Avonza Mechanism of Action

Pharmacotherapeutic group: Antivirals for treatment of HIV infections, combinations. ATC code: J05AR.
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Efavirenz binds directly to reverse transcriptase and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by inducing a conformational change that causes a disruption of the enzyme's catalytic site. The activity of efavirenz does not compete with template or nucleoside triphosphates. HIV-2 reverse transcriptase and eukaryotic DNA polymerases (such as human DNA polymerases α, β, γ, or δ) are not inhibited by efavirenz.
Lamivudine, the negative enantiomer of 2'-deoxy-3'-thiacytidine, is a dideoxynucleoside analogue. Tenofovir disoproxil fumarate is converted in vivo to tenofovir, a nucleoside monophosphate (nucleotide) analogue of adenosine monophosphate.
Lamivudine and tenofovir are phosphorylated by cellular enzymes to form lamivudine triphosphate and tenofovir diphosphate, respectively. Lamivudine triphosphate and tenofovir diphosphate competitively inhibit HIV-1 reverse transcriptase (RT), resulting in DNA chain termination. Both substances are active against HIV-1 and HIV-2, as well as against hepatitis B virus.
Resistance: A large proportion of patients experiencing virological failure while receiving efavirenz will develop resistance to efavirenz. The main mutations occurring are K103N, G190S/A/E and Y188L; a single one of these mutations is sufficient to cause high-grade resistance. The cross resistance between efavirenz and nevirapine or delavirdine is extensive; therefore patients who have experienced virological failure with either of these drugs, are likely to harbour virus not susceptible to efavirenz, and vice versa. With an accumulating number of NNRTI mutations, the susceptibility to etravirine will also be compromised.
Due to the long half-life of efavirenz, a period of functional monotherapy with efavirenz may follow upon discontinuation of effective efavirenz-containing antiretroviral therapy. This may cause significant resistance, and compromise the efficacy of future efavirenz, nevirapine or delavirdine therapy (see Precautions).
In many cases when a lamivudine-containing treatment regimen fails, the M184V mutation will be selected for at an early stage. M184V causes high-level resistance to lamivudine (>300-fold reduced susceptibility). Virus with M184V replicates less well than does wild type virus. M184V causes high-level resistance to lamivudine (>300-fold reduced susceptibility).
In vitro data tend to suggest that the continuation of lamivudine in an antiretroviral regimen despite the development of M184V might provide residual anti-retroviral activity (likely through impaired viral fitness). The clinical relevance of these findings is not established.
Cross-resistance conferred by the M184V mutation is limited within the nucleoside/nucleotide inhibitor class of antiretroviral agents. M184V confers full cross-resistance against emtricitabine. Zidovudine and stavudine maintain their antiretroviral activities against lamivudine-resistant HIV-1. Abacavir maintains its antiretroviral activities against lamivudine-resistant HIV-1 harbouring only the M184V mutation. The M184V mutant shows a <4-fold decrease in susceptibility to didanosine; the clinical significance of this is unknown.
The K65R mutation is selected in vitro when HIV-1 is cultured in the presence of increasing tenofovir concentrations. It may also emerge in vivo upon virological failure of a treatment regimen including tenofovir. K65R reduces tenofovir susceptibility in vitro approximately 2-fold, and has been associated with a lack of response to tenofovir-containing regimens.
Clinical studies in treatment-experienced patients have assessed the anti-HIV activity of tenofovir against strains of HIV-1 with thymidine analogue mutations (TAMs), which are not selected for by tenofovir. Patients whose HIV expressed 3 or more TAMs that included either the M41L or L210W mutation showed reduced response to tenofovir.
Clinical efficacy: When tenofovir disoproxil fumarate and lamivudine were combined with efavirenz in treatment-naïve patients with HIV-1, the proportion of patients (ITT) with HIV-RNA <50 copies/ml were 76.3% and 67.8% at 48 and 144 weeks, respectively.
No specific studies with the combination tenofovir disoproxil fumarate, emtricitabine and efavirenz have been conducted in adolescents.
Pharmacokinetics: Efavirenz: Absorption and Bioavailability: Bioavailability is 40% to 45% without food. Food increases absorption significantly. 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.
Following single dose of administration of one tablet of Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg tablets in healthy volunteers, mean (±SD) efavirenz C_max value was 1584.052 (± 551.8406) ng/ml and the corresponding value for AUC_0-72h was 35676.476 (± 9531.4953) ng.h/ml. The mean efavirenz t_max value was 4.500 (range: 0.500 - 6.000) hours.
Distribution: Efavirenz is highly bound (more than 99%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients who received efavirenz 200 to 600 mg once daily for at least one month, mean cerebrospinal fluid concentrations 0.69% of the corresponding plasma concentration were reached. This proportion is approximately 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma.
Metabolism: Efavirenz is principally metabolised by the cytochrome P450 system to hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. In vitro studies, supported by in vivo observations, suggest that CYP3A4 and CYP2B6 are the major isoenzymes responsible for efavirenz metabolism. Efavirenz has been shown to induce cytochrome P450 enzymes, resulting in the induction of its own metabolism.
