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Pharmacokinetics of Once-Daily Etravirine Without and with Once-Daily Darunavir/Ritonavir in Antiretroviral-Naive HIV Type-1-Infected Adults

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Pharmacokinetics of Once-Daily Etravirine Without and with Once-Daily Darunavir/Ritonavir in Antiretroviral-Naive HIV Type-1-Infected Adults Antiviral Therapy 2010 15:711–720 (doi: 10.3851/IMP1562) Original article Pharmacokinetics of once-daily etravirine without and with once-daily darunavir/ritonavir in antiretroviral-naive HIV type-1-infected adults Edwin DeJesus1*, Jacob P Lalezari2, Olayemi O Osiyemi3, Peter J Ruane4, Robert Ryan5, Thomas N Kakuda5, James Witek6 1Orlando Immunology Center, Orlando, FL, USA 2Quest Clinical Research, San Francisco, CA, USA 3Triple O Medical Services, Inc., West Palm Beach, FL, USA 4Lightsource Medical, Los Angeles, CA, USA 5Tibotec, Inc., Titusville, NJ, USA 6Tibotec Therapeutics, Titusville, NJ, USA *Corresponding author e-mail: [email protected] Background: A pharmacokinetic trial was conducted to The plasma concentration–time profile and pharmacoki- evaluate the potential for once-daily etravirine in anti- netics for etravirine were unchanged with or without daru- retroviral regimens without and with darunavir/ritonavir. navir/ritonavir. The mean maximum plasma concentration Methods: During this multicentre, open-label, Phase IIa (Cmax) was reached 4 h after administration and was 790 trial, treatment-naive patients aged ≥18 years with HIV and 801 ng/ml on day 14 and 28, respectively; mean area type-1 (HIV-1) received etravirine 400 mg once daily with under the plasma concentration–time curve (AUC) from tenofovir disoproxil fumarate/emtricitabine 300/200 mg before administration to 24 h after administration was once daily from days 1–14; on days 15–28, darunavir/ 10,410 ng•h/ml on day 14 and 10,720 ng•h/ml on day 28. ritonavir 800/100 mg once daily was added. On day 29, In a post-hoc analysis, etravirine Cmax was higher, mini- etravirine was discontinued and patients continued with mum plasma concentration was lower and AUC was similar the other medications to day 42. Serial blood sampling when compared with etravirine 200 mg twice daily. for etravirine pharmacokinetics was performed over 24 h Conclusions: Addition of darunavir/ritonavir to etravirine, on day 14 and 28; patients fasted for ≥10 h prior to all dosed once daily, did not have a clinically significant these visits. effect on the pharmacokinetics of etravirine. Findings Results: Of 23 enrolled patients (male 87%, Caucasian support further investigation of etravirine 400 mg once 39%), pharmacokinetic profiles for etravirine were avail- daily in HIV-1-infected patients. (Trial registration number able for 21 and 20 patients on day 14 and 28, respectively. NCT00534352.) Introduction Etravirine (formerly TMC125) is a potent non- Therefore, many available antiretrovirals are also nucleoside reverse transcriptase inhibitor (NNRTI) being investigated for once-daily dosing in an attempt active against wild-type HIV type-1 (HIV-1) and to simplify regimens and increase adherence. Early for- NNRTI- resistant HIV-1 that has been shown in vitro mulations of etravirine required a relatively high pill to have a higher genetic barrier to the development burden to achieve good bioavailability, so etravirine of resistance compared with available first-generation was evaluated twice daily. However, etravirine has a NNRTIs [1]. Etravirine is approved at a dose of 200 long half-life (approximately 41 h) and recent formu- mg twice daily for use in treatment-experienced adult lation improvements have increased the oral bioavail- patients. Regimens with higher numbers of daily drug ability of the drug, thereby reducing pill burden and doses are associated with lower adherence than regi- potentially allowing for once-daily dosing [3,4]. The mens with lower numbers of daily drug doses [2]. current etravirine formulation is recommended to be ©2010 International Medical Press 1359-6535 (print) 2040-2058 (online) 711 AVT-09-OA-1409_DeJesus.indd 711 23/7/10 13:45:52 E DeJesus et al. administered with food in order to optimize bioavail- profiles, insulin and glucose during the treatment period. ability [5]. A study assessing the pharmacokinetics of Following a 4 week screening period, patients received etravirine 400 mg once daily versus 200 mg twice daily etravirine 400 mg once daily with tenofovir disoproxil in healthy volunteers demonstrated similar exposure fumarate/emtricitabine 300/200 mg once daily from between the regimens, as evaluated by area under the days 1–14 (treatment A); on days 15–28, darunavir/ plasma concentration–time curves (a curve over 12 h ritonavir 800/100 mg once daily was added to the regi- after each twice-daily dose administration [AUC12 h ×2] men (treatment B). On day 29, etravirine was discon- versus a curve over 24 h from administration [AUC24 h]), tinued and patients continued on