Drug-drug Interaction between Lopinavir/Ritonavir and Rosuvastatin
D Hoody1, Jennifer J. Kiser*2, J Predhomme2, D Flynn1, and J Gerber2
1Univ of Colorado Hosp, Denver, US and 2Univ of Colorado Hlth Sci Ctr, Denver, US
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.
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 Cmax
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).
Of 20 subjects we
enrolled, 15 (60% female) were eligible for statistical analysis of pharmacokinetic
data. Mean (±SD) ROS AUC and Cmax 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 Cmax 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 Cmax were bioequivalent with
ROS AUC and Cmax
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.