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Prodrug of Tenofovir Diphosphate Approved for Combination HIV Therapy

Cheryl A. Thompson

Gilead Sciences received accelerated approval from FDA to market tenofovir disoproxil fumarate (Viread [PDF]), a prodrug of the nucleotide analogue tenofovir diphosphate, for use with other antiretroviral agents in the treatment of adults with human immunodeficiency virus (HIV) infection. The nucleotide analogue inhibits the activity of HIV reverse transcriptase.

Tenofovir disoproxil fumarate is converted through a series of enzymatic reactions to the base compound and then to tenofovir diphosphate.

FDA made its decision about the drug’s efficacy on the basis of two double-blind, placebo-controlled, multicenter studies involving adults, predominantly white men, with evidence of HIV replication despite ongoing antiretroviral therapy, often of several years duration. All participants received standard antiretroviral therapy during the studies regardless of treatment assignment.

Treatment with tenofovir disoproxil fumarate 300 mg (the frequency was not stated in the product’s labeling) for 24 weeks resulted in 40% of the 368 patients having a plasma HIV RNA level of <400 copies/mL and 19% having a level of <50 copies/mL, compared with 11% and 1%, respectively, of the 182 participants who received placebo. At week 24, the absolute CD4+ lymphocyte count had increased by a mean of 11 cells/mm3 in the tenofovir group and decreased by a mean of 5 cells/mm3 in the placebo group.

Patients in the other major study received placebo or tenofovir disoproxil fumarate 75, 150, or 300 mg daily for 24 weeks. After the initial 24 weeks, the placebo group began to receive tenofovir disoproxil fumarate 300 mg daily while the other groups continued their treatment assignments for another 24 weeks. A plasma HIV RNA level of <400 copies/mL was achieved by 19% of tenofovir-treated patients at week 24, compared with 7% of the placebo group. Eleven percent of tenofovir-treated patients had a plasma RNA level of <50 copies/mL at week 24, whereas no one in the placebo group did. The absolute CD4+ lymphocyte count had decreased by a mean of 14 cells/mm3 in the tenofovir group at week 24, compared with a gain of 20 cells/mm3 in the placebo group, but had increased by a mean of 11 cells/mm3 at week 48.

In the two major studies of tenofovir efficacy, the K65R mutation in reverse transcriptase, which can occur after therapy with didanosine, zalcitabine, or abacavir, developed in viruses isolated from 3% of the patients after treatment began. Certain zidovudine-associated mutations were also found to decrease patients’ response to tenofovir. A correlation was found between the susceptibility of patients’ HIV infection to tenofovir at baseline and the serologic response to treatment.

The oral bioavailability of tenofovir is about 25% in fasting patients, and the mean peak serum concentration occurs 60 minutes after a single 300-mg dose. Administration of the drug with a high-fat meal increases the body’s total exposure by about 40% and delays the time to peak serum concentration by about one hour. Less than 1% of tenofovir is bound to plasma proteins.

Tenofovir is eliminated primarily by glomerular filtration and active tubular secretion. Neither tenofovir disoproxil nor tenofovir is a substrate of cytochrome P-450 isoenzymes. The pharmacokinetics of tenofovir have not been studied in patients with renal or hepatic impairment. Because of the lack of data related to safety, the product’s labeling advises against the use of tenofovir in patients with a creatinine clearance of <60 mL/min and raises the issue of monitoring for changes in serum creatinine and phosphorus concentrations in patients at risk for renal dysfunction during long-term therapy.

The product's labeling includes a black-box warning on the risk of potentially fatal lactic acidosis and severe hepatomegaly with steatosis during therapy with nucleoside analogues, particularly in women. Possible risk factors for these adverse reactions are obesity and prolonged exposure to nucleoside analogues.

Because of tenofovir’s dependence on the kidneys for elimination, drugs that decrease renal function or compete for active tubular secretion may increase the serum concentration of tenofovir; likewise, the serum concentration of renally eliminated drugs may increase during tenofovir therapy. Patients who receive tenofovir and didanosine should be monitored for adverse effects related to didanosine therapy, since tenofovir was found to increase total exposure to didanosine, when taken in its buffered form, by 44%.

The most common adverse effects of tenofovir during the clinical studies were mild to moderate gastrointestinal events.

The product’s labeling encourages health care providers to contact the Antiretroviral Pregnancy Registry (800-258-4263) when a pregnant women receives tenofovir. Women should not breastfeed during tenofovir therapy because the drug may be secreted into the milk.

Under the conditions of FDA’s accelerated approval of tenofovir disoproxil fumarate, Gilead will submit the results of its study of the drug in adults who have not undergone antiretroviral therapy and in children who have. The company must also report on the drug’s effect on bone mineral density and bone metabolism, evaluate the pharmacokinetics in people with renal insufficiency, and conduct genotypic and phenotypic analyses of HIV isolates from adults and children who no longer respond to tenofovir therapy.

The recommended dosage of tenofovir disoproxil fumarate is 300 mg once daily with a meal. During concomitant therapy with didanosine, the daily dose of tenofovir should be taken two hours before a dose of didanosine or one hour afterward.

Viread is supplied in bottles of 30 tablets, each containing 300 mg of tenofovir disoproxil fumarate and coated with a blue film. The bottles also contain a desiccant.