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Tudofovir (Tenofovir Disoproxil Fumarate 300mg) TDF

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Brand: Aprazer
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Tenofovir disoproxil fumarate is recommended by who as a component of first-line antiretroviral therapy regimens and as an alternative component of second-line regimens for adults. It is also recommended as a component of alternative modes 1 and 2 lines for children over three years of age.

Pharmacological action
Tenofovir disoproxil fumarate is the fumarate salt of the tenofovir disoproxil prodrug. Tenofovir disoproxil is absorbed and converted to the active substance tenofovir, which is an analog of nucleoside monophosphate (nucleotide). Tenofovir is then converted to the active metabolite, tenofovir diphosphate, which is an obligate chain terminator, by constructively expressed cellular enzymes. Tenofovir diphosphate has an intracellular T1 / 2 of 10 h in activated mononuclear cells of peripheral blood and 50 h at rest. Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and hepatitis b virus (HBV) polymerase by competing for direct binding to the active site of the enzyme with a natural deoxyribonucleotide substrate and breaking the DNA chain after incorporation into it. Tenofovir diphosphate is a weak inhibitor of cell polymerases α, β and γ. In vitro analyses of tenofovir at concentrations up to 300 mmol / l also showed no effect on mitochondrial DNA synthesis or lactic acid production.

Activity against HIV in vitro

The concentration of tenofovir required for 50% inhibition (EC50-50% effective concentration) of the wild-type laboratory strain of HIV - 1IIIB is 1-6 mmol/l in the lymphoid cell line and 1.1 mmol/l against primary HIV-1 subtype b isolates in peripheral blood mononuclear cells. Tenofovir is also active against HIV-1 subtypes A, C, D, E, F, G, and O, as well as against Vichbal in primary monocytes/macrophages. Tenofovir also shows in vitro activity against HIV-2 with a 50% effective EC50 concentration of 4.9 mmol / l in MT-4 cells.

Activity against HBV in vitro

The antiviral activity of tenofovir against HBV in vitro was evaluated on the HepG2 2.2.15 cell line. ES50 values for tenofovir ranged from 0.14 to 1.5 mmol/l, and SS50 values (50% cytotoxic concentration) exceeded 100 mmol/l.

Resistance

HIV-1 strains with reduced sensitivity to tenofovir and k65r substitution in the reverse transcriptase gene were isolated in vitro and in some patients. Tenofovir disoproxil fumarate should be avoided in patients who have previously received antiretroviral therapy and whose strains contain the K65R mutation.

In clinical studies involving patients who had previously received antiretroviral therapy, the anti-HIV activity of 300 mg of tenofovir disoproxil fumarate against HIV-1 strains with resistance to nucleoside inhibitors was evaluated. The results showed that patients whose HIV expressed 3 or more mutations associated with thymidine analogues, including m41l or L210W substitutions in reverse transcriptase, showed a reduced response to 300 mg of tenofovir disoproxil fumarate therapy.

No mutations were found in the HBV polymerase associated with resistance to tenofovir disoproxil fumarate. In cell models, HBV variants expressing rtv173l, rtL180M and rtM204I/V substitutions associated with resistance to lamivudine and telbivudine demonstrated sensitivity to tenofovir 0.7-3.4 times higher than that of the wild-type virus.

HBV strains expressing substitutions of rtL180M, rtT184G, rtS202G/I, rtM204V and rtM250V associated with entecavir resistance demonstrated sensitivity to tenofovir 0.6-6.9 times greater than wild-type virus. HBV strains expressing rta181v and rtN236T substitutions associated with adefovir resistance demonstrated sensitivity to tenofovir 2.9-10 times greater than wild-type virus. Viruses containing rta181t substitution remained sensitive to tenofovir, the values of EC50 were 1.5 times greater than those of the wild-type virus.

Pharmacokinetics
Tenofovir disoproxil fumarate is a water-soluble prodrug ether that is rapidly converted in vivo to tenofovir and formaldehyde. Tenofovir is converted intracellularly to tenofovir monophosphate and to the active component, tenofovir diphosphate.

After ingestion of tenofovir disoproxil by HIV-infected patients, fumarate is rapidly absorbed and converted to tenofovir. Taking multiple doses of tenofovir disoproxil fumarate with food in HIV-infected patients resulted in average (coefficient of variation, % [CV,%]) values for tenofovir Cmax, AUC and Cmin of 326 (36.6%) ng/ml, 3324 (41.2%) ng/h/ml and 64.4 (39.4%) ng / ml, respectively. Cmax of tenofovir are observed in serum within 1 hour after fasting and within 2 hours when it is taken with food. When taking tenofovir disoproxil fumarate in patients on an empty stomach, the bioavailability was approximately 25%. Taking tenofovir disoproxil fumarate with a fat-rich diet increased bioavailability, with the AUC value of tenofovir increasing by approximately 40%, and the Cmax by approximately 14%. After the first dose of tenofovir disoproxil fumarate received after eating a fat-rich food, the median serum Cmax was in the range of 213 to 375 ng / ml. However, taking tenofovir disoproxil fumarate with low-calorie food does not significantly affect the pharmacokinetics of tenofovir.

