Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers

Abstract

The combination of efavirenz with HIV-1 protease inhibitors (PI) results in complex interactions secondary to mixed induction and inhibition of oxidative metabolism. ACTG A5043 was a prospective, open-label, controlled, two-period, multiple-dose study with 55 healthy volunteers. The objective of the present study was to evaluate the potential pharmacokinetic interaction between efavirenz and dual PIs. The subjects received a daily dose of 600 mg efavirenz for 10 days with amprenavir 600 mg twice daily added at day 11 and were randomized to receive nelfinavir, indinavir, ritonavir, saquinavir, or no second PI on days 15-21. Intensive pharmacokinetic studies were conducted on day 14 and 21. Efavirenz plasma concentrations were fit to candidate models using weighted non-linear regression. The disposition of efavirenz was described by a linear two-compartment model with first order absorption following a fitted lag time. Apparent clearance (CL t /F), volume of distribution at steady state (V ss /F), intercompartmental clearance, and the central and peripheral volume of distribution were estimated. The mean CL t /F and V ss /F of efavirenz were 0.126 l/h/kg and 4.412 l/kg, respectively. Both AUC and CL t /F of efavirenz remained unchanged after 7 days of dual PI dosing. The mean V ss /F of efavirenz increased an average of 89% across arms, ranging from 52% (nelfinavir) to 115% (indinavir) relative to efavirenz with amprenavir alone. Increases were also observed in V p /F after the addition of nelfinavir, indinavir, ritonavir and saquinavir by 85%, 170%, 162% and 111%, respectively. In conclusion, concomitant administration of dual PIs is unlikely to have any clinically significant effect on the pharmacokinetics of CYP2B6 substrates in general or oral efavirenz specifically.

Pharmacokinetics of the nonnucleoside reverse transcriptase inhibitor efavirenz among HIV‐infected Ugandans

“…The majority of studies that have reported long expected half-lives of 40-55 h or more were conducted in health volunteers with data collected over a longer time period [30]. The half-life obtained in this study is similar to that obtained in a study by Ma et al, in which samples were collected over a 12-h period (t 1/2 23-30.8 h) [31], although the protease inhibitor amprenavir was co-administered to the volunteers between days 10 and 14 of the study.…”

Changes in clearance, volume and bioavailability of immunosuppressants when given with HAART in HIV‐1 infected liver and kidney transplant recipients

“…demonstrated in healthy volunteers that increased P‐gp activity as measured by Rh123 uptake in lymphocytes correlated with increased apparent oral CL / F and apparent oral V / F , and both were decreased with indinavir exposure . In healthy volunteers, adding PIs to EFV increased V / F but not CL / F for EFV . In another study in HIV‐1 infected volunteers, the concomitant use of EFV or NVP increased the apparent oral clearance of lopinavir by 39%, ( p < 0.001) .…”

“…This picture is also additionally complicated by the effects that these agents have on the efflux transporter P‐gp, which could lead to increased F through intestinal transporter–enzyme interplay resulting in a decreased CL / F . Cyclosporine and the PIs themselves are substrates as well as inhibitors of P‐gp and the NNRTIs have differential effects on P‐gp, but are generally thought to act as inducers of this transporter .…”

Rapid and Simultaneous Determination of Efavirenz, 8-Hydroxyefavirenz, and 8,14-Dihydroxyefavirenz Using LC–MS–MS in Human Plasma and Application to Pharmacokinetics in Healthy Volunteers

“…The lower limit of quantification (LLOQ) for efavirenz and 8-hydroxyefavirenz were both 5 ng mL -1 at a signal-to-noise (S/N) ratio of 10. This LLOQ value (5 ng mL -1 ) is lower than values previously reported (5-205 ng mL -1 ) [21,22,28,39,40]. In addition, these sensitivities were enough to apply pharmacokinetic studies of efavirenz and its metabolites after oral administration of efavirenz.…”

“…Several organic solvents including ethyl acetate [15], methyl-t-butyl ether [27], and hexane/ethyl acetate mixture [28] were previously used to extract efavirenz in plasma samples. Among organic solvents (ethyl acetate, ether, dichloromethane, chloroform and their mixtures) tested, ethyl acetate was found to be optimal, which can produce a clean chromatogram for blank plasma samples and the best recovery, and the least matrix effect.…”