–24 h for elvitegravir and scheme for Group 2 was pre-dose (0) and 0.5, 1, 1.5, 2, ritonavir and 0–12 h for etravirine), elimination half-

3, 4, 5, 6, 8, 10 and 12 h after dosing. Morning doses life (T1/2) and concentration at the end of the dosing

of study drugs were administered under the supervision interval (Ctau). of clinic staff. Because elvitegravir and etravirine exposures are higher when taken with food, participants Statistical analyses received study drugs immediately after a standardized A parametric (normal theory) analysis of variance morning meal (approximately 400 kcal) with 240 ml (ANOVA), using a mixed effects model appropriate (8 fluid ounces) of water. On the days of pharmaco- for a crossover design, was fit to the natural loga-

kinetic sampling, participants fasted until collection of rithmic transformations of AUCtau, Cmax and Ctau of the 4 h post-dose blood draw was completed. Partici- elvitegravir, etravirine and ritonavir. Sample size of

pants were allowed to consume water as desired, with the study was based on variability estimates of Cmax,

the exception of 1 h before and 2 h after study drug dos- AUCtau and Ctau for elvitegravir (Group 1) and AUCtau ing. Elvitegravir was supplied as 150 mg tablets, rito- for etravirine (Group 2), and accounted for poten- navir as 100 mg soft gelatin capsules (Norvir®; Abbott tial dropouts. The final sample size provided at least Laboratories, North Chicago, IL, USA), and etravirine 90% power to conclude a lack of pharmacokinetic as 100 mg tablets, all for oral administration. Blood alteration based on the expected geometric mean ratio samples were collected in a Vacutainer® tube containing (GMR) of treatments (coadministered versus alone)

anticoagulant (spray-dried K2EDTA; Becton Dickinson, of 1.0 and associated 90% confidence interval (CI) of Franklin Lakes, NJ, USA) and inverted several times to 70–143% for elvitegravir and 80–125% for etravirine. mix the blood and the anticoagulant. Samples were kept The 90% CI boundaries for lack of pharmacokinetic on wet ice or refrigerated for ≤30 min and centrifuged alteration of 70–143% were chosen based on the effi- for 10 min at a 1,200 relative centrifuge force (g‑force) cacy of elvitegravir/r in a Phase II study [7] that evalu- in a refrigerated centrifuge set at approximately 4°C to ated multiple elvitegravir doses (125, 50 and 20 mg) harvest plasma. and the cumulative safety data at the 125 mg dose and higher doses evaluated in Phase I studies. The bound- Bioanalysis aries for etravirine were the classical bioequivalence Plasma concentrations of analytes were determined criteria of 80–125% based on the understanding of the using validated HPLC/tandem mass spectrometry (MS/ relationship between etravirine exposure and antiviral MS) bioanalytical assays at Gilead Sciences, Inc. (Dur- response. The pharmacokinetics of ritonavir, used at ham, NC, USA; elvitegravir and ritonavir) or Johnson a subtherapeutic dose as a pharmacokinetic booster, & Johnson Pharmaceutical Research and Development was evaluated using exploratory 90% CI boundaries (Mechelen, Belgium; etravirine). Elvitegravir and etra- of 70–143%. Participants with an evaluable pharma- virine assay conditions have been reported in detail cokinetic profile for the coadministered versus alone

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treatment pair were included in the pharmacokinetic Cmax, AUCtau and Ctau were contained within the lack analysis sets. of pharmacokinetic alteration bounds of 70–143%, indicating that elvitegravir pharmacokinetics were Results unaffected by etravirine coadministration.

Demographics Etravirine In total, 34 participants were enrolled in the study The plasma concentration–time profiles of etravirine (Group 1, n=20; Group 2, n=14). The mean age was following multiple dose administration alone and 33 years (range 18–45) and participants were distributed with elvitegravir/r are presented in Figure 2B and etra- equally by sex. Median body mass index at screening was virine pharmacokinetic parameters are presented in 26.0 kg/m2 (range 20.7–30.0). Overall, 32 participants Table 1. Etravirine reached peak plasma concentra-

