Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: SONKE PHARMACEUTICALS (PTY) LTD, Ground Floor, Tugela House, Riverside Office Park, 1303 Heuwel Avenue, Centurion
Class & Category: A 20.2.8 Antiviral agents
ATENEF is a fixed dose combination tablet containing efavirenz, emtricitabine and tenofovir disoproxil fumarate (tenofovir DF).
Efavirenz is a non-nucleoside reverse transcriptase inhibitor of HIV-1. Efavirenz activity is mediated predominantly by non-competitive inhibition of HIV-1 reverse transcriptase (RT). HIV-2 RT and human cellular DNA polymerases α, β, γ, and σ are not inhibited by efavirenz.
Emtricitabine is a synthetic nucleoside analogue of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5' –triphosphate. Emtricitabine 5'–triphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5' –triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'–triphosphate is a weak inhibitor of mammalian DNA polymerase α, β, ε- and mitochondrial DNA polymerase γ.
Tenofovir DF is an acyclic nucleoside phosphonate diester analogue of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxyadenosine 5' –triphosphate and after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerase α, β and mitochondrial DNA polymerase γ.
In combination studies evaluating the antiviral activity in cell culture of emtricitabine and efavirenz together, efavirenz and tenofovir together, and emtricitabine and tenofovir together, additive to synergistic antiviral effects were observed.
The concentration of efavirenz inhibiting replication of wild-type laboratory adapted strains and clinical isolates in cell culture by 90–95% (EC90-95) ranged from 1,7−25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells, and macrophage/monocyte cultures. Efavirenz demonstrated additive antiviral activity against HIV-1 in cell culture when combined with non-nucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine and nevirapine), nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), protease inhibitors (PIs) (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), and the fusion inhibitor enfuvirtide. Efavirenz demonstrated additive to antagonistic antiviral activity in cell culture with atazanavir. Efavirenz demonstrated antiviral activity against clade B and most non-clade B isolates (subtypes A, AE, AG, C, D, F, G, J, and N), but had reduced antiviral activity against group O viruses. Efavirenz is not active against HIV2.
The antiviral activity in cell culture of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for emtricitabine were in the range of 0,0013–0,64 μM (0,0003–0,158 μg/ml). In medicine combination studies of emtricitabine with NRTIs (abacavir, lamivudine, stavudine, zalcitabine, and zidovudine), NNRTIs (delavirdine, efavirenz, and nevirapine), and PIs (amprenavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0,007–0,075 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0,007–1,5 μM).
The antiviral activity in cell culture of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0,04–8,5 μM. In medicine combination studies of tenofovir with NRTIs (abacavir, didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), NNRTIs (delavirdine, efavirenz, and nevirapine), and PIs (amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G and O (EC50 values ranged from 0,5–2,2 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from 1,6 μM to 4.9 μM).
HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture and in clinical studies. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral RT. In a clinical trial of treatment-naive patients resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure patients with greater than 400 copies/ml of HIV-1 RNA at Week 48 or early discontinuations. Genotypic resistance to efavirenz, predominantly the K103N substitution, was the most common form of resistance that developed. Resistance to efavirenz occurred in 9/12 (75%) analysed patients in the emtricitabine + tenofovir DF group and in 16/22 (73%) analysed patients in the zidovudine/lamivudine fixed-dose combination group. The M184V amino acid substitution, associated with resistance to emtricitabine and lamivudine, was observed in 2/12 (17%) analysed subject isolates in the emtricitabine + tenofovir DF group and in 7/22 (32%) analysed subject isolates in the zidovudine/lamivudine group. Through 48 weeks no patients developed a detectable K65R mutation in their HIV-1 as analysed through standard genotypic analysis. Insufficient data are available to assess the development of the K65R mutation upon prolonged exposure to this regimen.
In a clinical trial of treatment-naive subjects, isolates from 8/47 analysed patients receiving tenofovir DF developed the K65R substitution through 144 weeks of therapy; 7 of these occurred in the first 48 weeks of treatment and one at Week 96. In treatment experienced subjects, 14/304 (5%) of tenofovir DF treated subjects with virologic failure through Week 96 showed greater than 1,4 fold (median 2,7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a substitution in the HIV1 RT gene resulting in the K65R amino acid substitution.
