Efavirenz (EFV) is associated with hyperlipidemia when used in combination with other antiretroviral drugs. EFV is a mixed inducer/inhibitor of cytochrome P450 (CYP) 3A4 isozyme and may interact with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that are primarily metabolized via CYP3A4. To assess the drug-drug interaction of EFV used in combination with simvastatin (SIM), atorvastatin (ATR), or pravastatin (PRA), an open-label trial was conducted in 52 healthy adult HIV-seronegative subjects across AIDS Clinical Trials Group sites in the United States. Subjects received 40 mg of SIM, 10 mg of ATR, or 40 mg of PRA daily on days 0 through 3 and days 15 through 18. EFV was administered daily at a dose of 600 mg on days 4 through 18. SIM, ATR, and PRA concentrations were determined before and after EFV, and EFV concentrations were determined before and after statins. EFV reduced SIM acid exposure (area under the curve at 0 to 24 hours [AUC0-24h]) by 58% (Wilcoxon signed rank test, P = 0.003) and active HMG-CoA reductase inhibitory activity by 60% (P < 0.001). EFV reduced ATR exposure by 43% (P < 0.001) and the total active ATR exposure by 34% (P = 0.005). EFV administration resulted in a 40% decrease in PRA exposure (P = 0.005). SIM, ATR, and PRA had no effect on non-steady-state EFV concentrations. In conclusion, EFV, when administered with SIM, ATR, or PRA, can result in significant induction of statin metabolism. The reduced inhibition of HMG-CoA reductase activity during coadministration of EFV may result in diminished antilipid efficacy at usual doses of SIM, ATR, and PRA.
From the *University of Colorado Health Sciences Center, Denver, CO; †Statistical Data and Analysis Center, Harvard School of Public Health, Boston, MA; ‡University of Cincinnati College of Medicine, Cincinnati, OH; §Merck and Company, Inc., West Point, PA; ¶Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; #Social and Scientific Systems, Inc., Silver Spring, MD; and **Washington University, St. Louis, MO.
Received for publication October 12, 2004; accepted March 29, 2005.
Supported by the National Institute of Allergy and Infectious Diseases grants AI-38858 to the Adult AIDS Clinical Trials Group, AI-38855 to the Statistical Data and Analysis Center of Harvard School of Public Health, AI-27666 to Stanford University, AI-25897 to the University of Cincinnati, AI-27668 to Johns Hopkins University, AI-25903 to Washington University, AI-27658 to the University of Rochester Medical Center, and AI-27664 to the University of Washington. Additional support provided by Stanford University GCRC grant 5-M01-RR00070, Johns Hopkins University GCRC grant 5-M01-RR00052, University of Colorado Health Sciences Center GCRC grant 5-M01-RR00051, and University of Rochester Medical Center GCRC grant 5-M01-RR0044.
Funded in part by Merck and Company, Bristol-Myers Squibb Company, Dupont Pharmaceuticals Company, and Pfizer Pharmaceutical.
Presented in part at the Second IAS Conference on HIV Pathogenesis and Treatment (abstract 870), 2003, Paris, and the 11th Conference on Retroviruses and Opportunistic Infections (abstract 603), 2004, San Francisco.
Reprints: John G. Gerber, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Box C237, Denver, CO 80262 (e-mail: John.gerber@UCHSC.edu).