(94%) were White and 2 participants (6%) were Black. tions 4.0–4.5 h after dosing and displayed similar T1/2 All participants in Group 2 and 17 of 20 in Group 1 com- values (9.5 and 7.9 h without and with elvitegravir/r, pleted the study (three participants withdrew consent and respectively) with overlapping interquartile ranges discontinued the study prematurely). between the treatments. The GMR (%) and 90% CI

for etravirine plasma Cmax, AUCtau and Ctau were within Safety the predefined lack of alteration bounds of 80–125%, The most common treatment-emergent adverse events indicating etravirine pharmacokinetics were unaffected (AEs) were headache and/or nausea. In Group 1, six by elvitegravir/r coadministration. participants (31.6%) and two participants (10.5%), respectively, had AEs during elvitegravir/r plus etra- Ritonavir virine and elvitegravir/r alone. Headache was the only Ritonavir plasma concentration–time profiles follow- event reported in more than one participant during ing multiple dose administration of elvitegravir/r alone either treatment (two participants on elvitegravir/r and in combination with etravirine are presented in plus etravirine and none on elvitegravir/r alone). Figure 2C and pharmacokinetic parameters are pre- In Group 2, five participants (35.7%) and four- par sented in Table 1. Plasma profiles of ritonavir were ticipants (28.6%), respectively, had AEs during treat- similar between the two treatments, with concentra- ment with etravirine plus elvitegravir/r and etravirine tions slightly lower in the combination arm. Ritonavir

alone. Headache and nausea were the only events that Tmax (4.5 h in both groups) and T1/2 (4.6 and 4.3 h with occurred in more than one participant during either elvitegravir/r and with elvitegravir/r and etravirine, treatment (headache occurred in two participants dur- respectively) were similar between the two study treat-

ing each treatment and nausea occurred in two partici- ments. The GMR (%) and 90% CI for ritonavir Cmax

pants receiving etravirine and one participant receiv- and AUCtau were within the exploratory lack of altera-

ing elvitegravir/r plus etravirine. All AEs were grade tion boundaries of 70–143%, whereas Ctau was lower 1 (mild) in severity, with the exception of one grade 2 in the combination treatment. event of dysmenorrhoea that was considered unrelated to study treatment. No deaths, serious AEs, grade 3 Discussion or 4 AEs or discontinuations because of AEs occurred. No clinically relevant treatment-related changes from The potent antiviral activity independently demonstrated pre-dose were observed for any clinical laboratory or for elvitegravir and etravirine, each in combination with vital sign parameters. other antiretrovirals, in treatment-experienced HIV-infected patients coupled with the present data offers the Pharmacokinetics potential to coadminister these two new antiretrovirals Elvitegravir in patients with limited treatment options. This study The plasma concentration–time profiles of elvitegravir showed that coadministration of elvitegravir/r and etra- after administration of multiple elvitegravir/r doses virine does not alter the pharmacokinetics of elvitegra- alone and in combination with etravirine are presented vir or etravirine based on predefined criteria. Following in Figure 2A. Corresponding elvitegravir pharmaco- administration of study treatments, AEs were primarily kinetic parameters are presented in Table 1. Peak elvite- grade 1, with no grade 3 or 4 AEs, serious AEs or dis- gravir concentrations were observed 4.0–4.5 h fol- continuations because of AEs, indicating that the study

lowing dosing and elvitegravir T1/2 was similar across treatments were well tolerated. treatments (8.0 and 8.2 h without and with etravirine, Review of etravirine drug interaction data with respectively). Consistent with the overlapping elvite- HIV protease inhibitors provides a context for the gravir concentration–time profiles between treatments, present interaction data with elvitegravir/r [13]. Etra-

the GMR (%) and 90% CI for elvitegravir plasma virine AUCtau values decreased 76% and 37% with

Ramanathan.indd 1014 4/12/08 16:52:59 Pharmacokinetics of elvitegravir and etravirine

Figure 2. Plasma concentration–time profiles for elvitegravir, etravirine and ritonavir

A B Elvitegravir/r Etravirine Elvitegravir/r + etravirine Etravirine + elvitegravir/r 5,000 5,000

1,000

1,000 Etravirine concentration, ng/ml Elvitegravir concentration, ng/ml 100 100 0 6 12 18 24 0 3 6 9 12 Time, h Time, h C Elvitegravir/r Elvitegravir/r + etravirine 5,000

1,000

100

Ritonavir concentration, ng/ml 10 0 6 12 18 24 Time, h

(A) Elvitegravir plasma concentration–time profiles (mean ±s d ; Group 1, n=17) after administration of ritonavir-boosted elvitegravir (elvitegravir/r; 150/100 mg once daily) with or without etravirine (200 mg twice daily). (B) Etravirine plasma concentration–time profiles (mean ±s d ; Group 2, n=14) after administration of etravirine (200 mg twice daily) with or without elvitegravir/r (150/100 mg once daily). (C) Ritonavir plasma concentration–time profiles (mean ±s d ; Group 1, n=17) after administration of elvitegravir/r (150/100 mg once daily) with or without etravirine (200 mg twice daily).

