title: Apricitabine: a novel deoxycytidine analogue nucleoside reverse transcriptase inhibitor for the treatment of nucleoside-resistant HIV infection.
abstract: Existing nucleoside reverse transcriptase inhibitors for HIV disease are limited by problems of resistance and, in some cases, long-term toxicity. Apricitabine (ATC; formerly BCH10618, SPD754 and AVX754) is a deoxycytidine analogue nucleoside reverse transcriptase inhibitor in clinical development. ATC retains substantial in vitro activity against HIV-1 containing many mutations associated with nucleoside reverse transcriptase inhibitor resistance, showing a less than twofold reduction in susceptibility in the presence of either up to five thymidine analogue mutations or the M184V mutation. ATC showed a low potential for cellular or mitochondrial toxicity in vitro. ATC is well absorbed orally, with a bioavailability of 65-80%. Its plasma elimination half-life (approximately 3 h), and the intracellular half-life of its triphosphate (TP) metabolite (6-7 h) support twice-daily dosing. Intracellular ATC-TP levels are markedly reduced in the presence of lamivudine or emtricitabine, indicating that clinical co-administration of ATC together with these agents will not be possible. The drug is renally eliminated, giving a low potential for hepatic drug interactions. In a double-blind, randomized, placebo-controlled Phase II monotherapy trial in antiretroviral-naive patients, ATC doses of 1,200 and 1,600 mg/day reduced plasma viral load levels by 1.65 and 1.58 log10 HIV RNA copies/ml, respectively, after 10 days of treatment (P<0.0001 versus placebo). ATC showed a low propensity to select for resistance mutants in vitro and during clinical monotherapy. ATC was well tolerated in volunteers and in HIV-infected patients. This promising profile suggests that ATC may be useful in treating patients who have failed previous lamivudine- or emtricitabine-containing regimens. Further studies to evaluate the long-term efficacy and tolerability of ATC are underway.
authors.affiliation: McGill University AIDS Center, Lady Davis Institute-Jewish General Hospital, Montreal, Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
authors.forename: Pedro
authors.initials: P
authors.lastname: Cahn
authors.forename: Richard C
authors.initials: RC
authors.lastname: Bethell
authors.forename: James
authors.initials: J
authors.lastname: Sawyer
authors.forename: Susan
authors.initials: S
authors.lastname: Cox
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans
chemical_list: D019380:Anti-HIV Agents; D003841:Deoxycytidine; C508042:apricitabine