Pharmacokinetics and Pharmacodynamics of the Non-Nucleoside Reverse-Transcriptase Inhibitor Etravirine in Treatment-Experienced HIV-1-Infected Patients

Abstract

The pharmacokinetics and pharmacodynamics of the antiretroviral agent etravirine were evaluated in two phase III clinical trials. Pharmacokinetic data were available in 577 patients randomized to receive etravirine. The mean (SD) population-pharmacokinetics-derived area under the concentration-time curve at 12 h (AUC(12 h)) and concentration at 0 h (C(0 h)) were 5,501 (4,544) ng·h/ml and 393 (378) ng/ml, respectively. Hepatitis C coinfection raised etravarine exposure, and concomitant use of tenofovir disoproxil fumarate lowered etravirine exposure, but these changes were not considered clinically relevant. Etravirine apparent oral clearance was not affected by age, weight, sex, race, hepatitis B coinfection status, creatinine clearance, or concomitant use of enfuvirtide. Virologic response (<50 copies/ml) at week 24 was 59% in patients randomized to etravirine vs. 41% in those receiving placebo (P < 0.0001). There was no apparent relationship between etravirine pharmacokinetics and either efficacy or safety. Factors other than the pharmacokinetics of etravirine such as the characteristics of the patients and the disease, as well as characteristics of the treatment regimen, predict virologic response.

Pharmacokinetics and Pharmacodynamics of Darunavir and Etravirine in HIV-1–Infected, Treatment-Experienced Patients in the Gender, Race, and Clinical Experience (GRACE) Trial

“…Similar darunavir exposures have been observed in treatment-experienced patients from the performance of TMC114/r when evaluated in treatment- experienced patients with PI resistance (POWER 1, 2, and 3 and TITAN trials [4, 14]). Likewise, previous studies of etravirine pharmacokinetics have yielded median values similar to those seen here [7]. Furthermore, the ranges of darunavir and etravirine exposure observed in this study were numerically similar to those from previous studies [4, 7].…”

“…Likewise, previous studies of etravirine pharmacokinetics have yielded median values similar to those seen here [7]. Furthermore, the ranges of darunavir and etravirine exposure observed in this study were numerically similar to those from previous studies [4, 7]. …”

“…Pharmacokinetics were considered evaluable if the sample had measurable darunavir and ritonavir or etravirine (if applicable) concentrations, and if the time of last intake or administration was known. Previously developed population pharmacokinetic models [7, 9] were applied to the sparse sampling data to derive empirical Bayesian estimates of darunavir and etravirine area under the plasma concentration–time curve (AUC 12h ) and trough concentration (C 0h ).…”

“…The once-daily darunavir in treatment-experienced patients (ODIN) trial, which studied 294 patients receiving once-daily darunavir versus 296 patients receiving twice-daily darunavir, found that women had higher exposures than men, and Asian patients had lower exposure than white patients; however, these differences were not considered clinically significant [6]. Data from the pooled TMC125 to demonstrate undetectable viral load in patients experienced with antiretroviral therapy (DUET)-1 and DUET-2 trials, which compared treatment with etravirine ( n = 599) versus placebo ( n = 604) in treatment-experienced patients, did not demonstrate any sex or racial differences in etravirine pharmacokinetic parameters [7]. These trials, however, were not specifically designed to investigate sex-based or race-based differences in darunavir or etravirine pharmacokinetics.…”

Biotransformation of the Antiretroviral Drug Etravirine: Metabolite Identification, Reaction Phenotyping, and Characterization of Autoinduction of Cytochrome P450-Dependent Metabolism

“…Therefore, ETR has a higher genetic barrier to viral resistance and as such is often prescribed for treatment-experienced patients who have developed mutations that confer resistance to first-generation NNRTIs (Lazzarin et al, 2007;Madruga et al, 2007;Nadler et al, 2007). Because ETR is always taken concurrently with other antiretrovirals that are substrates, inhibitors, and inducers of drug-metabolizing enzymes (Kakuda et al, 2010;Calcagno et al, 2011), gaining a comprehensive understanding of the metabolic pathways involved in the clearance of ETR is important to minimize drug-drug interactions and adverse events. For instance, it has recently been demonstrated in healthy adults that ETR decreases exposure to certain antiretrovirals prescribed for the treatment of HIV including dolutegravir (by 70%) (Song et al, 2011) and maraviroc (by 53%) (Kakuda et al, 2011).…”