Pharmacokinetic Interactions between Protease Inhibitors and 3 Lipid-Lowering Drugs (Pravastatin, Simvastatin, and Atorvastatin)

Carl Fichtenbaum from Washington University in St.Louis reported for an ACTG study group on the effects of 3 lipid lowering agents when taken with 400mg RTV+ 400 mg SQV. Fichtenbaum said that treatment with statins is becoming increasingly common despite the absence of data on drug interactions or safety. So his group evaluated the pharmacokinetic (PK) interactions between three HMG-CoA reductase inhibitors (statins) commonly used to treat this disorder and the protease inhibitor combination of ritonavir (RTV) + saquinavir (SQV). Most statins are metabolized by cytochrome P450 3A4, as are the PIs in current use. Fichtenbaum concluded that pravaststin appears to be the safest one to use.

HIV seronegative adults (n=52) received Pravastatin 40 mg/day, Simvastatin 40 mg/day or Atorvastatin 40 mg/d on days 1-4 & 15-18. On days 5-18, subjects took RTV 400mg BID + SQV 400mg BID. Blood samples for PK analysis were obtained pre-dose and at 1/2, 1, 2, 3, 4, 6, 8, 12 hours on days 4 & 18. The AUC 0-24 on days 4 & 18 were compared using the paired Wilcoxon signed rank test.

14 subjects in each group completed both PK study days. The median estimated 24-hour AUC for Pravastatin was 149.7 & 72.0 ng /mL*hr on days 4 & 18, respectively (P=0.05). The median estimated 24-hour AUC  for Atorvastatin was 67.4 & 267.4 ng/mL*hr on days 4 & 18, respectively (P<0.001). The median estimated 24-hour AUC (n=14) for Simvastatin was 19.6 & 519.9 ng/mL*hr on days 4 and 18, respectively (P<0.0001). Fichtenbaum reported there were no significant adverse events with simultaneous use of RTV+SQV & the statins.

Pravastatin concentrations declined 47% in the presence of RTV+SQV. There was a significant increase in median AUC for Atorvastatin acid levels by 343%; total active atorvastatin levels increased by 74%. Simvastatin acid levels increased by 2,676% in the presence of RTV+SQV. Fichtenbaum concluded that pravastatin appears to be safe for further study. Simvastatin should be avoided, Atorvastatin shouls be used with caution.

He added that additional safety data are needed to determine whether statins affect the levels of protease inhibitors. Data from this study of RTV/SQV is being analyzed.