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Efavirenz Is a Significant Inducer of Simvastatin and Atorvastatin Metabolism: Results of ACTG A5108 Study
J G Gerber*1, C J Fichtenbaum2, S Rosenkranz3, J M Vega4, A Yang4, B Alston5, SW Brobst6, Y Segal3, J A Aberg7, and The ACTG A5108 team
1Univ. of Colorado Hlth. Sci. Ctr., Denver, USA; 2Univ. of Cincinnati, OH, USA; 3Statistical and Data Analysis Ctr. (SDAC), Harvard Sch. of Publ. Hlth., Boston, MA, USA; 4Merck & Co, Inc., West Point, PA, USA; 5NIAID, NIH, DHHS, Bethesda, MD, USA; 6Social and Sci. Systems, Inc., Silver Spring, MD, USA; and 7Washington Univ., St. Louis, MO, USA
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.
Keywords: drug-drug interaction; efavirenz; statins
