Not applicable.
Non-clinical safety pharmacology studies reveal no special hazard for humans. Findings in repeated dose toxicity studies in rats, dogs and monkeys at exposure levels greater than or equal to clinical exposure levels and with possible relevance to clinical use include renal and bone toxicity and a decrease in serum phosphate concentration. Bone toxicity was diagnosed as osteomalacia (monkeys) and reduced bone mineral density (BMD) (rats and dogs). The bone toxicity in young adult rats and dogs occurred at exposures >5-fold the exposure in paediatric or adult patients; bone toxicity occurred in juvenile infected monkeys at very high exposures following subcutaneous dosing (>40-fold the exposure in patients). 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 BMD.
Genotoxicity studies revealed positive results in the in vitro mouse lymphoma assay, equivocal results in one of the strains used in the Ames test, and weakly positive results in an UDS test in primary rat hepatocytes. However, it was negative in an in vivo mouse bone marrow micronucleus assay.
Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at an extremely high dose in mice. These tumours are unlikely to be of relevance to humans.
Reproductive studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal parameters. However, Atripla (tenofovir) disoproxil reduced the viability index and weight of pups in peri-postnatal toxicity studies at maternally toxic doses.
The active substance Atripla (tenofovir) disoproxil and its main transformation products are persistent in the environment.
Non-clinical safety pharmacology studies reveal no special hazard for humans. Findings in repeated dose toxicity studies in rats, dogs and monkeys at exposure levels greater than or equal to clinical exposure levels and with possible relevance to clinical use include renal and bone toxicity and a decrease in serum phosphate concentration. Bone toxicity was diagnosed as osteomalacia (monkeys) and reduced bone mineral density (BMD) (rats and dogs). The bone toxicity in young adult rats and dogs occurred at exposures > 5-fold the exposure in paediatric or adult patients; bone toxicity occurred in juvenile infected monkeys at very high exposures following subcutaneous dosing (> 40-fold the exposure in patients). 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 BMD.
Genotoxicity studies revealed positive results in the in vitro mouse lymphoma assay, equivocal results in one of the strains used in the Ames test, and weakly positive results in an UDS test in primary rat hepatocytes. However, it was negative in an in vivo mouse bone marrow micronucleus assay.
Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at an extremely high dose in mice. These tumours are unlikely to be of relevance to humans.
Reproductive studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal parameters. However, tenofovir disoproxil fumarate reduced the viability index and weight of pups in peri-postnatal toxicity studies at maternally toxic doses.
The active substance tenofovir disoproxil fumarate and its main transformation products are persistent in the environment.
Atripla (tenofovir) disoproxil is a water soluble ester prodrug which is rapidly converted in vivo to Atripla (tenofovir).
Atripla (tenofovir) is converted intracellularly to Atripla (tenofovir) monophosphate and to the active component, Atripla (tenofovir) diphosphate.
Absorption
Following oral administration of Atripla (tenofovir) disoproxil to HIV infected patients, Atripla (tenofovir) disoproxil is rapidly absorbed and converted to Atripla (tenofovir). Administration of multiple doses of Atripla (tenofovir) disoproxil with a meal to HIV infected patients resulted in mean (%CV) Atripla (tenofovir) Cmax, AUC, and Cmin values of 326 (36.6%) ng/ml, 3,324 (41.2%) ng·h/ml and 64.4 (39.4%) ng/ml, respectively. Maximum Atripla (tenofovir) concentrations are observed in serum within one hour of dosing in the fasted state and within two hours when taken with food. The oral bioavailability of Atripla (tenofovir) from Atripla (tenofovir) disoproxil in fasted patients was approximately 25%. Administration of Atripla (tenofovir) disoproxil with a high fat meal enhanced the oral bioavailability, with an increase in Atripla (tenofovir) AUC by approximately 40% and Cmax by approximately 14%. Following the first dose of Atripla (tenofovir) disoproxil in fed patients, the median Cmax in serum ranged from 213 to 375 ng/ml. However, administration of Atripla (tenofovir) disoproxil with a light meal did not have a significant effect on the pharmacokinetics of Atripla (tenofovir).
Distribution
Following intravenous administration the steady-state volume of distribution of Atripla (tenofovir) was estimated to be approximately 800 ml/kg. After oral administration of Atripla (tenofovir) disoproxil, Atripla (tenofovir) is distributed to most tissues with the highest concentrations occurring in the kidney, liver and the intestinal contents (preclinical studies). In vitro protein binding of Atripla (tenofovir) to plasma or serum protein was less than 0.7 and 7.2%, respectively, over the Atripla (tenofovir) concentration range 0.01 to 25 μg/ml.
