Tenofovir disoproxil fumarate (DF) is the first nucleotide reverse transcriptase inhibitor
approved for use in combination with other antiretroviral agents in the treatment
of HIV-1 infection in the United States. Unlike the nucleoside reverse transcriptase
inhibitors, which must undergo 3 intracellular phosphorylation steps for activation.
nucleotide analogues such as tenofovir require only 2 such steps. This reduction in
the phosphorylation requirement has the potential to produce more rapid and complete
conversion of the drug to its pharmacologically active metabolite.
This article describes the pharmacologic properties and potential clinical usefulness
of tenofovir DF.
Relevant information was identified through searches of MEDLINE (1996-April 2002),
Iowa Drug Information Service (1996-April 2002), and International Pharmaceutical
Abstracts (1970-April 2002), as well as from meeting abstracts of major HIV/AIDS conferences
(1996-2002), using the search terms tenofovir tenofovir disoproxil fumarate, PMPA,
bis(POC)PMPA, GS-4331-05, acyclic nucleoside phosphonate, and nucleotide reverse transcriptase
inhibitor. Additional information was obtained from material submitted to the US Food
and Drug Administration by the manufacturer of tenofovir DF in support of its New
Drug Application.
In vitro, tenofovir DF has exhibited anti-HIV activity in various HIV-infected cell
lines and has produced a synergistic or additive effect against HIV when combined
with other antiretroviral agents. In adult humans, tenofovir has a volume of distribution
of 0.813 L/kg, is minimally bound to plasma protein (7.2%), has a plasma elimination
half-life of 12.0 to 14.4 hours, and is mainly excreted unchanged in urine (70%-80%).
Dose adjustment based on sex or body weight does not appear to be necessary, although
dose reduction may be necessary in the elderly; there are currently no data on tenofovir
DF in renal or hepatic insufficiency. The results of clinical trials suggest the efficacy
of tenofovir DF in reducing plasma levels of HIV-1 RNA when used as an add-on to a
stable antiretroviral regimen. The most commonly (>3%) reported adverse events in
clinical trials have included nausea, diarrhea, asthenia, headache, vomiting, flatulence,
abdominal pain, and anorexia. The most commonly (>2%) reported laboratory abnormalities
(grade III or IV) included increases in creatine kinase, triglycerides, amylase, aspartate
aminotransferase, and alanine aminotransferase, as well as hyperglycemia and glucosuria.
Serious adverse events leading to discontinuation of tenofovir DF were infrequent
(5%), occurring with an incidence similar to that with placebo (8%). The recommended
dosage of tenofovir DF in adults is 300 mg/d PO; pharmacokinetic and efficacy studies
in children are ongoing.
Although additional studies are needed, tenofovir DF appears to be a promising agent
for the treatment of HIV infection.