tenofovir disoproxil with a 44% increase in maximum concentration (Cmax) fumarate/emtricitabine and darunavir/ritonavir to day and a 25% decrease in minimum concentration (Cmin) 42 (treatment C). All doses were administered following when etravirine was dosed once daily relative to twice a meal. Patients with adherence of <90% to darunavir, daily [6]. etravirine or ritonavir, using a 4 day recall assessment, Darunavir, an HIV protease inhibitor, combined with on two separate clinic visits during the first 42 days were a low dose of ritonavir has been shown to be an effective discontinued from the study. After completion of the therapeutic option for both treatment-naive (800/100 mg 42-day study period, patients could choose to continue once daily) and treatment-experienced (600/100 mg twice into an open-label extension phase of the trial consisting daily) HIV-1-infected patients [7–9]. The coadministra- of treatment with darunavir/ritonavir 800/100 mg once tion of darunavir/ritonavir 600/100 mg twice daily and daily and tenofovir disoproxil fumarate/emtricitabine etravirine 200 mg twice daily was previously evaluated in 300/200 mg once daily for up to 48 weeks. Here we healthy volunteers and resulted in a 37% decrease in the report only the results through to day 42, with a focus etravirine AUC from before administration to 12 h after on pharmacokinetic analyses [15]. administration [10]. This interaction was not judged to This study was conducted in line with Good Clinical be clinically relevant and subsequently two Phase III, Practice guidelines and the principles of the Declara- double-blind, randomized studies (DUET-1 and DUET-2) tion of Helsinki. The research protocol received ethi- with coadministration of darunavir/ritonavir and etra- cal approval from all study sites and written, informed virine were conducted in treatment-experienced HIV-1- consent was provided by all patients. This trial is regis- infected patients. The combination was shown to have a tered at clinicaltrials.gov (NCT00534352). good safety and efficacy profile when administered with an investigator selected optimized background regimen Study population [11–13]. Moreover, in these trials, no apparent relation- Antiretroviral treatment-naive men and women aged ship between etravirine pharmacokinetics and efficacy or ≥18 years with documented HIV-1 infection and a safety was observed [5,14]. life expectancy ≥6 months were eligible for the study. In order to explore the potential for once-daily use Patients were required to have no antiretroviral resist- of etravirine, we examined the pharmacokinetics and ance based on screening or historical resistance assays. short-term safety and efficacy of etravirine 400 mg once Exceptions were made for patients with isolated muta- daily with tenofovir disoproxil fumarate/emtricitabine, tions that did not affect susceptibility to any of the study and also investigated this dosing regimen in combina- drugs. Susceptibility to etravirine was defined as pres- tion with darunavir/ritonavir 800/100 mg once daily. ence of fewer than three etravirine resistance-associated This trial was conducted in antiretroviral-naive HIV-1- mutations (list of 13; virco® TYPE HIV-1 version 4.1.01, infected adult patients; treatment-experienced patients Virco Lab Inc. USA, Titusville, NJ, USA) [16]. Predicted were excluded to minimize the need for other active fold-change values for etravirine were not available at agents and to avoid any potential induction or inhibi- the time of screening. tory effects of prior antiretroviral use that could con- Key exclusion criteria included previous or current found data interpretation. use of antiretrovirals, including non-antiretrovirals with known anti-HIV activity or those that could potentiate Methods antiretroviral activity (for example, hydroxyurea); use of concomitant medications that might interact with Study design darunavir, emtricitabine, etravirine, ritonavir or teno- The primary objective of this multicentre, open-label, fovir disoproxil fumarate; the presence of any currently single-arm, Phase IIa trial was to determine the phar- active AIDS-defining illness, chronic hepatitis B and/or macokinetic profile of etravirine 400 mg once daily C coinfection or acute viral hepatitis; diabetes mellitus without and with darunavir/ritonavir 800/100 mg once or hyperlipidaemia requiring lipid-lowering therapy; daily. Secondary objectives included assessment of the and any grade 3 or 4 laboratory abnormality, as defined short-term safety and tolerability of this dosing regimen by the Division of AIDS grading tables. Additionally, and evaluation of short-term changes in fasting lipid patients were excluded if they had any condition or 712 ©2010 International Medical Press AVT-09-OA-1409_DeJesus.indd 712 23/7/10 13:45:52 Once-daily etravirine pharmacokinetics without and with darunavir/ritonavir clinically significant active disease that, in the opin-
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