Biotransformation
In vitro studies have determined that neither Atripla (tenofovir) disoproxil nor Atripla (tenofovir) are substrates for the CYP450 enzymes. Moreover, at concentrations substantially higher (approximately 300-fold) than those observed in vivo, Atripla (tenofovir) did not inhibit in vitro drug metabolism mediated by any of the major human CYP450 isoforms involved in drug biotransformation (CYP3A4, CYP2D6, CYP2C9, CYP2E1, or CYP1A1/2). Atripla (tenofovir) disoproxil at a concentration of 100 μmol/l had no effect on any of the CYP450 isoforms, except CYP1A1/2, where a small (6%) but statistically significant reduction in metabolism of CYP1A1/2 substrate was observed. Based on these data, it is unlikely that clinically significant interactions involving Atripla (tenofovir) disoproxil and medicinal products metabolised by CYP450 would occur.
Elimination
Atripla (tenofovir) is primarily excreted by the kidney by both 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 Atripla (tenofovir). Following oral administration the terminal half-life of Atripla (tenofovir) is approximately 12 to 18 hours.
Studies have established the pathway of active tubular secretion of Atripla (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).
Linearity/non-linearity
The pharmacokinetics of Atripla (tenofovir) were independent of Atripla (tenofovir) disoproxil dose over the dose range 75 to 600 mg and were not affected by repeated dosing at any dose level.
Age
Pharmacokinetic studies have not been performed in the elderly (over 65 years of age).
Gender
Limited data on the pharmacokinetics of Atripla (tenofovir) in women indicate no major gender effect.
Ethnicity
Pharmacokinetics have not been specifically studied in different ethnic groups.
Paediatric population
HIV-1: Steady-state pharmacokinetics of Atripla (tenofovir) were evaluated in 8 HIV-1 infected adolescent patients (aged 12 to < 18 years) with body weight > 35 kg. Mean (± SD) Cmax and AUCtau are 0.38 ± 0.13 μg/ml and 3.39 ± 1.22 μg·h/ml, respectively. Atripla (tenofovir) exposure achieved in adolescent patients receiving oral daily doses of Atripla (tenofovir) disoproxil 245 mg was similar to exposures achieved in adults receiving once-daily doses of Atripla (tenofovir) disoproxil 245 mg.
Chronic hepatitis B: Steady-state Atripla (tenofovir) exposure in HBV infected adolescent patients (12 to < 18 years of age) receiving an oral daily dose of Atripla (tenofovir) disoproxil 245 mg was similar to exposures achieved in adults receiving once-daily doses of Atripla (tenofovir) disoproxil 245 mg.
Pharmacokinetic studies have not been performed with Atripla (tenofovir) disoproxil 245 mg tablets in children under 12 years or with renal impairment.
Renal impairment
Pharmacokinetic parameters of Atripla (tenofovir) were determined following administration of a single dose of Atripla (tenofovir) disoproxil 245 mg to 40 non-HIV, non-HBV infected adult 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) Atripla (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 Cmin 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 Atripla (tenofovir) concentrations substantially increased over 48 hours achieving a mean Cmax of 1,032 ng/ml and a mean AUC0-48h of 42,857 ng·h/ml.
It is recommended that the dosing interval for Atripla (tenofovir) disoproxil 245 mg is modified in adult patients with creatinine clearance < 50 ml/min or in patients who already have ESRD and require dialysis.
The pharmacokinetics of Atripla (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.
The pharmacokinetics of Atripla (tenofovir) in paediatric patients with renal impairment have not been studied. No data are available to make dose recommendations.
Hepatic impairment
A single 245 mg dose of Atripla (tenofovir) disoproxil was administered to non-HIV, non-HBV infected adult patients with varying degrees of hepatic impairment defined according to Child-Pugh-Turcotte (CPT) classification. Atripla (tenofovir) pharmacokinetics were not substantially altered in subjects with hepatic impairment suggesting that no dose adjustment is required in these subjects. The mean (%CV) Atripla (tenofovir) Cmax and AUC0-∞ 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 2,310 (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
In non-proliferating human peripheral blood mononuclear cells (PBMCs) the half-life of Atripla (tenofovir) diphosphate was found to be approximately 50 hours, whereas the half-life in phytohaemagglutinin-stimulated PBMCs was found to be approximately 10 hours.
