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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 2-line regimens for adults. It is also recommended as a component of alternative modes 1 and 2 lines for children older than three years.
Pharmachologic effect
Tenofovir disoproxil fumarate is a fumarate salt of the prodrug of tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted into the active substance tenofovir, which is an analog of the nucleoside monophosphate (nucleotide). Tenofovir is then converted into an active metabolite, tenofovir diphosphate, which is an obligate chain terminator, using structurally expressed cellular enzymes. Tenofovir diphosphate has intracellular T1 / 2 10 hours in activated peripheral blood mononuclear cells and 50 hours at rest. Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and hepatitis B virus polymerase (HBV) by competing for direct binding to the active site of the enzyme with the natural substrate deoxyribonucleotide and breaking the DNA strand after incorporation into it. Tenofovir diphosphate is a weak inhibitor of cell polymerases α, β and γ. In in vitro assays, tenofovir at concentrations up to 300 μmol / L also showed no effect on mitochondrial DNA synthesis or on lactic acid production.
In vitro anti-HIV activity
The concentration of tenofovir required for 50% inhibition (EC50 - 50% effective concentration) of the wild-type laboratory HIV-1IIIB strain is 1-6 μmol / L in the lymphoid cell line and 1.1 μmol / L against the primary HIV-1 subtype B isolates in mononuclear peripheral blood cells. Tenofovir is also active against HIV-1 subtypes A, C, D, E, F, G, and O, as well as against HIVBaL in primary monocytes / macrophages. Tenofovir also exhibits in vitro activity against HIV-2 with a 50% effective EC50 concentration of 4.9 μmol / L in MT-4 cells.
In vitro anti-HBV activity
The antiviral activity of tenofovir against HBV in vitro was evaluated on a HepG2 2.2.15 cell line. EC50 values for tenofovir ranged from 0.14 to 1.5 μmol / L, and CC50 values (50% cytotoxic concentration) exceeded 100 μmol / 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. Avoid the use of tenofovir disoproxyl fumarate in patients previously treated with antiretroviral therapy, strains of which contain the K65R mutation.
In clinical studies involving patients previously treated with antiretroviral therapy, anti-HIV activity of 300 mg tenofovir disoproxyl fumarate against HIV-1 strains with resistance to nucleoside inhibitors was evaluated. The results showed that patients with HIV expressed 3 or more mutations associated with thymidine analogs, including substitutions of M41L or L210W in reverse transcriptase, showed a reduced response to therapy with 300 mg of tenofovir disoproxil fumarate.
No mutations were detected in HBV polymerase associated with tenofovir disoproxyl fumarate resistance. In cell models, HBV variants expressing rtV173L, rtL180M, and rtM204I / V substitutions associated with resistance to lamivudine and telbivudine demonstrated tenofovir sensitivity 0.7–3.4 times that of wild-type virus.
HBV strains expressing the substitutions rtL180M, rtT184G, rtS202G / I, rtM204V and rtM250V associated with resistance to entecavir showed a sensitivity to tenofovir 0.6-6.9 times greater than the wild-type virus. HBV strains expressing rtA181V and rtN236T substitutions associated with adefovir resistance showed tenofovir sensitivity 2.9-10 times greater than wild-type virus. Viruses containing rtA181T substitution remained sensitive to tenofovir, EC50 values were 1.5 times greater than that of the wild-type virus.
Pharmacokinetics
Tenofovir disoproxil fumarate is a water-soluble prodrug ester that is rapidly converted in vivo to tenofovir and formaldehyde. Tenofovir is converted intracellularly into tenofovir monophosphate and the active component is tenofovir diphosphate.
After oral administration of tenofovir disoproxil by HIV-infected patients, fumarate is rapidly absorbed and converted into tenofovir. Taking multiple doses of tenofovir disoproxil fumarate with food by HIV-infected patients led to average (coefficient of variation,% [CV,%]) values for tenofovir Cmax, AUC and Cmin 326 (36.6%) ng / ml, 3324 (41.2%) ng × h / ml and 64.4 (39.4%) ng / ml, respectively. Cmax of tenofovir is observed in blood serum within 1 hour after fasting and within 2 hours when taken with food. When tenofovir disoproxyl fumarate was taken by patients on an empty stomach, the bioavailability was approximately 25%. The intake of tenofovir disoproxil fumarate with a fat-rich diet increased bioavailability, with the AUC of tenofovir increasing by approximately 40% and Cmax by approximately 14%. After the first dose of tenofovir disoproxyl fumarate obtained after ingestion of a diet rich in fats, the median serum Cmax was in the range of values from 213 to 375 ng / ml. However, taking tenofovir disoproxyl fumarate with low-calorie foods does not significantly affect the pharmacokinetics of tenofovir.
