Description
Apricitabine (formerly known as BCH-10618, SPD754, and AVX754)
is a deoxycytidine nucleoside reverse transcriptase inhibitor (NRTI) in
clinical development for the treatment of HIV disease. Specifically,
apricitabine is the (–)-enantiomer of the heterosubstituted analog 2udeoxy-3u-oxa-4u-thiocytidine and has the molecular formula
C8H11N3O3S. Apricitabine is structurally similar to lamivudine, but differs in
the inversion of the oxygen and sulfur in the furanosyl ring.
Apricitabine has a molecular weight of 229.26 (1 mM = 0.229 mg/ml).
Description
In common with other NRTIs, apricitabine is activated by intra-cellular phosphorylation. The initial phosphorylation to apricitabine
monophosphate is catalyzed by deoxycytidine kinase. After further phosphorylation, the
triphosphate form of the molecule competes with endogenous
deoxycytidine triphosphate for binding to HIV-1 reverse transcriptase. The subsequent incorporation of apricitabine triphosphate into
nascent DNA by this enzyme interrupts viral replication by
terminating the elongation of the DNA chain.
Apricitabine triphosphate is a potent and highly selective inhibitor
of HIV-1 reverse transcriptase in vitro. Its inhibitory constant (Ki) for
reverse transcriptase from wild-type HIV-1 (0.08 mM) was half that of
lamivudine triphosphate under the same conditions and 150- to 3750-
fold lower than for human DNA polymerases, including the
mitochondrial DNA polymerase γ .
Uses
(-)-2''-Deoxy-3''-oxa-4''-thiocytidine (Apricitabine) is a drug that is used in the treatment of HIV aids. It as also been shown to be useful against lamivudine and zidovudine resistant virus strains
Clinical Use
Apricitabine is an NRTI currently under clinical development that has a good safety profile, including a good mitochondrial toxicity profile. There may be a niche for apricitabine in the treatment of individuals infected with viral strains with reduced susceptibility to other nucleoside analogs, including strains with M184V and TAMs. NRTIs are recommended for clinical use in combination with other classes of antiretrovirals within highly active antiretroviral treatment (HAART) regimens for HIV infection. In light of its activity in vitro against HIV strains resistant to existing NRTIs, apricitabine is likely to be most useful for the treatment of antiretroviral-experienced patients failing therapy containing one of these agents. Investigating the efficacy, tolerability, and resistance selection properties of new antiretrovirals within combination HAART regimens is complicated by the confounding effects of the other prescribed agents. Therefore, developmental NRTIs are commonly evaluated first within short-term (r14 day) trials of monotherapy in antiretroviral naive HIV-infected patients. To date, apricitabine has shown efficacy in two phase II trials, one as monotherapy in antiretroviral-naive patients, and one within HAART for antiretroviral-experienced patients.
in vivo
Apricitabine (SPD754; AVX754) (oral adminstation; 10 mg/kg; once a day) exhibits a good oral bioavailability of 68% for males and 69.4% for females rats. And the T1/2, AUC0–∞, Tmax, Cmax are 62.2 mins, 157.4 μg/min/ml and 37.3 mins, 1.16 μg/ml in female rats[1].
Apricitabine (SPD754; AVX754) (intravenous?injection; 10 mg/kg; once a day) exhibits the T1/2, AUC0–∞ values of 12.7 mins, 226.9 μg/min/ml in female rats[1].