tipranavir/r and darunavir/r, respectively, and increased coadministration of a low boosting dose (for example, approximately 50% with atazanavir [13]. Changes in 100 mg once daily) of ritonavir fully countered the amprenavir exposures (69% increase with fosampre- potential inductive effect of etravirine. These results navir dosing) and atazanavir (38% decrease in mini- underscore the need for clinical evaluation of three‑way mum plasma concentration) have been observed upon interactions. Results of this study also reinforce the coadministration with etravirine [16]. In comparison, lack of a significant role of Pgp or the CYP2C subfam- etravirine and elvitegravir pharmacokinetics were not ily (inhibited by etravirine) in elvitegravir disposition, altered upon etravirine plus elvitegravir/r coadministra- in agreement with a lack of pharmacokinetic changes tion. Data for etravirine with HIV protease inhibitors in elvitegravir upon coadministration with tipranavir/r, illustrate that the involvement of multiple enzymes or a net Pgp inducer at steady-state, or omeprazole, the transporters, as well as their mixed inhibitory or induc- proton pump inhibitor and prototypical CYP2C19 tive effects, often confounds mechanistic delineation in substrate and inhibitor [17,18]. Elvitegravir/r has pre- three‑way drug–drug interactions. Despite some over- viously been shown to lack clinically relevant drug lap in their metabolic routes, etravirine and elvitegravir interactions with nucleos(t)ide reverse transcriptase pharmacokinetics are unaffected upon coadministra- inhibitors and several ritonavir-boosted protease tion. Although etravirine is a weak inducer of CYP3A, inhibitors [15,17,19–21]. Accordingly, the observed

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Table 1. Pharmacokinetic parameters of elvitegravir, etravirine and ritonavir following multiple dose administration of ritonavir- boosted elvitegravir or etravirine alone and in combination

Elvitegravir Etravirine Ritonavir EVG/r GMR, % EVG/r GMR, % EVG/r GMR, % Parameter EVG/r + ETR (90% CI) ETR + ETR (90% CI) EVG/r + ETR (90% CI)

Mean Cmax, ng/ml 1,700 1,830 107 852 865 102 970 956 97.6 (CV, %) (28.2) (28.4) (101–113) (44.1) (42.0) (85.8–120) (57.1) (61.9) (86.2–110)

Mean AUCtau*, ng•h/ml 17,600 18,500 106 6,960 7,050 97.6 6,350 5,550 87.7 (CV, %) (27.3) (19.5) (99.9–113) (31.4) (42.7) (88.3–108) (46.9) (44.9) (80.8–95.1)

Mean Ctau, ng/ml 311 311 106 433 418 89.6 55.3 36.9 70.6 (CV, %)† (53.4) (36.8) (97.0–116) (31.2) (51.7) (82.7–97.1) (65.7) (58.8) (63.7–78.2)

Median Tmax, h 4.0 4.5 NA 4.5 4.0 NA 4.5 4.5 NA (IQR) (4.0–4.5) (4.0–4.5) (4.0–5.0) (3.0–5.0) (4.0–5.0) (4.0–5.0)

Median T1/2, h 8.0 8.2 NA 9.5 7.9 NA 4.6 4.3 NA (IQR) (6.6–8.8) (6.8–9.2) (8.2–11.2) (6.2–10.3) (4.3–5.1) (4.1–4.5)

Ritonavir-boosted elvitegravir (EVG/r) n=17, etravirine (ETR) n=14. Data were rounded to be presented as three significant figures. *0–24 h for EVG and ritonavir; † 0–12 h for ETR. 24 h after dosing for EVG and ritonavir; 12 h after dosing for ETR. AUCtau, area under the plasma concentration–time curve over the dosing interval;

CI, confidence interval; tauC , concentration at the end of the dosing interval; CV, coefficient of variation; GMR, geometric mean ratio; IQR, interquartile range; NA, not

applicable; Tmax, time to maximum concentration; T1/2, elimination half-life.

