Intracellular and plasma pharmacokinetics of 400 mg of etravirine once daily versus 200 mg of etravirine twice daily in HIV-infected patients

Objectives: To compare intracellular and plasma etravirine concentrations when etravirine was given at 200 mg/12 h versus 400 mg/24 h and to evaluate whether the results would support once-daily dosing. Methods:This was an open-label sequential study in which eight patients on protease inhibitor (PI)-sparing regimens containing etravirine were included. Full pharmacokinetic profiles were performed while on 200 mg of etravirine/12 h and after switching to 400 mg of etravirine/24 h. Intracellular and plasma levels were determined by liquid chromatography coupled with mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental analysis and compared by geometric mean ratios (GMRs) using 200 mg of etravirine/12 h as the reference group. Trial registration: ClinicalTrials.gov NCT01121809. Results:The geometric mean (GM) for etravirine AUC(0TAU) (5602 versus 5076 ngh/mL, GMR 0.91), C-max (403 versus 495 ng/mL, GMR 1.23) and C-min (139 versus 102 ng/mL, GMR 0.74) were similar with both dosing schedules at the intracellular level. In plasma, the GMRs for AUC(0TAU), C-max and C-min were 1.31, 1.76 and 0.99, respectively. The mean intracellular penetration, evaluated as intracellular and plasma AUC(0TAU) ratios, was 81 when etravirine was dosed twice daily and 56 with once-daily dosing. Conclusions:Our results show that intracellular etravirine levels were similar with both dosing regimens in patients with PI-sparing regimens, while etravirine plasma AUC(0TAU) and C-max were 30 and 76 higher with the once-daily regimen, respectively. Thus, a once-daily dosing regimen is supported not only by plasma etravirine pharmacokinetic profiles but also by intracellular levels.