Pharmacokinetics and short-term safety and tolerability of etravirine in treatment-experienced HIV-1-infected children and adolescents.

OBJECTIVES: To evaluate the pharmacokinetics, weight-based dose selection and short-term safety and tolerability of etravirine in HIV-1-infected children and adolescents. DESIGN: Phase I, nonrandomized, open-label study in two stages. METHODS: Children and adolescents aged at least 6 years to 17 years or less on a stable lopinavir/ritonavir-based antiretroviral regimen with HIV-1 RNA plasma viral load less than 50 copies/ml were enrolled. In both stages, etravirine (4 mg/kg twice daily in stage I, 5.2 mg/kg twice daily in stage II), added to the existing antiretroviral regimen, was administered for 7 days followed by a morning dose and 12-h pharmacokinetic assessment on day 8. Pharmacokinetic parameters were determined using noncompartmental analysis. Data were compared with those previously established in HIV-1-infected adults on a similar etravirine (200 mg twice daily) combination antiretroviral regimen. RESULTS: Twenty-one patients were recruited to each stage; 19 and 20 had evaluable pharmacokinetics in stages I and II, respectively. Mean (SD) maximum plasma concentrations in stages I and II were 495 (453) and 757 ng/ml (680), respectively; area under the plasma concentration-time curve over 12 h was 4050 (3602) and 6141 ng h/ml (5586), respectively. Statistical/qualitative comparisons showed comparable exposures with adults in stage II; however, the upper 90% confidence interval fell outside the predefined range. Plasma viral load remained undetectable on day 8 in all patients, and etravirine was well tolerated at both doses. CONCLUSION: Etravirine 5.2 mg/kg was well tolerated in this study and this dose was selected for further investigation in clinical trials.

Pharmacokinetic interactions of maraviroc with darunavir-ritonavir, etravirine, and etravirine-darunavir-ritonavir in healthy volunteers: results of two drug interaction trials.

The effects of darunavir-ritonavir at 600 and 100 mg twice daily (b.i.d.) alone, 200 mg of etravirine b.i.d. alone, or 600 and 100 mg of darunavir-ritonavir b.i.d. with 200 mg etravirine b.i.d. at steady state on the steady-state pharmacokinetics of maraviroc, and vice versa, in healthy volunteers were investigated in two phase I, randomized, two-period crossover studies. Safety and tolerability were also assessed. Coadministration of 150 mg maraviroc b.i.d. with darunavir-ritonavir increased the area under the plasma concentration-time curve from 0 to 12 h (AUC12) for maraviroc 4.05-fold relative to 150 mg of maraviroc b.i.d. alone. Coadministration of 300 mg maraviroc b.i.d. with etravirine decreased the maraviroc AUC12 by 53% relative to 300 mg maraviroc b.i.d. alone. Coadministration of 150 mg maraviroc b.i.d. with etravirine-darunavir-ritonavir increased the maraviroc AUC12 3.10-fold relative to 150 mg maraviroc b.i.d. alone. Maraviroc did not significantly affect the pharmacokinetics of etravirine, darunavir, or ritonavir. Short-term coadministration of maraviroc with darunavir-ritonavir, etravirine, or both was generally well tolerated, with no safety issues reported in either trial. Maraviroc can be coadministered with darunavir-ritonavir, etravirine, or etravirine-darunavir-ritonavir. Maraviroc should be dosed at 600 mg b.i.d. with etravirine in the absence of a potent inhibitor of cytochrome P450 3A (CYP3A) (i.e., a boosted protease inhibitor) or at 150 mg b.i.d. when coadministered with darunavir-ritonavir with or without etravirine.

Efficacy and safety of etravirine (TMC125) in treatment-experienced HIV-1-infected patients: 48-week results of a phase IIb trial.

Forty-eight-week results from a randomized, multicentre, part-blinded, phase IIb clinical trial assessing the efficacy and safety of 400 and 800 mg etravirine twice daily (phase IIb formulation) and optimized background regimen versus standard-of-care regimen are presented. Both etravirine doses demonstrated sustained virological suppression at 48 weeks and a favourable tolerability profile. Etravirine demonstrated higher efficacy than control, irrespective of the number of detectable nonnucleoside reverse transcriptase inhibitor-resistance-associated mutations at baseline or active background antiretrovirals.