After iv administration of Css, the distribution of tenofovir was estimated at approximately 800 ml / kg. After tenofovir disoproxil fumarate is taken, tenofovir is distributed into many tissues, with the highest concentrations being observed in the kidneys, liver, and intestinal epithelium in different areas (preclinical studies). In vitro binding of tenofovir to plasma proteins or blood serum was less than 0.7 and 7.2%, respectively, in the range of tenofovir concentrations from 0.01 to 25 μg / ml.
The pharmacokinetics of tenofovir did not depend on the dose of tenofovir disoproxyl fumarate in the range from 75 to 600 mg and did not change upon 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 (about 300 times) that observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the major isoforms of human CYP450 involved in biotransformation (CYP3A4, CYP2D6, CYP2C9, CYP2E1 or CYP1A1 / 2). Tenofovir disoproxyl fumarate at a concentration of 100 μmol / L did not affect any of the CYP450 isoforms, with the exception of CYP1A1 / 2, where a slight (6%) but statistically significant decrease in the metabolism of the CYP1A1 / 2 substrate was observed. Based on this information, it can be concluded 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 excreted mainly by the kidneys, both by filtration and by the active tubular transport system, and after iv administration, approximately 70-80% of the dose is excreted unchanged in the urine. The 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 suggests that tubular secretion is an important part of tenofovir excretion. After oral administration, the terminal T1 / 2 of tenofovir is from 12 to 18 hours.
Studies have shown that an active tubular secretion transport system involves the uptake of tenofovir by the proximal tubule cells through organic human anion transporters (hOATs) 1 and 3, and its excretion into the urine using a marker marker protein of multidrug resistance 4 (MRP4).
Pharmacokinetics in special patient groups
Limited data on the pharmacokinetics of tenofovir in women indicate the absence of a significant sexual effect.
The pharmacokinetic parameters of tenofovir in equilibrium were evaluated in 8 children (age 12 to 18 years) with a body weight of ≥35 kg infected with HIV-1. The mean (± SD) values of Cmax and AUCtau were 0.38 ± 0.13 μg / ml and 3.39 ± 1.22 μg × h / ml, respectively. The exposure of tenofovir that was achieved in adolescents receiving a daily dose of 300 mg of tenofovir disoproxil fumarate inward was similar to that of adults who received a single daily dose of 300 mg of tenofovir disoproxil fumarate.
The equilibrium exposure of tenofovir in children (12 to 18 years old) infected with hepatitis B virus who received an oral daily dose of 300 mg of tenofovir disoproxyl fumarate was similar to that achieved in adults who received doses of 300 mg of tenofovir disoproxil fumarate once a day. / day
Tenofovir pharmacokinetics 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 impaired renal function of varying degrees, which were determined according to the initial value of KK (renal function is not impaired if KK> 80 ml / min. mild violation - if KK is 50-79 ml / min, a moderate violation - with KK 30-49 ml / min and severe violation - with KK 10-29 ml / min). Compared with patients with normal renal function, the average (% CV) exposure of tenofovir increased from 2185 (12%) ng × h / ml in individuals with CC> 80 ml / min to, respectively, 3064 (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. It is expected that increasing the interval between drug administration will lead to higher plasma Cmax and lower Cmin levels in patients with impaired renal function compared with patients with normal renal function. The clinical significance of this is unknown.
In patients with end-stage renal failure (CC <10 ml / min) who needed hemodialysis, the tenofovir concentrations between dialyses increased significantly for 48 h, reaching an average Cmax of 1032 ng / ml and an average AUC0-48h of 42,857 ng × h / ml
It is recommended that the interval between doses of 300 mg of tenofovir disoproxil fumarate be changed in adult patients with CC <50 ml / min or in patients already having end-stage renal failure and in need of dialysis.
A single dose of 300 mg of tenofovir disoproxil fumarate was taken by patients not infected with HIV and HBV, with impaired liver function of varying degrees, determined by the Child-Pugh classification. In patients with impaired liver function, significant changes in the pharmacokinetics of tenofovir were not observed, which suggests that there is no need for dose adjustment. The average (% CV) values of Cmax and AUC0-∞ of tenofovir were 223 (34.8%) ng / ml and 2050 (50.8%) ng × h / ml, respectively, in individuals without impaired liver function, 289 (46%) ng / ml and 2310 (43.5%) ng × h / ml in individuals with moderate hepatic impairment, 305 (24.8%) ng / ml and 2740 (44%) ng × h / ml in individuals with severe hepatic impairment.
