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.