Tenofovir disoproxil

Uses

Tenofovir disoproxil is a nucleotide analog reverse transcriptase inhibitor used in the treatment of Hepatitis B infection and used in the management of HIV-1 infection.

Tenofovir is indicated in combination with other antiretroviral agents for the management of HIV-1 infection in adults and pediatric patients 2 years of age and older. It is also indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older . This drug is also a component of multiple products used for the management of HIV-1 infection , .

Safety and effectiveness of tenofovir disoproxil in pediatric patients younger than 2 years of age has not been established to this date .

Tenofovir disoproxil is also used to associated treatment for these conditions: Hepatitis B Chronic Infection, Human Immunodeficiency Virus Type 1 (HIV-1) Infection

How Tenofovir disoproxil works

Tenofovir belongs to a class of antiretroviral drugs known as nucleotide analog reverse transcriptase inhibitors (NtRTIs), which block reverse transcriptase, an enzyme necessary for viral production in HIV-infected individuals. This enables the management of HIV viral load through decreased viral replication .

Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted to its active form, tenofovir, a nucleoside monophosphate (nucleotide) analog. Tenofovir is then converted to the active metabolite, tenofovir diphosphate, a chain terminator, by constitutively expressed enzymes in the cell. Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and the Hepatitis B polymerase by direct binding competition with the natural deoxyribonucleotide substrate (deoxyadenosine 5’-triphosphate) and, after integration into DNA, causes viral DNA chain termination , .

A note on resistance

HIV-1 isolates with decreased susceptibility to tenofovir have been identified in cell culture studies. These viruses expressed a K65R substitution in reverse transcriptase and showed a 2– 4 fold decrease in susceptibility to treatment with tenofovir .

Toxicity

A note on breastfeeding

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to prevent postnatal transmission of HIV-1. Mothers should be advised not to breast-feed if they are receiving tenofovir disoproxil .

Carcinogenesis

Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were performed at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the higher dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose .

Pregnancy

This drug is considered a pregnancy Category B drug. Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the recommended human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. There are, however, no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not consistently reflective of human effects, tenofovir disoproxil should be used during pregnancy only if clearly required. To monitor fetal outcomes of pregnant women taking tenofovir disoproxil, an Antiretroviral Pregnancy Registry has been formed. Healthcare providers are encouraged and advised to register patients by calling the number listed on the FDA label for tenofovir disoproxil .

Mutagenesis

Tenofovir disoproxil fumarate was mutagenic in the in vitro mouse lymphoma assay and negative for mutagenesis in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil fumarate was negative when administered to male mice.

Impairment of Fertility

There were no observed effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was given to male rats at a dose comparable to 10 times the human dose based on body surface area comparisons for 28 days before mating and to female rats for 15 days before mating through day seven of gestation. There was, however, changes in the estrous cycle in female rats .

Food Interaction

• Take with or without food.

Volume of Distribution

The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg .

After oral administration of tenofovir disoproxil, tenofovir is distributed to the majority tissues with the highest concentrations measured in the kidney, liver and the intestinal contents (based on data from preclinical studies) .

Elimination Route

After oral administration of tenofovir disoproxil to patients with HIV infection, tenofovir disoproxil is quickly absorbed and metabolized to tenofovir .

Administration of tenofovir disoproxil 300 mg tablets after a high-fat meal increases the oral bioavailability of this drug, as demonstrated by an increase in tenofovir AUC0-∞ of about 40% as well as an increase in Cmax of about 14%. On the contrary, the administration of tenofovir disoproxil with a light meal did not exert a relevant effect on the pharmacokinetics of tenofovir when compared to administration under fasting conditions. The presence of ingested food slows the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ± 0.12 μg/mL and 3.32 ± 1.37 μg•hr/mL after several doses of tenofovir disoproxil 300 mg once daily in the fed state when meal content is not controlled .

Half Life

When a single oral dose is given, the terminal elimination half-life is approximately 17 hours .

Clearance

The clearance of tenofovir is highly dependent on renal function and may vary greatly. Total clearance has been estimated to be approximately 230 ml/h/kg (approximately 300 ml/min) .

On average, 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 shows that active tubular secretion is an essential part of the elimination of tenofovir .

The FDA label provides specific guidelines for dosing according to renal function. It is important to consult product labeling before administering tenofovir to individuals with renal dysfunction, as the clearance of this drug may vary greatly among these patients .

Elimination Route

Following IV administration of tenofovir, approximately 70–80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion . There may be competition for elimination with other compounds that are also eliminated by the kidneys.

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