Cross-resistance has been recognised among NNRTIs. Cross-resistance has also been recognised among certain NRTIs. The M184V/I and/or K65R substitutions selected in cell culture by the combination of emtricitabine and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either lamivudine or emtricitabine, and either abacavir or didanosine. Therefore, cross-resistance among these medicines may occur in patients whose virus harbours either or both of these amino acid substitutions.
In HIV-1 infected patients time-to-peak plasma concentrations are approximately 3–5 hours and steady-state plasma concentrations are reached in 6–10 days. In 35 patients receiving efavirenz 600 mg once daily, steady-state Cmax was 12,9 ± 3,7 μM (mean ± SD), Cmin was 5,6 ± 3,2 μM, and AUC was 184 ± 73 μM·hr. Efavirenz is highly bound (approximately 99,5–99,75%) to human plasma proteins, predominantly albumin. Following administration of 14C-labelled efavirenz, 14–34% of the dose is recovered in the urine (mostly as metabolites) and 16–61% is recovered in faeces (mostly as parent medicine). In vitro studies suggest CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism. Efavirenz has been shown to induce CYP enzymes, resulting in induction of its own metabolism. Efavirenz has a terminal half-life of 52–76 hours after single doses and 40–55 hours after multiple doses.
Following oral administration, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. Following multiple dose oral administration of emtricitabine to 20 HIV-1 infected subjects, the steady-state plasma emtricitabine Cmax 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 post-dose was 0,09 μg/ml. The mean absolute bioavailability of emtricitabine was 93%. In vitro binding of emtricitabine to human plasma proteins is less than 4% and is independent of concentration over the range of 0,02−200 μg/ml. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3′-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with normal renal function of 213 ± 89 ml/min (mean ± SD). Following a single oral dose, the plasma emtricitabine half-life is approximately 10 hours.
Following oral administration of a single 300 mg dose of tenofovir DF to HIV-1 infected patients in the fasted state, maximum serum concentrations (Cmax) were achieved in 1,0 ± 0,4 hrs (mean ± SD) and Cmax and AUC values were 296 ± 90 ng/ml and 2287 ± 685 ng•hr/ml, respectively. The oral bioavailability of tenofovir from tenofovir DF in fasted subjects is approximately 25%. In vitro binding of tenofovir to human plasma proteins is less than 0,7% and is independent of concentration over the range of 0,01–25 μg/ml. Approximately 70−80% of the intravenous dose of tenofovir is recovered as unchanged medicine in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with normal renal function of 243 ± 33 ml/min (mean ± SD). Following a single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours.
Efavirenz, emtricitabine and tenofovir disoproxil fumarate fixed dose combination tablet has not been evaluated in the presence of food. Administration of efavirenz tablets with a high fat meal increased the mean AUC and Cmax of efavirenz by 28% and 79%, respectively, compared to administration in the fasted state. Compared to fasted administration, dosing of tenofovir DF and emtricitabine in combination with either a high fat meal or a light meal increased the mean AUC and Cmax of tenofovir by 35% and 15%, respectively, without affecting emtricitabine exposures.
Pharmacokinetic studies of tenofovir DF have not been performed in paediatric patients (less than 18 years). Efavirenz has not been studied in paediatric patients below 3 years of age or who weigh less than 13 kg. Emtricitabine has been studied in paediatric patients from 3 months to 17 years of age. Efavirenz, emtricitabine and tenofovir disoproxil fumarate fixed dose combination tablet is not recommended for paediatric administration. Pharmacokinetics of efavirenz, emtricitabine and tenofovir have not been fully evaluated in the elderly (more than 65 years) (see section 4.4).
Efavirenz: The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal.
Emtricitabine and Tenofovir disoproxil fumarate: The pharmacokinetics of emtricitabine and tenofovir DF are altered in patients with renal impairment. In patients with creatinine clearance below 50 ml/min, Cmax and AUC0-∞ of emtricitabine and tenofovir were increased (see section 4.3 and section 4.4, Renal Impairment).
Efavirenz: The pharmacokinetics of efavirenz have not been adequately studied in patients with hepatic impairment (see section 4.4, Liver Enzymes).
Emtricitabine: The pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment; however, emtricitabine is not significantly metabolised by liver enzymes, so the impact of liver impairment should be limited.
Tenofovir disoproxil fumarate: The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir DF have been studied in non-HIV infected patients with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients.
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