Elimination: Efavirenz has a relatively long terminal half-life of 17 to 154 hours after single doses, and 40 - 55 hours after multiple doses. In individuals with certain mutant CYP2B6 genotypes (e.g. the T/T genotype at G516T) the terminal half-life may be substantially prolonged, and drug exposures higher. These genotypes are particularly common among Africans and African Americans. In patients with liver impairment, lower efavirenz clearance and higher drug exposures have been reported.
Approximately 14 - 34% of a radio-labelled dose of efavirenz was recovered in the urine and less than 1% of the dose was excreted in urine as unchanged efavirenz.
Lamivudine: Absorption and Bioavailability: Lamivudine is rapidly absorbed following oral administration. Bioavailability is between 80 and 85%. Following single dose administration of one tablet of Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg tablets in healthy volunteers, the mean (±SD) lamivudine C_max value was 2152.270 (± 608.3966) ng/ml and the corresponding value for AUC was 12098.895 (± 3034.3792) ng.h/ml. The mean (±SD) lamivudine t_max value was 1.750 (range: 0.830 - 4.500) hours.
Co-administration of lamivudine with food results in a delay of t_max and a lower C_max (decreased by 47%). However, the extent (based on the AUC) of lamivudine absorbed is not influenced.
Distribution: Intravenous studies with lamivudine showed that the mean apparent volume of distribution is 1.3 l/kg. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited binding to the major plasma protein albumin (< 36% serum albumin in vitro).
Metabolism: Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominantly cleared unchanged by renal excretion. The likelihood of metabolic drug interactions with lamivudine is low due to the small extent of hepatic metabolism (5 - 10%) and low plasma protein binding.
Elimination: The observed lamivudine half-life of elimination is 5 to 7 hours. The half-life of intracellular lamivudine triphosphate has been estimated to approximately 22 hours. The mean systemic clearance of lamivudine is approximately 0.32 l/h/kg, with predominantly renal clearance (> 70%), including tubular secretion through the organic cationic transport system.
Special populations: Renal impairment: Studies in patients with renal impairment show that lamivudine elimination is affected by renal dysfunction. Dose reduction is recommended for patients with creatinine clearance ≤50 ml/min (see Dosage & Administration).
Tenofovir disoproxil fumarate: Tenofovir disoproxil fumarate is a water-soluble ester prodrug, which is rapidly converted in vivo to tenofovir and formaldehyde. Tenofovir is converted intracellularly to tenofovir monophosphate and to the active component, tenofovir diphosphate.
Absorption: Following oral administration of tenofovir disoproxil fumarate to HIV infected patients, tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate in fasted patients was approximately 25%.
Administration of tenofovir disoproxil fumarate with a high fat meal enhanced the oral bioavailability, with an increase in tenofovir AUC by approximately 40% and C_max by approximately 14%.
Following single dose administration of one tablet of Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg tablets in healthy volunteers, the mean (±SD) tenofovir C_max value was 276.176 (± 77.2409) ng/ml and the corresponding value for AUC was 2269.573 (± 583.3770) ng.h/ml. The mean (±SD) tenofovir tmax value was 1.250 (range: 0.500 - 3.000) hours.
Distribution: Following intravenous administration the steady-state volume of distribution of tenofovir was estimated to be approximately 800 ml/kg. In vitro protein binding of tenofovir to plasma or serum protein was less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 μg/ml.
Elimination: Tenofovir is primarily excreted by the kidney, both by filtration and an active tubular transport system with approximately 70-80% of the dose excreted unchanged in urine following intravenous administration. Total clearance has been estimated to be approximately 230 ml/h/kg (approximately 300 ml/min). Renal clearance has been estimated to be approximately 160 ml/h/kg (approximately 210 ml/min), which is in excess of the glomerular filtration rate. This indicates that active tubular secretion is an important part of the elimination of tenofovir. Following oral administration the terminal half-life of tenofovir is approximately 12 to 18 hours.
Studies have established the pathway of active tubular secretion of tenofovir to be influx into proximal tubule cell by the human organic anion transporters (hOAT) 1 and 3 and efflux into the urine by the multidrug resistant protein 4 (MRP 4). In vitro studies have determined that neither tenofovir disoproxil fumarate nor tenofovir are substrates for the CYP450 enzymes.
Age and gender: Limited data on the pharmacokinetics of tenofovir in women indicate no major gender effect. Tenofovir exposure achieved in adolescent patients receiving oral daily doses of tenofovir 300 mg was similar to exposures achieved in adults receiving once-daily doses of tenofovir 300 mg.
Pharmacokinetic studies have not been performed in children or in the elderly (over 65 years). Pharmacokinetics have not been specifically studied in different ethnic groups.
