Pharmacokinetics

Absorption: Peak efavirenz plasma concentrations of 1.6-9.1 mM were attained by 5 hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose-related increases in C_max and AUC were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses.

In HIV-infected patients at steady state, mean C_max , mean C_min , and mean AUC were dose proportional following 200-mg, 400-mg, and 600-mg daily doses. Time to-peak plasma concentrations were approximately 3-5 hours and steady-state plasma concentrations were reached in 6-10 days. In 35 patients receiving SUSTIVA 600 mg once daily, steady-state C_max was 12.9 ± 3.7 µM (mean ± SD), steady-state C_min was 5.6 ± 3.2 mM, and AUC was 184 ± 73 mM·h.

Capsules-Administration of a single 600-mg dose of efavirenz capsules with a high fat/high-caloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with a mean increase of 22% and 17% in efavirenz AUC .and a mean increase of 39% and 51% in efavirenz C_max , respectively, relative to the exposures achieved when given under fasted conditions. (See DOSAGE AND ADMINISTRATION and PRECAUTIONS: Information for Patients.)

TabletsAdministration of a single 600-mg efavirenz tablet with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) was associated with a 28% increase in mean AUC . of efavirenz and a 79% increase in mean C_max of efavirenz relative to the exposures achieved under fasted conditions. (See DOSAGE AND ADMINISTRATION and PRECAUTIONS: Information for Patients.)

Distribution: Efavirenz is highly bound (approximately 99.5-99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n=9) who received SUSTIVA 200 to 600 mg once daily for at least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentration. This proportion is approximately 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma.

Metabolism: Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. The in vitro studies suggest that CYP3A4 and CYP2B6 are the major isozymes responsible for efavirenz metabolism.

Efavirenz has been shown to induce P450 enzymes, resulting in the induction of its own metabolism. Multiple doses of 200-400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22-42% lower) and a shorter terminal half-life of 40-55 hours (single dose half-life 52- 76 hours).

Elimination: Efavirenz has a terminal half-life of 52-76 hours after single doses and 40 55 hours after multiple doses. A one-month mass balance/excretion study was conducted using 400 mg per day with a ¹⁴C-labeled dose administered on Day 8. Approximately 14-34% of the radiolabel was recovered in the urine and 16-61% was recovered in the feces. Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. Efavirenz accounted for the majority of the total radioactivity measured in feces.

Hepatic Impairment: The pharmacokinetics of efavirenz have not been adequately studied in patients with hepatic impairment (See PRECAUTIONS: General).

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