indication

For use, in combination with other antiretroviral agents, in the treatment of HIV-1 infection in adults.

pharmacology

Didanosine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Didanosine differs from other nucleoside analogues, as it does not have any of the regular bases, instead it has hypoxanthine attached to the sugar ring. Didanosine is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. Didanosine is effective against HIV, and usually used in combination with other antiviral therapy. Switching from long term AZT treatment to didanosine has been shown to be beneficial. Didanosine has weak acid stability and therefore, it is often combined with an antacid.

mechanism of action

Didanosine (ddI) is metabolized intracellularly by a series of cellular enzymes to its active moiety, dideoxyadenosine triphosphate (ddATP), which inhibits the HIV reverse transcriptase enzyme competitively by competing with natural dATP. It also acts as a chain terminator by its incorporation into viral DNA as the lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated.

toxicity

Side effects include pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and hepatic dysfunction

biotransformation

Rapidly metabolized intracellularly to its active moiety, 2,3-dideoxyadenosine-5-triphosphate (ddA-TP). It is then further metabolized hepatically to yield hypoxanthine, xanthine, and uric acid.

absorption

Rapidly absorbed (bioavailability 30-40%) with peak plasma concentrations appearing within 0.5 and 1.5 hrs.

half life

30 minutes in plasma and more than 12 hours in intracellular environment.

route of elimination

Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines. Purines are eliminated by the kidneys.

drug interactions

Ganciclovir: The antiviral agent, ganciclovir, may increase the effect and toxicity of didanosine.

Tenofovir: Tenofovir may decrease the therapeutic effects and increase the adverse effects of Didanosine. Monitor for changes in virologic response and Didanosine toxicity during concomitant therapy.

Tipranavir: Tipranavir may decrease the concentration of Didanosine.

Tobramycin: Increased risk of nephrotoxicity

Trovafloxacin: Didanosine may decrease the absorption of orally administered Trovafloxacin. The Didanosine formulation contains magnesium and aluminum ions that intefere with Trovafloxacin absorption. Administer Trovafloxacin 2 hours before or 6 hours after the Didanosine dose to minimize the interaction. This interaction is not observed with enteric coated Didanosine.

Valganciclovir: The adverse/toxic effects of Didanosine, a reverse transcriptase inhibitor (nucleoside), may be enhanced by Valganciclovir. There is a significant risk of hematologic toxicity. Concomitant therapy should be avoided.

Voriconazole: Didanosine may interfere with the absorption of orally administered voriconazole. Enteric coated didanosine does not exert this effect. Didanosine buffered formulations should be administered at least 2 hours from oral voriconazole administration.

Zalcitabine: Additive toxicities (peripheral neuropathy)