Renal impairment: Pharmacokinetic parameters of tenofovir were determined following administration of a single dose of tenofovir disoproxil fumarate 300 mg to 40 non-HIV, non-HBV infected patients with varying degrees of renal impairment defined according to baseline creatinine clearance (CrCl) (normal renal function when CrCl > 80 ml/min; mild with CrCl = 50-79 ml/min; moderate with CrCl = 30-49 ml/min and severe with CrCl = 10-29 ml/min). Compared with patients with normal renal function, the mean (%CV) tenofovir exposure increased from 2,185 (12%) ng·h/ml in subjects with CrCl > 80 ml/min to respectively 3,064 (30%) ng·h/ml, 6,009 (42%) ng·h/ml and 15,985 (45%) ng·h/ml in patients with mild, moderate and severe renal impairment. The dosing recommendations in patients with renal impairment, with increased dosing interval, are expected to result in higher peak plasma concentrations and lower C_min levels in patients with renal impairment compared with patients with normal renal function. The clinical implications of this are unknown.
In patients with end-stage renal disease (ESRD) (CrCl < 10 ml/min) requiring haemodialysis, between dialysis tenofovir concentrations substantially increased over 48 hours achieving a mean C_max of 1,032 ng/ml and a mean AUC_0-48h of 42,857 ng·h/ml. It is recommended that the dosing interval for tenofovir disoproxil fumarate 300 mg is modified in patients with creatinine clearance < 50 ml/min or in patients who already have ESRD and require dialysis (see Dosage & Administration).
The pharmacokinetics of tenofovir in non-haemodialysis patients with creatinine clearance < 10 ml/min and in patients with ESRD managed by peritoneal or other forms of dialysis have not been studied.
Hepatic impairment: A single 300 mg dose of tenofovir disoproxil fumarate was administered to non-HIV, non-HBV infected patients with varying degrees of hepatic impairment defined according to Child-Pugh Turcotte (CPT) classification. Tenofovir pharmacokinetic parameters were not substantially altered in subjects with hepatic impairment suggesting that no dose adjustment is required in these subjects. The mean (%CV) tenofovir C_max and AUC_0-∞ values were 223 (34.8%) ng/ml and 2,050 (50.8%) ng·h/ml, respectively, in normal subjects compared with 289 (46.0%) ng/ml and 231 (43.5%) ng·h/ml in subjects with moderate hepatic impairment, and 305 (24.8%) ng/ml and 2,740 (44.0%) ng·h/ml in subjects with severe hepatic impairment.
Intracellular pharmacokinetics: Tenofovir diphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheral blood mononuclear cells (PBMCs).
Toxicology: Preclinical safety data: Efavirenz: Preclinical data revealed no special hazard for humans other than those observed in clinical studies based on conventional studies of safety, pharmacology, repeated dose toxicity, and genotoxicity. In reproductive toxicology studies, 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. Carcinogenicity studies showed an increased incidence of hepatic and pulmonary tumours in female mice, but not in male mice.
Lamivudine: Administration of lamivudine in animal toxicity studies at high doses was not associated with any major organ toxicity. Lamivudine was not mutagenic in bacterial tests, but showed activity in an in vitro cytogenetic assay and the mouse lymphoma assay. Lamivudine was not genotoxic in vitro at doses that gave plasma concentrations around 40-50 times higher than the anticipated clinical plasma levels. As the in vitro mutagenic activity of lamivudine could not be confirmed in in vivo tests, it is concluded that lamivudine should not represent a genotoxic hazard to patients undergoing treatment.
The results of long-term carcinogenicity studies in rats and mice did not show any carcinogenic potential relevant for humans.
Tenofovir: Preclinical studies conducted in rats, dogs and monkeys revealed target organ effects in gastrointestinal tract, kidney, bone and a decrease in serum phosphate concentration. Bone toxicity was diagnosed as osteomalacia (monkeys) and reduced bone mineral density (rats and dogs). Findings in the rat and monkey studies indicated that there was a substance-related decrease in intestinal absorption of phosphate with potential secondary reduction in bone mineral density. However, no conclusion could be drawn on the mechanism(s) underlying these toxicities.
Reproductive studies were conducted in rats and rabbits. There were no effects on mating or fertility parameters or on any pregnancy or foetal parameter. There were no gross foetal alterations of soft or skeletal tissues. Tenofovir disoproxil fumarate reduced the viability index and weight of pups in peri-post natal toxicity studies.
Genotoxicity studies have shown that tenofovir disoproxil fumarate was negative in the in vivo mouse bone marrow micronucleus assay but was positive for inducing forward mutations in the in vitro L5178Y mouse lymphoma cell assay in the presence or absence of S9 metabolic activation. Tenofovir disoproxil fumarate was positive in the Ames test (strain TA 1535) in two out of three studies, once in the presence of S9 mix (6.2- to 6.8-fold increase) and once without S9 mix. Tenofovir disoproxil fumarate was also weakly positive in an in vivo/in vitro unscheduled DNA synthesis test in primary rat hepatocytes.
Tenofovir disoproxil fumarate did not show any carcinogenic potential in a long-term oral carcinogenicity study in rats. A long-term oral carcinogenicity study in mice showed a low incidence of duodenal tumours, considered likely related to high local concentrations of tenofovir disoproxil fumarate in the gastrointestinal tract at a dose of 600 mg/kg/day. While the mechanism of tumour formation is uncertain, the findings are unlikely to be of relevance to humans.