BACKGROUND: The use of antiretroviral drugs is associated with increases in serum lipid levels often requiring lipid-lowering therapy to reduce the risk of cardiovascular complications. Efavirenz (EFV) is one of the most commonly used and effective drugs for the treatment of HIV infection. EFV use is associated with hyperlipidemia either when used in combination with protease inhibitors or nucleoside reverse transcriptase inhibitors. EFV is a mixed inducer/inhibitor of CYP3A4; simvastatin (SIM) and atorvastatin (ATR), 2 widely used and potent HMG-CoA reductase inhibitors, are primarily metabolized via CYP3A4. Thus for the safe and effective use of SIM or ATR with EFV, it is important to establish how concomitant EFV affects the metabolism of these 2 drugs.

METHODS: ACTG A5108 examined the effect of 600 mg/day EFV on the plasma pharmacokinetics of 40 mg/day SIM and 10 mg/day ATR, 2 of the most popular and effective statins used for lipid-lowering therapy. Also participating in the SIM and ATR arms of this study were 27 HIV-seronegative healthy subjects. The protocol compared the pharmacokinetics of SIM and ATR alone and following administration of 14 days of EFV. The non-steady state effects of SIM and ATR on EFV plasma pharmacokinetics were examined as well.

RESULTS: EFV was very well tolerated in these subjects with no dropouts or significant toxicities reported. EFV reduced SIM acid exposure (AUC 0-24 h) by 58% from 36.5 to 14.5 ng*h/mL (medians, Wilcoxon signed rank, p = 0.003; 90% CI of GMR 0.32-0.61). In addition, the AUC0-24 h of the active HMG-CoA reductase inhibitory activity was reduced by 60% (medians, p = 0.0001, 90% CI of GMR 0.32-0.48). EFV reduced ATR exposure by 43% from 11.8 to 6.1 ng*h/mL (medians, p = 0.0002; 90% CI of GMR 0.47-0.60). In addition, the total active ATR exposure (AUC0-24 h) was reduced by 48% (medians, p = 0.027, 90% CI of GMR 0.41-0.88), because EFV induces the metabolism of ATR active metabolites as well. Neither SIM nor ATR affected the non-steady state EFV concentrations.

CONCLUSIONS: These data suggest that EFV, when used with SIM or ATR therapeutically, can result in significant induction of their metabolism. The reduced inhibition of HMG-CoA reductase activity during co-administration of EFV may result in diminished antilipid efficacy at the usual doses of SIM and ATR. Some patients taking EFV may require titration to higher SIM and ATR doses to achieve target lipid goals, but this should only be attempted with increased monitoring for toxicity.

040208
603

Copyright © 2004 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.