Tenofovir is an acyclic nucleoside phosphonate, or nucleotide, analog of adenosine 5u-monophosphate. Tenofovir is manufactured as the prodrug tenofovir disoproxil fumarate (TDF) and subsequently converted in vivo to its active form, tenofovir diphosphate. TDF undergoes initial diester hydrolysis to tenofovir followed by subsequent intracellular phosphorylations to form tenofovir diphosphate, the active agent. TDF is manufactured by Gilead Sciences and marketed under the trade name Vireads, or, when in coformulation with emtricitabine, as Truvadas and with the combination of emtricitabine and efavirenz as Atriplas. TDF has antiviral activity against both human immunodeficiency virus (HIV) and hepatitis B virus (HBV). TDF was originally registered for the treatment of HIV infection in 2001 and is now in widespread use globally for this indication. TDF has been recently approved for the treatment of chronic hepatitis B infection by the US Food and Drug Administration (FDA).

MECHANISM OF DRUG ACTION

Tenofovir diphosphate, the active metabolite of TDF, inhibits HIV-1 reverse transcriptase by competing with deoxyadenosine 5u-triphosphate and, when incorporated into the growing DNA chain, by causing DNA chain termination. Unlike many other nucleoside analogs, tenofovir cannot be easily removed from the growing DNA chain by the ATP-dependent excision mechanism, and this may explain why tenofovir (like abacavir and didanosine) is relatively unaffected by thymidine analog mutations. Tenofovir inhibits HBV polymerase by competitively inhibiting binding of dATP to the enzyme, but it is not incorporated and hence does not cause chain termination. Tenofovir is converted to its diphosphate form not only in lymphoid cells, but also in human hepatoblast cell lines (HepG2 cells) and in primary human hepatocytes.

Bioavailability

Compared with parenteral administration, the oral bioavailability of tenofovir from the soluble prodrug TDF was approximately 25% in fasted individuals. A single oral dose of 300 mg results in a Cmax and AUC of 296 7 90 ng/ml and 2287 7 685 ng h/ml, respectively, with the Cmax achieved 1.0 7 0.4 h after administration. Although a high fat meal prior to dosing increased both Cmax and AUC (by 14% and 40%, respectively), no changes in Cmax or AUC were seen following a light meal. TDF is marketed with no food restrictions or dietary requirements. The serum elimination half-life of tenofovir is 17 h.

Drug interactions

Since tenofovir is predominantly excreted through the kidneys by a combination of glomerular filtration and active tubular secretion, any drug which is also actively secreted in the renal tubules (e.g. cidofovir, aciclovir, valaciclovir, ganciclovir, and valganciclovir) may alter the concentrations and cause an increase in serum levels of tenofovir or the drug concerned. Similarly, any drug which results in impaired renal function may also increase the levels of tenofovir. Tenofovir is not metabolized through the hepatic CYP450 enzyme system and does not participate in any known CYP450-mediated interactions with other drugs. TDF does not have any relevant pharmacokinetic drug interactions with abacavir, adefovir, lamivudine, emtricitabine, efavirenz, nevirapine, methadone, rifampicin, or ribavirin. Tenofovir levels are increased when prescribed with zidovudine, although the clinical significance of this is unknown.