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Pharmacokinetics of etravirine are not affected by sex, age, race, treatment duration or use of enfuvirtide in HIV-1 infected patients
T.N. Kakuda1, M. Schöller-Gyüre2, M. Peeters2, C. Corbett2, G. De Smedt2, B.J. Woodfall2, R.W. Hoetelmans2
1Tibotec Inc., Research & Development, Yardley, United States, 2Tibotec BVBA, Research & Development, Mechelen, Belgium
Background: Etravirine (INTELENCEä) is an FDA-approved next generation NNRTI. In vitro, etravirine has potent activity against both wild-type and NNRTI-resistant HIV. Etravirine was superior to placebo in the proportion of treatment-experienced HIV-1 infected patients achieving viral load <50 copies/mL at week 48 from two ongoing trials (DUET-1 and -2).
Methods: A 2-compartment model with sequential zero-order and first-order absorption including lag-time was developed for population pharmacokinetics analyses; AUC12h and C0h were individually estimated from sparse sampling over 48 weeks using Bayesian feedback. The effect of sex, age, race, weight, adherence, enfuvirtide or tenofovir use, hepatitis B or C co-infection on etravirine AUC12h or C0h was assessed using ANCOVA. The effect of treatment duration was assessed graphically.
Results: Etravirine population pharmacokinetics were estimated in 575 patients. Mean (SD) etravirine AUC12h and C0h was 5506 (4710) ng•h/mL and 393 (391) ng/mL, respectively. Inter- and intra-patient variability was 60% and 40%, respectively. Mean (SD) AUC12h in 57 women was 6027 (3591) ng•h/mL compared to 5449 (4817) ng•h/mL in 518 men (p=0.20). Exposure in Caucasians (n=360), Blacks (n=67), Hispanics (n=56) and Asians (n=7) was not significantly different (p=0.23). Etravirine AUC12h increased with increasing adherence (p=0.0187) or decreasing weight (p=0.0490). Use of enfuvirtide had no effect on AUC12h (p=0.80); tenofovir use was associated with 26% lower AUC12h (p=0.0005). Hepatitis co-infection was associated with a 1.35-fold increase in AUC12h (p=0.0028). There was a trend for higher etravirine exposure with higher age (p=0.0645). Graphically, plasma concentrations over 24 weeks revealed no time-dependent effects.
Conclusions: Etravirine pharmacokinetics do not vary by sex, race, age or use of enfuvirtide. Tenofovir was associated with lower, whereas hepatitis co-infection with higher etravirine exposure. Exposures were slightly higher in patients with lower weight and greater adherence. No dose adjustments for etravirine are necessary for these covariates. Etravirine pharmacokinetics were not time-dependent.
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