Efavirenz - How It Works
Clinical pharmacology details from the US FDA-approved label: how Efavirenz works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Efavirenz, emtricitabine and tenofovir disoproxil fumarate is a fixed-dose combination of antiviral drugs EFV, FTC, and TDF [See Microbiology ].
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Efavirenz, emtricitabine and tenofovir disoproxil fumarate is a fixed-dose combination of antiviral drugs EFV, FTC, and TDF [See Microbiology ].
12.2 Pharmacodynamics Cardiac Electrophysiology Efavirenz: The effect of EFV on the QTc interval was evaluated in an open-label, positive and placebo-controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms.
The mean C max of EFV in subjects with CYP2B6 *6/*6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean C max observed in subjects with CYP2B6 *1/*1 genotype.
A positive relationship between EFV concentration and QTc prolongation was observed.
Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7 msec and 11.3 msec in subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days [See Warnings and Precautions ].
12.3 Pharmacokinetics Efavirenz, emtricitabine and tenofovir disoproxil fumarate: One efavirenz,emtricitabine and tenofovir disoproxil fumarate tablet: is bioequivalent to one Sustiva tablet (600 mg) plus one EMTRIVA ® capsule (200 mg) plus one VIREAD ® tablet (300 mg) following single-dose administration to fasting healthy subjects (N=45).
Efavirenz: In HIV-1 infected subjects time-to-peak plasma concentrations were approximately 3–5 hours and steady-state plasma concentrations were reached in 6–10 days.
In 35 HIV-1 infected subjects receiving EFV 600 mg once daily, steady-state C max was 12.9 ± 3.7 μM (mean ± SD), C min was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM•hr.
EFV is highly bound (approximately 99.5–99.75%) to human plasma proteins, predominantly albumin.
Following administration of 14 C-labeled EFV, 14–34% of the dose was recovered in the urine (mostly as metabolites) and 16–61% was recovered in feces (mostly as parent drug).
In vitro studies suggest CYP3A and CYP2B6 are the major isozymes responsible for EFV metabolism.
EFV has been shown to induce CYP enzymes, resulting in induction of its own metabolism.
EFV has a terminal half-life of 52–76 hours after single doses and 40–55 hours after multiple doses.
Emtricitabine: Following oral administration, FTC is rapidly absorbed, with peak plasma concentrations occurring at 1–2 hours postdose.
Following multiple dose oral administration of FTC to 20 HIV-1 infected subjects, the steady-state plasma FTC C max was 1.8 ± 0.7 μg/mL (mean ± SD) and the AUC over a 24-hour dosing interval was 10.0 ± 3.1 μg•hr/mL.
The mean steady-state plasma trough concentration at 24 hours postdose was 0.09 μg/mL.
The mean absolute bioavailability of FTC was 93%.
Less than 4% of FTC binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.02−200 μg/mL.
Following administration of radiolabelled FTC, approximately 86% is recovered in the urine and 13% is recovered as metabolites.
The metabolites of FTC include 3'-sulfoxide diastereomers and their glucuronic acid conjugate.
Pharmacokinetics
12.3 Pharmacokinetics Efavirenz, emtricitabine and tenofovir disoproxil fumarate: One efavirenz,emtricitabine and tenofovir disoproxil fumarate tablet: is bioequivalent to one Sustiva tablet (600 mg) plus one EMTRIVA ® capsule (200 mg) plus one VIREAD ® tablet (300 mg) following single-dose administration to fasting healthy subjects (N=45). Efavirenz: In HIV-1 infected subjects time-to-peak plasma concentrations were approximately 3–5 hours and steady-state plasma concentrations were reached in 6–10 days. In 35 HIV-1 infected subjects receiving EFV 600 mg once daily, steady-state C max was 12.9 ± 3.7 μM (mean ± SD), C min was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM•hr. EFV is highly bound (approximately 99.5–99.75%) to human plasma proteins, predominantly albumin. Following administration of 14 C-labeled EFV, 14–34% of the dose was recovered in the urine (mostly as metabolites) and 16–61% was recovered in feces (mostly as parent drug). In vitro studies suggest CYP3A and CYP2B6 are the major isozymes responsible for EFV metabolism. EFV has been shown to induce CYP enzymes, resulting in induction of its own metabolism. EFV has a terminal half-life of 52–76 hours after single doses and 40–55 hours after multiple doses. Emtricitabine: Following oral administration, FTC is rapidly absorbed, with peak plasma concentrations occurring at 1–2 hours postdose. Following multiple dose oral administration of FTC to 20 HIV-1 infected subjects, the steady-state plasma FTC C max was 1.8 ± 0.7