Tenofovir Disoproxil Fumarate

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Abstract
Tenofovir disoproxil fumarate (tenofovir DF; Viread®), an ester prodrug of the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir, is indicated in combination with other antiretroviral agents in the treatment of HIV infection. As a component of an antiretroviral regimen, oral tenofovir DF 300mg once daily effectively reduces viral load in patients with HIV infection who are treatment-experienced with baseline NRTI resistance mutations or treatment-naive. Tenofovir DF provides a simple and convenient once-daily dosage regimen, and is generally well tolerated and able to produce sustained suppression of viral replication. Tenofovir DF is metabolised to tenofovir diphosphate, which inhibits the activity of HIV reverse transcriptase and terminates the DNA chain. In vitro, the drug demonstrates good inhibitory activity against HIV strains, synergistic or additive activity when combined with certain other antiretroviral drugs, minimal cytotoxicity and no evidence of reduced mitochondrial DNA synthesis. Reduced susceptibility to tenofovir is associated with the reverse transcriptase mutation K65R. In patients with baseline resistance mutations in clinical trials, the greatest response to tenofovir DF was associated with the M184V mutation and no thymidine analogue-associated mutations. Reduced responses were associated with the L210W or M41L mutations, and a lack of response with the K65R mutation. The emergence of the K65R mutation during clinical trials using more than one class of antiretroviral therapy was specifically associated with tenofovir DF; however, the K65R mutation developed infrequently and was not associated with viral rebound. The oral bioavailability of tenofovir DF administered without food is 25%. After multiple doses of tenofovir DF 300mg once daily, the median maximum serum concentration of 326 ng/mL at steady state is reached after a median of 2.3 hours. Tenofovir has a median serum terminal elimination half-life of 14.4 hours, and undergoes primarily renal elimination as the unchanged drug. Exposure to tenofovir is increased in patients with moderate-to-severe renal impairment. Tenofovir does not inhibit cytochrome P450 enzymes, so few drug interactions are expected with drugs metabolised via this route. Coadministration of tenofovir DF with didanosine substantially increases didanosine exposure, coadministration with lopinavir/ritonavir increases tenofovir exposure and coadministration with atazanavir decreases atazanavir exposure. In two well designed clinical trials in antiretroviral treatment-experienced patients with HIV infection, oral tenofovir DF 300mg once daily in combination with other antiretroviral drugs produced significantly greater time-weighted reductions from baseline in HIV RNA levels than placebo at week 4 and/or 24; these reductions were maintained at week 48 in the placebo cross-over phase of the trials. In the dose-ranging trial, tenofovir DF 75, 150 or 300mg once daily were all more effective than placebo; however, the greatest reduction in viral load at weeks 4, 24 and 48 was produced by tenofovir DF 300mg once daily, which is the approved dosage in patients with HIV infection. The proportion of antiretroviral therapy-naive patients with HIV infection achieving HIV RNA levels <400 copies/mL was similar with tenofovir DF 300mg once daily and stavudine 40mg twice daily at weeks 48, 96 and 144 in a well designed trial. All patients also received lamivudine 150mg twice daily and efavirenz 600mg once daily. For the primary endpoint, the stratum-weighted lower 95% confidence interval of the difference between tenofovir DF and stavudine at week 48 slightly exceeded (by 0.4) the predefined equivalence criteria (−10.4 vs −10). In nonblind clinical trials, tenofovir DF 300mg once daily was effective in treating HIV infection when used in a regimen containing antiretroviral therapies from more than one class and as part of a simplified dosage regimen. However, as with other triple NRTI regimens, tenofovir DF with lamivudine plus either didanosine or abacavir showed high rates of suboptimal response and/or early failure. Oral tenofovir DF 300mg once daily, as part of combination therapy, was generally well tolerated in controlled clinical trials. The tolerability profiles of tenofovir-containing regimens were similar to those of regimens containing placebo or stavudine in controlled clinical trials. Mild-to-moderate gastrointestinal disorders (e.g. nausea, diarrhoea, vomiting and flatulence) were the most commonly reported adverse events. The frequency of laboratory abnormalities with tenofovir DF was similar to that with placebo and stavudine. However, tenofovir DF was associated with a more favourable serum lipid profile than stavudine. The risk of adverse events potentially associated with mitochondrial dysfunction with tenofovir DF appears similar to that with placebo and lower than that with stavudine. In clinical trials, the incidence of tenofovir DF-related renal abnormalities was low and similar in frequency between tenofovir DF- and stavudine-containing regimens.