New drugs—reports of new drugs recently approved by the FDA lamivudine

Abstract

Several 2′,3′-dideoxynucleosides are potential inhibitors of HIV. In vitro activity of lamivudine against HIV-1 was assessed in a number of cell lines using standard susceptibility assays. IC 50 values were in the range of 2 nM to 15 μM. Lamivudine has anti HIV-1 activity in all acute virus-cell infections tested. Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. Absolute bioavailability in adult patients was ∼ 86% for the tablet and ∼ 87% for the oral solution. After oral administration of 2 mg/kg twice a day, the peak serum lamivudine concentration was ∼ 1.5 μg/mL. The AUC and C max increased in proportion to oral dose over the range 0.25–10 mg/kg. Lamivudine is also active against zidovudine-resistant clinical isolates of HIV. In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine. The lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight. Metabolism of lamivudine is a minor route of elimination. In man, the only known metabolism of lamivudine is the trans-sulfoxide metabolite in the urine. The majority of lamivudine is eliminated unchanged in urine. The recommended oral dose of lamivudine for adult is 150 mg twice a day administered in combination with zidovudine. In genetic toxicology tests, lamivudine, like many other nucleoside analogue, has shown evidence of weak activity in in vitro cytogenic assays and the mouse lymphoma assay. However, no evidence of genotoxic activity was seen when the racemate was examined in the rat bone marrow micronucleus test and the rat liver UDS test using doses of up to 600 mg/kg by the iv route. Negative results have also been obtained in an in vitro cell transformation assay using Balb/3T3 cells. Epivir™ tablets are for oral administration. Each tablet contains 150 mg of lamivudine and the inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. Epivir™ Oral Solution is for oral administration. One milliliter of Epivir™ Oral Solution contains 10 mg of lamivudine (6% v/v), methylparaben, propylene glycol, propylparaben, and sucrose.