Lack of effect of efavirenz on the pharmacokinetics of tipranavir-ritonavir in healthy volunteers

Abstract

Previously it has been shown that tipranavir-ritonavir (TPV/r) does not affect efavirenz (EFV) plasma concentrations. This study investigates the effect of steady-state EFV on steady-state TPV/r pharmacokinetics. This was a single-center, open-label, multiple-dose study of healthy adult female and male volunteers. TPV/r 500/200 mg twice a day (BID) was given with food for 24 days. After dosing with TPV/r for 10 days, EFV 600 mg once a day was added to the regimen. Intensive pharmacokinetic (PK) sampling was done on days 10 and 24. Validated bioanalytical high-pressure liquid chromatography-tandem mass spectrometry methods were used to determine plasma tipranavir (TPV), ritonavir (RTV), and EFV concentrations. Thirty-four subjects were entered into the study, and 16 subjects completed it. The geometric mean ratios (90% confidence intervals) for TPV and RTV area under the curves, C(max)s, and C(min)s comparing TPV/r alone and in combination with EFV were 0.97 (0.87 to 1.09), 0.92 (0.81 to 1.03), and 1.19 (0.93 to 1.54) for TPV and 1.03 (0.78 to 1.38), 0.92 (0.65 to 1.30), and 1.04 (0.72 to 1.48) for RTV. Frequently observed adverse events were diarrhea, headache, dizziness, abnormal dreams, and rash. EFV had no effect on the steady-state PK of TPV or RTV, with the exception of a 19% increase in the TPV C(min), which is not clinically relevant. TPV/r can be safely coadministered with EFV and without the need for a dose adjustment.

FIG. 1.

Steady-state geometric mean plasma TPV (A) and RTV (B) concentration-time profile for subjects receiving TPV/r 500/200 mg alone BID and TPV/r 500/200 mg BID plus EFV 600 mg QD. Filled bullets and dashed line, TPV/r plus EFV; open bullets and solid line, TPV/r alone.

FIG. 2.

Effect of steady-state EFV on the steady-state TPV AUC, C_max, and C_min. Note that the symbols and lines represent individual subjects.