7th Conference

LB6 Pharmacokinetic Interactions between Protease Inhibitors and Selected HMG-CoA Reductase Inhibitors.

C. FICHTENBAUM*, J. GERBER, S. ROSENKRANZ, Y. SEGAL, T. BLASCHKE, J. ABERG, M. ROYAL, W. BURNING, K. LAMB, E. FERGUSON, B. ALSTON, F. AWEEKA and the ACTG A5047 Team. Univ. of Cincinnati, OH; Univ. of Colorado Hlth. Sci. Ctr., Denver; SDAC/Harvard Sch. of Publ. Hlth., Boston, MA; Stanford Univ., Palo Alto, CA; Univ. of California, San Francisco; Washington Univ., St. Louis, MO; Frontier Science and Technology Research Fndn., Buffalo, NY; and the AACTG Operations Ctr., Rockville, MD.

Background: Hyperlipidemia is an adverse effect of potent antiretroviral (protease inhibitor) therapy. Treatment with statins is becoming increasingly common despite the absence of data on drug interactions or safety. We 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).

Methods: HIV seronegative adults received Pravastatin 40 mg/d, Simvastatin 40 mg/d 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 ½, 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.

Results: 14 subjects in each group completed both PK study days. The median estimated AUC_0-24 for Pravastatin was 143.5 & 93.3 ng /mL*hr on days 4 & 18, respectively (P=0.05). The median estimated AUC_0-24 for Atorvastatin was 71.9 & 283.5 ng/mL*hr on days 4 & 18, respectively (P<0.001). The median estimated AUC_0-24 for Simvastatin was 17.1 & 548.7 ng/mL*hr on days 4 and 18, respectively (P<0.001). There were no significant adverse events with simultaneous use of RTV+SQV & the statins.

Conclusions: Pravastatin concentrations declined (median 0.5 fold) in the presence of RTV+SQV. There was a significant increase in the median AUC_0-24 for Atorvastatin (4.5 fold) and Simvastatin (31.6 fold) in the presence of RTV+SQV. Atorvastatin and Simvastatin doses should be reduced, or these agents avoided in persons taking RTV+SQV to avoid potential toxicity from these medications. Pravastatin dosing probably does not need adjustment in persons using RTV+SQV.

Key Words: