Effect of Efavirenz on the Pharmacokinetics of Simvastatin, Atorvastatin, and Pravastatin

Abstract

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 [AUC0-24 h]) 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.

Efficacy of Pravastatin in Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) and Protease Inhibitor (PI)-based HAART in HIV-Infected Patients

“…The attenuated lipid response is not unexpected and most likely related to a reduction in pravastatin concentrations similar to the observations of Gerber and colleagues [7]. The mechanism by which the pravastatin concentrations may decrease with coadministration of EFV has yet to be fully elucidated.…”

“…This study showed that the AUC of simvastatin acid was reduced by -58% (p = 0.003), the AUC of atorvastatin with active metabolites was reduced by -34% (p<0.001) and that the AUC of pravastatin was reduced by -40% (p = 0.005). While they did report an observed attenuation of LDL lowering with EFV with 4 days of statin use, these results were only statistically significant for the simvastatin arm nor do they reflect the effect that chronic concurrent administration used in real-world clinical practice might have on LDL-lowering efficacy [7]. The present study differs from this pharmacokinetic study in that we evaluated the lipid lowering efficacy and safety of pravastatin in both HIV-infected patients on NNRTI and PI-based HAART and after being on stable doses of the statin for at least 4 weeks to reflect a more clinically relevant scenario.…”

“…Pravastatin has historically been one of a few statins of choice in this patient population due to its lower dependency of the CYP450 isoenzyme system and thereby is theoretically less likely to result in drug interactions with various antiretroviral medications, especially protease inhibitors (PI) [6]. While most of the concerns regarding drug interaction reside with PI-based HAART, a recent pharmacokinetic study with pravastatin and efavirenz (EFV) in HIV-seronegative, adult patients revealed significant reductions in pravastatin concentrations [7]. Interestingly, there have also been reductions in pravastatin concentrations noted when given concurrently with (SQV/RTV) saquinavir/ritonavir-based regimens [8].…”

Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection

“…Co-administration of efavirenz (600 mg) with either simvastatin (40 mg once daily), atorvastatin (10 mg once daily), or pravastatin (40 mg once daily) resulted in significant reductions in the area under the curve (AUC) at 0 to 24 hours for all 3 statins: 58% reduction for simvastatin, 43% for atorvastatin, and 40% for pravastatin. 29 A separate study found that patients on an efavirenz-based ARV regimen who …”

“…35,49 Co-administration of the NNRTI efavirenz with simvastatin, atorvastatin, or pravastatin can result in significant induction of statin metabolism. 55 The reduced inhibition of HMG-CoA reductase activity during co-administration of efavirenz may result in diminished antilipid efficacy at usual doses, and statin dosages may need to be cautiously increased. Unlike PIs, NNRTIs, and cobicistat, raltegravir has no inhibitory or inductive potential in vitro.…”