Chemical formula: C₁₄H₉ClF₃NO₂ Molecular mass: 315.675 g/mol PubChem compound: 64139
Efavirenz is a NNRTI of HIV-1. Efavirenz is a non-competitive inhibitor of HIV-1 reverse transcriptase (RT) and does not significantly inhibit HIV-2 RT or cellular DNA polymerases (α, β, γ or δ).
The effect of efavirenz 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 Cmax of efavirenz in subjects with CYP2B6 *6/*6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean Cmax observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between efavirenz 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 ms and 11.3 ms in subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days.
The free concentration of efavirenz required for 90 to 95% inhibition of wild type or zidovudine-resistant laboratory and clinical isolates in vitro ranged from 0.46 to 6.8 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs) and macrophage/monocyte cultures.
The potency of efavirenz in cell culture against viral variants with amino acid substitutions at positions 48, 108, 179, 181 or 236 in RT or variants with amino acid substitutions in the protease was similar to that observed against wild type viral strains. The single substitutions which led to the highest resistance to efavirenz in cell culture correspond to a leucine-to-isoleucine change at position 100 (L100I, 17 to 22-fold resistance) and a lysine-to-asparagine at position 103 (K103N, 18 to 33-fold resistance). Greater than 100-fold loss of susceptibility was observed against HIV variants expressing K103N in addition to other amino acid substitutions in RT.
K103N was the most frequently observed RT substitution in viral isolates from patients who experienced a significant rebound in viral load during clinical studies of efavirenz in combination with indinavir or zidovudine + lamivudine. This mutation was observed in 90% of patients receiving efavirenz with virological failure. Substitutions at RT positions 98, 100, 101, 108, 138, 188, 190 or 225 were also observed, but at lower frequencies, and often only in combination with K103N. The pattern of amino acid substitutions in RT associated with resistance to efavirenz was independent of the other antiviral medicinal products used in combination with efavirenz.
Cross resistance profiles for efavirenz, nevirapine and delavirdine in cell culture demonstrated that the K103N substitution confers loss of susceptibility to all three NNRTIs. Two ofthree delavirdine-resistant clinical isolates examined were cross-resistant to efavirenz and contained the K103N substitution. A third isolate which carried a substitution at position 236 of RT was not cross-resistant to efavirenz.
Viral isolates recovered from PBMCs of patients enrolled in efavirenz clinical studies who showed evidence of treatment failure (viral load rebound) were assessed for susceptibility to NNRTIs. Thirteen isolates previously characterised as efavirenz-resistant were also resistant to nevirapine and delavirdine. Five of these NNRTI-resistant isolates were found to have K103N or a valine-to-isoleucine substitution at position 108 (V108I) in RT. Three of the efavirenz treatment failure isolates tested remained sensitive to efavirenz in cell culture and were also sensitive to nevirapine and delavirdine.
The potential for cross resistance between efavirenz and PIs is low because of the different enzyme targets involved. The potential for cross-resistance between efavirenz and NRTIs is low because of the different binding sites on the target and mechanism of action.
Peak efavirenz plasma concentrations of 1.6-9.1 μM were attained by 5 hours following single oral doses of 100 mg to 1,600 mg administered to uninfected volunteers. Dose related increases in Cmax and AUC were seen for doses up to 1,600 mg; the increases were less than proportional suggesting diminished absorption at higher doses. Time to peak plasma concentrations (3-5 hours) did not change following multiple dosing and steady-state plasma concentrations were reached in 6-7 days.
In HIV infected patients at steady state, mean Cmax, mean Cmin, and mean AUC were linear with 200 mg, 400 mg, and 600 mg daily doses. In 35 patients receiving efavirenz 600 mg once daily, steady state Cmax was 12.9 ± 3.7 μM (29%) [mean ± S.D. (% C.V.)], steady state Cmin was 5.6 ± 3.2 μM (57%), and AUC was 184 ± 73 μM·h (40%).
The AUC and Cmax of a single 600 mg dose of efavirenz film-coated tablets in uninfected volunteers was increased by 28% (90% CI: 22-33%) and 79% (90% CI:58-102%), respectively, when given with a high fat meal relative to when given under fasted conditions.
Efavirenz is highly bound (approximately 99.5-99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n=9) who received efavirenz 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.
Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolised 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 and that it inhibited P450 isozymes 2C9, 2C19, and 3A4. In in vitro studies efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 only at concentrations well above those achieved clinically.
Efavirenz plasma exposure may be increased in patients with the homozygous G516T genetic variant of the CYP2B6 isoenzyme. The clinical implications of such an association are unknown; however, the potential for an increased frequency and severity of efavirenz-associated adverse events cannot be excluded.
Efavirenz has been shown to induce CYP3A4 and CYP2B6, resulting in the induction of its own metabolism which may be clinically relevant in some patients. In uninfected volunteers, 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 compared with single dose administration (see below). Efavirenz has also been shown to induce UGT1A1. Exposures of raltegravir (a UGT1A1 substrate) are reduced in the presence of efavirenz. Although in vitro data suggest that efavirenz inhibits CYP2C9 and CYP2C19, there have been contradictory reports of both increased and decreased exposures to substrates of these enzymes when coadministered with efavirenz in vivo. The net effect of co-administration is not clear.
Efavirenz has a relatively long terminal half-life of at least 52 hours after single doses and 40-55 hours after multiple doses. Approximately 14-34% of a radiolabelled dose of efavirenz was recovered in the urine and less than 1% of the dose was excreted in urine as unchanged efavirenz.
In a single-dose study, half life was doubled in the single patient with severe hepatic impairment (Child-Pugh Class C), indicating a potential for a much greater degree of accumulation. A multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz pharmacokinetics.
Although limited data suggest that females as well as Asian and Pacific Island patients may have higher exposure to efavirenz, they do not appear to be less tolerant of efavirenz. Pharmacokinetic studies have not been performed in the elderly.
In 49 paediatric patients receiving the equivalent of a 600 mg dose of efavirenz (dose adjusted from calculated body size based on weight), steady state Cmax was 14.1 μM, steady state Cmin was 5.6 μM, and AUC was 216 μM·h. The pharmacokinetics of efavirenz in paediatric patients were similar to adults.
Efavirenz was not mutagenic or clastogenic in conventional genotoxicity assays.
Efavirenz induced foetal resorptions in rats. Malformations were observed in 3 of20 foetuses/newborns from efavirenz-treated cynomolgus monkeys given doses resulting in plasma efavirenz concentrations similar to those seen in humans. Anencephaly and unilateral anophthalmia with secondary enlargement of the tongue were observed in one foetus, microphthalmia was observed in another foetus, and cleft palate was observed in a third foetus. No malformations were observed in foetuses from efavirenz-treated rats and rabbits.
Biliary hyperplasia was observed in cynomolgus monkeys given efavirenz for ≥1 year at a dose resulting in mean AUC values approximately 2-fold greater than those in humans given the recommended dose. The biliary hyperplasia regressed upon cessation of dosing. Biliary fibrosis has been observed in rats. Non-sustained convulsions were observed in some monkeys receiving efavirenz for ≥1 year, at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the recommended dose.
Carcinogenicity studies showed an increased incidence of hepatic and pulmonary tumours in female mice, but not in male mice. The mechanism of tumour formation and the potential relevance for humans are not known.
Carcinogenicity studies in male mice, male and female rats were negative. While the carcinogenic potential in humans is unknown, these data suggest that the clinical benefit of efavirenz outweighs the potential carcinogenic risk to humans.
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