Background:  Hyperlipidemia is a complication of HIV-protease inhibitor (PI) therapy. Rosuvastatin (ROS) is not a substrate, inhibitor, or inducer of CYP450 3A4, but its concentrations are increased 2- to 4-fold when given with lopinavir/ritonavir (LPV/r). We conducted a pharmacokinetic study to determine if a similar interaction between rosuvastatin and tipranavir/ritonavir (TPV/r) occurs at steady-state.
Methods:  This was an open label, single-arm, inpatient pharmacokinetic study in HIV-negative male and female subjects (n = 29). Subjects received a single 10-mg dose of ROS on day 1, followed by TPV 500 mg/RTV 200 mg twice daily for 11 days (days 3 to 13), with a single 10-mg dose of ROS given on day 12. Intensive pharmacokinetic sampling was performed on days 1 to 3 and 12 to 14 for ROS, and days 12 and 13 for TPV and RTV. Pharmacokinetic parameters were calculated using non-compartmental methods (WinNonlin). Geometric mean ratios (GMR) and 90%CI were determined.
Results:  To obtain 16 evaluable subjects, we enrolled 29 subjects. The mean age was 42 years, 83% were males, and 76% were African American. Geometric mean (CV%) ROS AUC and C_max were 28.2 ng·h/mL (59%) and 2.59 ng/mL (41%), respectively, when given alone vs 38.6 ng·h/mL (38%) and 5.78 ng/mL (55%) when combined with TPV/r. The GMR was 1.37 (90%CI 1.15 to 1.62) for ROS AUC and 2.23 (90%CI 1.83 to 2.72) for ROS C_max with TPV/r vs alone. TPV and RTV pharmacokinetic parameters were not affected by a single dose of ROS. Of the 13 subjects who discontinued prematurely, 6 had grade 2 (2.5 to 5.0x ULN) LFT elevations, 2 had grade 3 (>5 to 10x ULN) LFT elevations, 1 had grade 1 rash, 1 had a grade 3 hypersensitivity reaction, 2 withdrew consent, and 1 was administratively discharged. All liver enzyme elevations occurred on day 8 (before ROS co-administration) and resolved with study drug discontinuation.
Conclusions:  With TPV/r co-administration, ROS AUC and C_max were increased by 37% and 123%, respectively. These increases are less than those seen with LPV/r. Initiation of ROS with TPV/r should be with the lowest dose of ROS (5 mg/day) and titrated to treatment response, with careful monitoring.