HIV-1 specific NNRTI.. ATC Code:
Pharmacology: Pharmacodynamics: Mechanism of Action:
Efavirenz is a NNRTI of HIV-1. Efavirenz is a noncompetitive 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 free concentration of efavirenz required for 90-95% inhibition of wild type or zidovudine resistant laboratory and clinical isolates in vitro
ranged from 0.46-6.8 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, 17-22 fold resistance) and a lysine to asparagine at position 103 (K103N, 18-33 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 medications 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 3 NNRTIs. Two of 3 delavirdine resistant clinical isolates examined were cross resistant to efavirenz and contained the K103N substitution. A 3rd 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.
Efavirenz has not been studied in controlled studies in patients with advanced HIV disease, namely with CD4 counts <50 cells/mm3
, or in PI or NNRTI experienced patients. Clinical experience in controlled studies with combinations including didanosine or zalcitabine is limited.
Two controlled studies (006 and ACTG 364) of approximately 1 yr duration with efavirenz in combination with NRTIs and/or PIs, have demonstrated reduction of viral load below the limit of quantification of the assay and increased CD4 lymphocytes in antiretroviral therapy naive and NRTI experienced HIV infected patients. Study 020 showed similar activity in NRTI experienced patients over 24 weeks. In these studies the dose of efavirenz was 600 mg once daily; the dose of indinavir was 1000 mg every 8 hrs when used with efavirenz and 800 mg every 8 hrs when used without efavirenz. The dose of nelfinavir was 750 mg given 3 times a day. The standard doses of NRTIs given every 12 hrs were used in each of these studies.
Study 006, a randomized, open-label trial, compared efavirenz + zidovudine + lamivudine or efavirenz + indinavir with indinavir + zidovudine + lamivudine in 1266 patients who were required to be efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The mean baseline CD4 cell count was 341 cells/mm3
and the mean baseline HIV-RNA level was 60,250 copies/mL. Efficacy results for study 006 on a subset of 614 patients who had been enrolled for at least 48 weeks are found in Table 1. In the analysis of responder rates (the non-completer equals failure analysis [NC=F]), patients who terminated the study early for any reason, or who had a missing HIV-RNA measurement that was either preceded or followed by a measurement above the limit of assay quantification were considered to have HIV-RNA >50 or >400 copies/mL at the missing time points. (See Table 1.)
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Long-term results at 168 weeks of study 006 (160 patients completed study on treatment with EFV+IDV, 196 patients with EFV+ZDV+3TC and 127 patients with IDV+ZDV+3TC, respectively), suggest durability of response in terms of proportions of patients with HIV-RNA <400 copies/mL, HIV-RNA <50 copies/mL and in terms of mean change from baseline CD4 cell count.
Efficacy results for studies ACTG 364 and 020 are found in Table 2. Study ACTG 364 enrolled 196 patients who had been treated with NRTIs but not with PIs or NNRTIs. Study 020 enrolled 327 patients who had been treated with NRTIs but not with PIs or NNRTIs. Physicians were allowed to change their patient's NRTI regimen upon entry into the study. Responder rates were highest in patients who switched NRTIs. (See Table 2.)
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ACTG 382 is an ongoing uncontrolled study of 57 NRTI-experienced paediatric patients (3-16 yrs) which characterises the pharmacokinetics, antiviral activity and safety of efavirenz in combination with nelfinavir (20-30 mg/kg given 3 times a day) and ≥1 NRTIs. The starting dose of efavirenz was the equivalent of a 600 mg dose (adjusted from calculated body size based on weight). The response rate, based on the NC=F analysis of the percentage of patients with plasma HIV-RNA <400 copies/mL at 48 weeks was 60% (95%, CI 47, 72), and 53% (CI 40, 66) based on percentage of patients with plasma HIV-RNA <50 copies/mL. The mean CD4 cell counts were increased by 63 ±34.5 cells/mm3
from baseline. The durability of the response was similar to that seen in adult patients.
Peak efavirenz plasma concentrations (Cmax
) of 1.6-9.1 μM were attained by 5 hrs following single oral doses of 100-1600 mg administered to uninfected volunteers. Dose related increases in Cmax
and AUC were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses. Time to peak plasma concentrations (3-5 hrs) 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, 400, 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 ±SD (% CV)], steady state Cmin
was 5.6 ±3.2 μM (57%), and AUC was 184 ±73 μM·h (40%).
Effect of Food:
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 200-600 mg once daily for at least 1 month, cerebrospinal fluid concentrations ranged from 0.26-1.19% (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 P450 enzymes, resulting in the induction of its own metabolism. In uninfected volunteers, multiple doses of 200-400 mg/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 a relatively long terminal half life of 52-76 hrs after single doses and 40-55 hrs after multiple doses. Approximately 14-34% of a radiolabelled dose of efavirenz was recovered in the urine and <1% of the dose was excreted in urine as unchanged efavirenz.
In the single patient studied with severe hepatic impairment (Child Pugh Grade C), half life was doubled indicating a potential for a much greater degree of accumulation.
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.
Gender, Race, Elderly:
Pharmacokinetics of efavirenz in patients appear to be similar between men and women and among the racial groups studied. Although limited data suggest that 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.
Toxicology: Preclinical Safety Data:
Efavirenz was not mutagenic or clastogenic in conventional genotoxicity assays.
Efavirenz induced foetal resorptions in rats. Malformations were observed in 3 of 20 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 1 foetus, microophthalmia was observed in another foetus, and cleft palate was observed in a 3rd foetus. No malformations were observed in foetuses from efavirenz treated rats and rabbits.
Biliary hyperplasia was observed in cynomolgus monkeys given efavirenz for 1 yr 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 yr, at doses yielding plasma AUC values 4-13 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.