Effect of ritonavir-boosted tipranavir or darunavir on the steady-state pharmacokinetics of elvitegravir.

OBJECTIVE: Elvitegravir (EVG) is in phase 3 development in combination with ritonavir (RTV)-boosted protease inhibitors in treatment-experienced, HIV-infected patients. Two studies evaluated pharmacokinetic (PK) interactions among EVG and RTV-boosted tipranavir (TPV/r) or darunavir (DRV/r). METHODS: Healthy volunteers received EVG/r alone (study 1: 200/100 mg once daily; study 2: 125/100 mg once daily), TPV/r (500/200 mg twice daily) or DRV/r (600/100 mg twice daily) alone, and EVG (200 or 125 mg as applicable) added to TPV/r (500/200 mg twice daily) or DRV/r (600/100 mg twice daily) in a randomized crossover design, with assessment of steady-state PK for EVG, TPV, DRV, and RTV. Safety was assessed by clinical monitoring. Studies were powered to conclude lack of an interaction if the 90% confidence interval for the geometric mean ratios of the AUCtau and Cmax for EVG, TPV, and DRV were within predefined no-effect boundaries. Trough concentrations were also assessed. RESULTS: No subjects discontinued for adverse events during treatment with EVG/r alone. On coadministration, AUCtau and Cmax of EVG and TPV and EVG and DRV were within prespecified no-effect boundaries versus treatment alone; trough concentrations were also not substantially altered. CONCLUSIONS: The PK of EVG and TPV or DRV were not altered after coadministration of EVG with TPV/r or DRV/r. EVG PK was similar with varied RTV doses of 100 mg once daily, 100 mg twice daily, or 200 mg twice daily. EVG can be added to TPV/r or DRV/r regimens without dose adjustment.

Pharmacokinetics of elvitegravir and etravirine following coadministration of ritonavir-boosted elvitegravir and etravirine.

BACKGROUND: This crossover, open-label clinical study evaluated the potential for clinically relevant drug interactions between ritonavir-boosted elvitegravir (elvitegravir/r), an HIV integrase inhibitor, and etravirine, a non-nucleoside reverse transcriptase inhibitor. METHODS: Healthy volunteers were randomized into one of two groups, each with two arms. Group 1 (n = 20) followed a sequence of 10-day dosing of elvitegravir/r (150/100 mg once daily) and elvitegravir/r plus etravirine (200 mg twice daily) or the reverse (n = 10 per sequence). Group 2 (n = 14) followed a sequence of 10-day dosing of etravirine and etravirine plus elvitegravir/r or the reverse (n = 7 per sequence), all under fed conditions. Elvitegravir, ritonavir and etravirine pharmacokinetics were determined on days 10 and 20 using non-compartmental analyses. Lack of pharmacokinetic alteration bounds for 90% confidence intervals (CI) about the geometric mean ratio (GMR; coadministration versus alone) were 70-143% for elvitegravir and ritonavir pharmacokinetics (maximum concentration [C(max)], concentration at the end of the dosing interval [C(tau)] and area under the plasma concentration-time curve [AUC(tau); 0-24 h] and 80-125% for etravirine pharmacokinetics (AUC(tau) 0-12 h). RESULTS: Of the 34 enrolled participants, 31 completed the study. There were three discontinuations, but none were caused by adverse events (AEs). The most common treatment-emergent AE was headache. Elvitegravir pharmacokinetic GMR was 6-7% higher following elvitegravir/r plus etravirine dosing versus elvitegravir/r. The GMR for etravirine and ritonavir AUC(tau) were 2.4% and 12.3% lower, respectively. Importantly, the 90% CI for elvitegravir and etravirine pharmacokinetics and AUC(tau) and C(max) for ritonavir were within the lack of alteration bounds. CONCLUSIONS: Elvitegravir/r and etravirine do not undergo clinically relevant drug interactions and can be coadministered without dose adjustment.