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. Administration of multiple doses of tenofovir disoproxil fumarate with a meal to HIV infected patients resulted in mean (%CV) tenofovir Cmax, AUC, and Cmin values of 326 (36.6%) ng/ml, 3,324 (41.2%) ng·h/ml and 64.4 (39.4%) ng/ml, respectively. Maximum tenofovir concentrations are observed in serum within one hour of dosing in the fasted state and within two hours when taken with food. 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 Cmax by approximately 14%. Following the first dose of tenofovir disoproxil fumarate in fed patients, the median Cmax in serum ranged from 213 to 375 ng/ml. However, administration of tenofovir disoproxil fumarate with a light meal did not have a significant effect on the pharmacokinetics of tenofovir.
Distribution
Following intravenous administration the steady-state volume of distribution of tenofovir was estimated to be approximately 800 ml/kg. After oral administration of tenofovir disoproxil fumarate, tenofovir is distributed to most tissues with the highest concentrations occurring in the kidney, liver and the intestinal contents (preclinical studies). 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.
Biotransformation
In vitro studies have determined that neither tenofovir disoproxil fumarate nor tenofovir are substrates for the CYP450 enzymes. Moreover, at concentrations substantially higher (approximately 300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the major human CYP450 isoforms involved in drug biotransformation (CYP3A4, CYP2D6, CYP2C9, CYP2E1, or CYP1A1/2). Tenofovir disoproxil fumarate at a concentration of 100 µmol/l had no effect on any of the CYP450 isoforms, except CYP1A1/2, where a small (6%) but statistically significant reduction in metabolism of CYP1A1/2 substrate was observed. Based on these data, it is unlikely that clinically significant interactions involving tenofovir disoproxil fumarate and medicinal products metabolised by CYP450 would occur.
Elimination
Tenofovir is primarily excreted by the kidney by both 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).
Linearity/non-linearity
The pharmacokinetics of tenofovir were independent of tenofovir disoproxil fumarate dose over the dose range 75 to 600 mg and were not affected by repeated dosing at any dose level.
Gender
Limited data on the pharmacokinetics of tenofovir in women indicate no major gender effect.
Ethnicity
Pharmacokinetics have not been specifically studied in different ethnic groups.
Paediatric population
Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected adolescent patients (aged 12 to < 18 years) with body weight > 35 kg and in 23 HIV-1 infected children aged 2 to < 12 years (see Table 3 below). Tenofovir exposure achieved in these paediatric patients receiving oral daily doses of tenofovir disoproxil 245 mg (as fumarate) or 6.5 mg/kg body weight tenofovir disoproxil (as fumarate) up to a maximum dose of 245 mg was similar to exposures achieved in adults receiving once-daily doses of tenofovir disoproxil 245 mg (as fumarate).
Table 3: Mean (± SD) tenofovir pharmacokinetic parameters by age groups for paediatric patients
| Dose and formulation | 245 mg film-coated tablet 12 to < 18 years (n = 8) | 6.5 mg/kg granules 2 to < 12 years (n = 23) |
| Cmax (μg/ml) | 0.38 ± 0.13 | 0.24 ± 0.13 |
| AUCtau (μg·h/ml) | 3.39 ± 1.22 | 2.59 ± 1.06 |
Pharmacokinetic studies have not been performed in children under 2 years.
Renal impairment
Pharmacokinetic parameters of tenofovir were determined following administration of a single dose of tenofovir disoproxil 245 mg to 40 non-HIV infected adult 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 pharmacokinetics of tenofovir in non-haemodialysis adult patients with creatinine clearance < 10 ml/min and in patients with ESRD managed by peritoneal or other forms of dialysis have not been studied.
The pharmacokinetics of tenofovir in paediatric patients with renal impairment have not been studied. No data are available to make dose recommendations.
Hepatic impairment
A single 245 mg dose of tenofovir disoproxil was administered to non-HIV infected adult patients with varying degrees of hepatic impairment defined according to Child-Pugh-Turcotte (CPT) classification. Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic impairment suggesting that no dose adjustment is required in these subjects. The mean (%CV) tenofovir Cmax and AUC0-∞ 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 2,310 (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
In non-proliferating human peripheral blood mononuclear cells (PBMCs) the half-life of tenofovir diphosphate was found to be approximately 50 hours, whereas the half-life in phytohaemagglutinin-stimulated PBMCs was found to be approximately 10 hours.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