lack of alteration in elvitegravir pharmacokinetics in Acknowledgements this study is consistent with its established metabolic and transport properties. Some of the data from this study were presented at the The processes affecting etravirine pharmacokinetics 47th Interscience Conference on Antimicrobial Agents upon elvitegravir/r coadministration are multifacto- and Chemotherapy, 17–20 September 2007, Chicago, IL, rial. Data from etravirine protease inhibitor studies USA. Financial support for the clinical study discussed in ( atazanavir and ritonavir-boosted atazanavir) suggest this manuscript was provided by Gilead Sciences, Inc. that elvitegravir/r, a net inhibitor of CYP3A4, might increase etravirine systemic concentrations [22]. How- Disclosure statement ever, low-dose ritonavir (100 mg twice daily) has been shown to induce CYP2C9 and 2C19, which contrib- SR, SW and BPK are employees of Gilead Sciences, Inc. ute towards etravirine metabolism [23]. Similarly, (Foster City, CA, USA). TNK and RM are employees of

etravirine exposures (AUCtau) are 50% higher with the Tibotec, Inc. (Yardley, PA, USA). CYP3A inhibitor atazanavir 400 mg, but only 30% higher with ritonavir-boosted atazanavir 300/100 mg References despite greater than twofold higher atazanavir expo- 1. Evering TH, Markowitz M. Raltegravir: an integrase inhibitor sures with the latter treatment. Furthermore, etravirine for HIV-1. Expert Opin Investig Drugs 2008; 17:413–422. undergoes glucuronidation, a pathway known to be 2. Reeves JD, Piefer AJ. Emerging drug targets for induced by ritonavir [24–26]. Anecdotal evidence also antiretroviral therapy. Drugs 2005; 65:1747–1766. suggests induction of glucuronidation by low-dose rito- 3. Ramanathan S, Wright M, West S, et al. Pharmacokinetics, metabolism, and excretion of ritonavir-boosted GS‑9137 navir (100 mg) [27], although the magnitude of this (Elvitegravir). 8th International Workshop on Clinical effect is unknown because of a paucity of direct clini- Pharmacology of HIV Therapy. 16–18 April 2007, cal interaction data between glucuronidation substrates Budapest, Hungary. Abstract 30. and low-dose ritonavir. Thus, ritonavir might display 4. Mathias A, West S, Hui J, et al. Effect of increasing ritonavir doses on hepatic CYP3A activity and GS‑9137 dose-dependent mixed inhibitory or inductive effects (elvitegravir) oral exposure. 8th International Workshop on towards the multiple CYP (CYP3A and CYP2C) and Clinical Pharmacology of HIV Therapy. 16–18 April 2007, Budapest, Hungary. Abstract 53. glucuronidation enzymes involved in etravirine metab- 5. Ramanathan S, West S, Hui J, et al. Clinical olism. The lack of observed pharmacokinetic alteration pharmacokinetics of once-daily elvitegravir boosted by when etravirine is coadministered with elvitegravir/r is ritonavir versus atazanavir. 9th International Workshop on Clinical Pharmacology of HIV Therapy. 7–9 April 2008, probably a net result of this complex interplay. New Orleans, LA, USA. Abstract O18. In conclusion, elvitegravir/r and etravirine do not 6. DeJesus E, Berger D, Markowitz M, et al. Antiviral activity, undergo clinically relevant drug–drug interactions. pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS‑9137 (JTK-303) in treatment-naive and Therefore, these agents could be coadministered with- treatment-experienced patients. J Acquir Immune Defic out dose adjustment in HIV-infected patients. Syndr 2006; 43:1–5.

Ramanathan.indd 1016 4/12/08 16:53:00 Pharmacokinetics of elvitegravir and etravirine

