Background:  Hyperlipidemia is a common complication in HIV-infected persons on ART, but few HMG Co-A reductase inhibitors are used in this population because of the potential for drug interactions. Rosuvastatin (ROS), a potent HMG Co-A reductase inhibitor, is not a substrate for CYP450 3A4. Thus, drug interactions with ROS and HIV protease inhibitors seem unlikely. This study was designed to demonstrate bioequivalence of lopinavir/ritonavir (LPV/r) and ROS when administered alone and in combination. Safety and tolerability data were also collected. 

Methods:  This was an open label, single-arm, 3-phase, pharmacokinetic study in HIV seronegative healthy volunteers. Subjects took ROS 20 mg once daily for 7 days, followed by LPV/r tablets 400/100 mg alone twice daily for 10 days, and then ROS+LPV/r for 7 days. Intensive pharmacokinetic sampling was performed on days 7, 17, and 24 following a standardized meal. The study was >80% powered for ROS AUC and C_max bioequivalence with 18 subjects. ROS and LPV/r pharmacokinetic were quantified with validated high-performance liquid chromatography/mass spectroscopy (HPLC/MS) assays and pharmacokinetic parameters obtained with non-compartmental methods (WinNonLin). Geometric mean ratios (GMR) and 90%CI were determined (SAS).   

Results:  Of 20 subjects we enrolled, 15 (60% female) were eligible for statistical analysis of pharmacokinetic data. Mean (±SD) ROS AUC and C_max were 50 ng*hr/mL (±15.3) and 4.7 ng/mL (±1.8), respectively, when given alone vs 115 ng*hr/mL (±65.5) and 25.2 ng/mL (±16.9) when combined with LPV/r. The GMR was 2.1 (90%CI 1.7 to 2.6) for ROS AUC and 4.7 (90%CI 3.4 to 6.4) for ROS C_max with LPV/r vs alone (p <0.0001). ROS elimination half-life was unaffected by LPV/r. There was one grade 4 (>10xULN) asymptomatic creatine phosphokinase elevation with ROS+LPV/r.  There was one grade 1 liver function test elevation (1.1-2.5xULN) with ROS+LPV/r vs none with ROS alone. LDL cholesterol reductions appeared attenuated with ROS+LPV/r (mean baseline LDL = 96 mg/dL; 40% decrease with ROS alone vs 27% decrease with ROS+LPV/r). LPV AUC and C_max were bioequivalent with ROS. 

Conclusions:  ROS AUC and C_max were unexpectedly increased 2.1- and 4.7-fold in the presence of LPV/r. Studies are needed to elucidate the mechanism for this interaction. An investigation of dose separation of LPV/r and ROS that would mitigate the interaction should also be pursued. Lowering the dose of ROS with LPV/r may affect the cholesterol-lowering efficacy. ROS+LPV/r should be used with caution until the safety, efficacy, and appropriate dosing of this combination have been demonstrated in larger populations.