It was found that in non-fissile mononuclear cells of human peripheral blood (MCPC) T1 / 2 of tenofovir diphosphate is about 50 hours, while in MCPC stimulated by phytohemagglutinin it is about 10 hours.
Drug indications
Treatment of HIV-1 infection in adults in combination with other antiretroviral drugs; treatment of HIV-1 infection in children from 12 to 18 years of age with resistance to nucleoside reverse transcriptase inhibitors or toxicity precluding the use of first-line antiretroviral drugs; treatment of chronic hepatitis B in adults with compensated liver disease, signs of active replication of the virus, constant increased activity in serum ALT and histologically confirmed active inflammatory process and / or fibrosis; treatment of chronic hepatitis B in adults with proven HBV resistance to lamivudine; treatment of chronic hepatitis B in adults with decompensated liver disease; treatment of chronic hepatitis B in children aged 12 to 18 years with compensated liver disease with signs of active inflammatory process and active replication of the virus, as evidenced by the constant increased ALT activity in serum and histologically confirmed active inflammatory process and / or fibrosis.
Dosage regimen
The drug is taken orally during meals. The tablet must be swallowed whole with water. Tablets should not be chewed or broken.
Treatment should be initiated and monitored by a physician with experience in treating HIV infection and / or chronic hepatitis B.
The choice of drug for the treatment of HIV-1-infected patients who have previously received treatment should be based on checking for individual viral resistance and / or patient treatment history.
Adults
The recommended dose of the drug for the treatment of HIV and chronic hepatitis B is 1 tab. (300 mg) 1 time / day.
Chronic hepatitis b
The optimal duration of treatment is unknown. The issue of discontinuation of treatment can be considered as follows:
treatment of HBeAg-positive patients without cirrhosis should continue for at least 6-12 months after confirmation of HBe seroconversion (disappearance of HBeAg and HBV DNA with the appearance of anti-HBe) or until HBs seroconversion, or until loss of effectiveness. After discontinuation of treatment, it is necessary to regularly check the serum ALT and DNA levels of hepatitis B virus in order to identify possible late relapses of viremia;
treatment of patients with HBeAg-negative hepatitis B without cirrhosis should continue, at least until HBs seroconversion or signs of treatment failure. In the case of prolonged treatment lasting more than 2 years, it is recommended to regularly review the treatment again to confirm that it is acceptable for the patient to continue the chosen therapy.
Children from 12 to 18 years old
HIV-1: at the age of 12 to 18 years and with a body weight of ≥35 kg, the recommended dose of the drug is 1 tab. (300 mg) 1 time / day. In exceptional cases, the tablet of the drug can be taken immediately after it is dissolved in approximately 100 ml of water, orange or grape juice.
Chronic hepatitis B: at the age of 12 to 18 years and with a body weight of ≥35 kg, the recommended dose of the drug is 1 tab. (300 mg) 1 time / day. The optimal duration of treatment has not yet been established. The safety and effectiveness of tenofovir in children with chronic hepatitis B in the age of 2 to 12 years and with a body weight of <35 kg have not been established.
Missed dose
If the dose has been skipped and less than 12 hours have passed from the usual time of taking the dose, the patient should take the drug with food as soon as possible and return to the usual regimen of the drug. If after skipping a dose more than 12 hours have passed and the time for taking the next dose of the drug is approaching, the patient should not take the missed dose, but take the next dose in accordance with the usual regimen of the drug.
If within 1 hour after taking the drug, the patient has vomited, take another 1 tab. If vomiting occurs in the patient more than 1 hour after taking the drug, an additional tablet should not be taken.
Special patient groups
To date, there is no data on the basis of which it is possible to give recommendations regarding dosing for patients over the age of 65 years.
Impaired renal function
Tenofovir is excreted in the urine, therefore, patients with impaired renal function have a longer T1 / 2 of tenofovir from the body.
Data on the safety and efficacy of tenofovir in adult patients with impaired renal function of moderate and severe degree (CC <50 ml / min) are limited. The assessment of safety indicators in patients with mild impaired renal function (CC 50-80 ml / min) in the long term has not been conducted. For this reason, in patients with impaired renal function, tenofovir should be used in cases where the potential benefit of treatment exceeds the potential risk of harm. Correction of the dosing interval is recommended for patients with CC <50 ml / min.
- Tenofovir 300mg
