Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047.

OBJECTIVE: Lipid lowering therapy is used increasingly in persons with HIV infection in the absence of safety data or information on drug interactions with antiretroviral agents. The primary objectives of this study were to examine the effects of ritonavir (RTV) plus saquinavir soft-gel (SQVsgc) capsules on the pharmacokinetics of pravastatin, simvastatin, and atorvastatin, and the effect of pravastatin on the pharmacokinetics of nelfinavir (NFV) in order to determine clinically important drug-drug interactions. DESIGN: Randomized, open-label study in healthy, HIV seronegative adults at AIDS Clinical Trials Units across the USA. METHODS: Three groups of subjects (arms 1, 2, and 3) received pravastatin, simvastatin or atorvastatin (40 mg daily each) from days 1-4 and 15-18. In these groups, RTV 400 mg and SQVsgc 400 mg twice daily were given from days 4-18. A fourth group (arm 4) received NFV 1250 mg twice daily from days 1-14 with pravastatin 40 mg daily added from days 15-18. Statin and NFV levels were measured by liquid chromatography/tandem mass spectrometry. RESULTS: Fifty-six subjects completed both pharmacokinetic study days. In arms 1-3, the median estimated area under the curves (AUC)(0-24) for the statins were: pravastatin (arm 1, n = 13), 151 and 75 ng.h/ml on days 4 and 18 (decline of 50% in presence of RTV/SQVsgc), respectively (P = 0.005); simvastatin (arm 2, n = 14), 17 and 548 ng.h/ml on days 4 and 18 (increase of 3059% in the presence of RTV/SQVsgc), respectively (P < 0.001); and total active atorvastatin (arm 3, n = 14), 167 and 289 ng.h/ml on days 4 and 18 (increase of 79% in the presence of RTV/SQVsgc), respectively (P < 0.001). In arm 4, the median estimated AUC(0-8) for NFV (24 319 versus 26 760 ng.h/ml; P = 0.58) and its active M8 metabolite (15 565 versus 14 571 ng.h/m; P = 0.63) were not statistically different from day 14 to day 18 (without or with pravastatin). CONCLUSIONS: Simvastatin should be avoided and atorvastatin may be used with caution in persons taking RTV and SQVsgc. Dose adjustment of pravastatin may be necessary with concomitant use of RTV and SQVsgc. Pravastatin does not alter the NFV pharmacokinetics, and thus appears to be safe for concomitant use.