Tenofovir (Viread®, TDF)

Class:

Tenofovir is a nucleotide analogue.

Antiviral Activity:

Tenofovir has activity against HIV-1, including non-clade B strains, HIV-2 and hepatitis B virus.

Mechanism of Action:

Tenofovir disoproxil fumarate is hydrolyzed to tenofovir, which is then phosphorylated to tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with the natural substrate, deoxyadenosine 5'-triphosphate, and by DNA chain termination.

Mechanism of Resistance:

Resistance to nucleotide analogues occurs through two mechanisms; decreased incorporation of the nucleotide analogue into the viral DNA and increased excision of the nucleotide from the viral DNA.

Pharmacodynamics:

In two phase I randomized, double blind, placebo-controlled trials, a dose-proportional increase in drug exposure was associated with incremental decreases of plasma HIV-1 RNA (viral load). The maximum effect was seen at an oral dose of 300 mg once daily. The antiviral effect of tenofovir may persist following drug discontinuation.

Pharmacokinetics:

The oral bioavailability of a 300 mg dose of TDF is 25% in the fasted state. Administration with high fat meal increases tenofovir AUC and Cmax by 40% and 14%, respectively. Protein binding in vitro is less than 7%. It is not appreciably metabolized by the liver and the renal route is the primary elimination pathway.

Adverse Effects:

Adverse effects include nausea, vomiting, diarrhea, asthenia, headache, flatulence, abdominal pain and anorexia.

Dosage:

Tablet 300mg

Adults and Adolescents:

300 mg orally once daily with a meal

Children: dose has not been established

Disease state based dosing:

Renal Impairment:

CrCl 30-49 ml/min – 300 mg every 48 hours

CrCl 10-29 ml/min – 300 mg twice per week

Hemodialysis – 300 mg every 7 days OR 300mg following a total of approximately 12

hours of dialysis

Hepatic Impairment:

No dose adjustment necessary

Contraindications/Warnings/ Precautions:

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleotide analogues.

Drug Interactions:

Tenofovir slightly inhibits CYP1A2. However, this is not expected to lead to any clinically significant drug interactions.

Pregnancy:

Category B: No evidence of risk in humans but studies inadequate.

Monitoring Requirements:

LFTs, baseline serum creatinine/BUN, serum phosphate

Brand names/Manufacturer:

Viread®/Gilead Sciences Inc