After I/V application of Css, the distribution of tenofovir was estimated at approximately 800 ml/kg. After taking tenofovir disoproxil fumarate inside, tenofovir is distributed to many tissues, with the highest concentrations observed in the kidneys, liver and intestinal epithelium in different parts (preclinical studies). In vitro binding of tenofovir to plasma or serum proteins was less than 0.7 and 7.2%, respectively, in the range of tenofovir concentrations from 0.01 to 25 mcg / ml.

The pharmacokinetics of tenofovir did not depend on the dose of tenofovir disoproxil fumarate in the range from 75 to 600 mg and did not change with repeated administration at any dose level.

In vitro studies have shown that neither tenofovir disoproxil fumarate nor tenofovir are substrates of CYP450 enzymes. Moreover, at concentrations significantly higher (approximately 300 times) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the major human CYP450 isoforms involved in biotransformation (CYP3A4, CYP2D6, CYP2C9, CYP2E1 or CYP1A1/2). Tenofovir disoproxil fumarate at a concentration of 100 mmol / l did not affect any of the CYP450 isoforms except for CYP1A1/2, where there was a small (6%), but statistically significant decrease in the metabolism of the CYP1A1/2 substrate. Based on this information, we can conclude that there is a low probability of a clinically significant interaction between tenofovir disoproxil fumarate and drugs whose metabolism is mediated by CYP450.

Tenofovir is mainly excreted by the kidneys, both by filtration and by the active tubular transport system, while after intravenous administration, approximately 70-80% of the dose is excreted unchanged in the urine. Total clearance was estimated at approximately 230 ml / h / kg (approximately 300 ml / min). Renal clearance was estimated at approximately 160 ml / h / kg (about 210 ml / min), which exceeds the glomerular filtration rate. This indicates that tubular secretion is an important part of tenofovir elimination. After oral administration, the terminal T1/2 of tenofovir is from 12 to 18 hours.

Studies have found that the active tubular transport system of secretion involves the absorption of tenofovir by proximal tubular cells via human organic anion transporters (hOAT) 1 and 3, and its excretion into the urine using a protein marker of multidrug resistance 4 (MRP4).

Pharmacokinetics in special groups of patients

Limited data on the pharmacokinetics of tenofovir in women indicate that there is no significant effect on the sexual principle.

Pharmacokinetic parameters of tenofovir in the equilibrium state were evaluated in 8 children (aged 12 to 18 years) with a body weight of ≥35 kg, infected with HIV-1. The average (±SD) values of Cmax and AUCtau were 0.38±0.13 mcg / ml and 3.39±1.22 mcg×h / ml, respectively. The exposure of tenofovir that was achieved in adolescents receiving daily doses of 300 mg of tenofovir disoproxil fumarate inside was similar to the exposure that was achieved in adults receiving single daily doses of 300 mg of tenofovir disoproxil fumarate.

The equilibrium exposure of tenofovir in children (ages 12 to 18 years) infected with hepatitis b virus who received an oral daily dose of 300 mg of tenofovir disoproxil fumarate was similar to the exposure achieved in adults who received doses of 300 mg of tenofovir disoproxil fumarate once / day.

Tenofovir pharmacokinetics parameters were determined after administration of a single dose of 300 mg of tenofovir disoproxil fumarate to 40 adult patients without HIV and HBV infection with various degrees of renal impairment, which were determined according to the initial value of the CC (renal function is not impaired if the CC is >80 ml/min, mild violation - if the CC is 50-79 ml/min, moderate violation - with a CC of 30-49 ml/min and severe violation - with a CC of 10-29 ml/min). Compared with patients with normal renal function, the average (%CV) exposure of tenofovir increased from 2,185 (12%) ng×h/ml in individuals with CC >80 ml/min to 3,064 (30%) ng×h/ml, 6009 (42%) ng×h/ml, and 15,985 (45%) ng×h/ml in patients with mild, moderate, and severe renal impairment, respectively. It is expected that increasing the interval between administration of the drug will lead to higher Cmax in blood plasma and lower Cmin levels in patients with impaired renal function compared to patients with normal renal function. The clinical significance of this is unknown.

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