7. Zolopa A, Lampiris H, Blick G, et al. The HIV integrase 18. Ramanathan S, Shen G, Hinkle J, et al. Pharmacokinetic inhibitor elvitegravir (EVG/r) has potent and durable evaluation of drug interactions with ritonavir-boosted antiretroviral activity in treatment-experienced patients HIV integrase inhibitor GS‑9137 (elvitegravir) and acid with active optimized background therapy (OBT). 47th reducing agents. 8th International Workshop on Clinical Interscience Conference on Antimicrobial Agents and Pharmacology of HIV Therapy. 16–18 April 2007, Chemotherapy. 17–20 September 2007, Chicago, IL, USA. Budapest, Hungary. Abstract 69. Presentation H‑714. 8. Zolopa A, Mullen M, Berger D, et al. The HIV integrase 19. Ramanathan S, Shen G, Hinkle J, et al. Pharmacokinetics inhibitor GS‑9137 demonstrates potent antiretroviral of co‑administered ritonavir-boosted elvitegravir and activity in treatment-experienced patients. 14th Conference zidovudine, didanosine, stavudine, and abacavir. J Acquir on Retrovirus and Opportunistic Infections. 25–28 Immune Defic Syndr 2007; 46:160–166. February 2007, Los Angeles, CA, USA. Abstract 143 LB. 20. Mathias AA, Shen G, Enejosa J, et al. Lack of 9. Andries K, Azijn H, Thielemans T, et al. TMC125, a pharmacokinetic interaction between ritonavir-boosted novel next-generation nonnucleoside reverse transcriptase GS‑9137 (elvitegravir) and darunavir/r. 4th International inhibitor active against nonnucleoside reverse transcriptase AIDS Society Conference on Pathogenesis, Treatment, and inhibitor-resistant human immunodeficiency virus type 1. Prevention. 22–25 July 2007, Sydney, Australia. Abstract Antimicrob Agents Chemother 2004; 48:4680–4686. TUBDB03. 10. Vingerhoets J, Azijn H, Fransen E, et al. TMC125 displays 21. Ramanathan S, Mathias AA, Shen G, et al. Lack of a high genetic barrier to the development of resistance: clinically relevant drug–drug interaction between ritonavir- evidence from in vitro selection experiments. J Virol 2005; boosted GS‑9137 (elvitegravir) and fosamprenavir/r. 4th 79:12773–12782. International AIDS Society Conference on Pathogenesis, 11. Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and Treatment, and Prevention. 22–25 July 2007, Sydney, safety of TMC125 (etravirine) in treatment-experienced Australia. Abstract WEBEP014. HIV-1-infected patients in DUET-1: 24‑week results from a randomized, double-blind, placebo-controlled trial. Lancet 22. Schöller-Gyüre M, Woodfall B, De Marez T, et al. 2007; 370:29–38. Pharmacokinetics of TMC125, with atazanavir (ATV) and atazanavir/ritonavir (ATV/r). 8th International Congress 12. Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV- on Drug Therapy in HIV Infection. 12–16 November, 1-infected patients in DUET-2: 24‑week results from a Glasgow, UK. Abstract 278. randomized, double-blind, placebo-controlled trial. Lancet 23. Liu P, Foster G, Gandelman K, et al. Steady-state 2007; 370:39–48. pharmacokinetic and safety profiles of voriconazole and 13. Kakuda TN, Scholler-Gyure M, Woodfall BJ, et al. ritonavir in healthy male subjects. Antimicrob Agents TMC125 in combination with other medications: summary Chemother 2007; 51:3617–3626. of drug-drug interactions. 8th International Congress on Drug Therapy in HIV Infection. 12–16 November 2006, 24. Smith CM, Faucette SR, Wang H, et al. Modulation of Glasgow, UK. Abstract PL5.2. UDP-glucuronosyltransferase 1A1 in primary human hepatocytes by prototypical inducers. J Biochem Mol 14. Schöller-Gyüre M, Kakuda TN, Sekar V, et al. Toxicol 2005; 19:96–108. Pharmacokinetics of darunavir/ritonavir and TMC125 alone and coadministered in HIV-negative volunteers. 25. Norvir® (ritonavir). Prescribing information, United States Antivir Ther 2007; 12:789–796. 2007. Abbott Laboratories, North Chicago, IL, USA. 15. Ramanathan S, Shen G, Cheng A, Kearney, BP. 26. Cato A, III, Qian J, Hsu A, et al. Multidose Pharmacokinetics of emtricitabine, tenofovir, and GS‑9137 pharmacokinetics of ritonavir and zidovudine in human following coadministration of emtricitabine/tenofovir immunodeficiency virus-infected patients. Antimicrob disoproxil fumarate and ritonavir-boosted GS‑9137. Agents Chemother 1998; 42:1788–1793. J Acquir Immune Defic Syndr 2007; 45:274–279. 27. Burger DM, Huisman A, Van Ewijk N, et al. The effect 16. Intelence™ (etravirine). US Prescribing Information 2008. of atazanavir and atazanavir/ritonavir on UGT1A4 using Tibotec Therapeutics, Raritan, NJ, USA. lamotrigine as a phenotypic substrate. 14th Conference on 17. Mathias AA, Hinkle J, Enejosa J, et al. Lack of Retrovirus and Opportunistic Infections. 25–28 February pharmacokinetic interaction between ritonavir-boosted 2008, Los Angeles, CA, USA. Abstract 566. GS‑9137 (elvitegavir) and tipranavir/r. 4th International AIDS Society Conference on Pathogenesis, Treatment, and Prevention. 22–25 July 2007, Sydney, Australia. Abstract TUBDB06.

Accepted for publication 21 August 2008

Antiviral Therapy 13.8 1017

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