In:
Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 49, No. 5 ( 2005-05), p. 1813-1822
Kurzfassung:
Alamifovir, a purine nucleotide analogue prodrug, and its hydrolyzed derivatives have shown preclincal efficacy activity against wild-type and lamivudine-resistant hepatitis B virus. Two studies were conducted to examine the single- and multiple-dose alamifovir pharmacokinetics after oral administration in healthy males. In study 1, subjects were given single doses (0.2 to 80 mg), with a subset receiving 20 mg in a fed state. Study 2 subjects were dosed with 2.5 to 15 mg twice daily for 15 days. Plasma samples were collected over 72 h in study 1 and over 24 h on days 1 and 15 in study 2. Concentrations of alamifovir and its major metabolites were determined using liquid chromatography/tandem mass spectrometry methods. The data were analyzed using a noncompartmental technique. Although alamifovir was rapidly absorbed, there was limited systemic exposure due to its rapid hydrolysis and formation of at least three metabolites, suggesting that alamifovir acts as a prodrug. The major metabolites detected were 602074 and 602076, with 602075 detectable only in higher-dose groups. Maximum 602074 plasma concentration was achieved at approximately 0.5 h ( T max ) and declined with a 1- to 2-h terminal half-life ( t 1/2 ). Maximum concentrations of 602076 ( C max ) averaged 10% of the 602074 C max and reached T max in 2.5 h with a 4-h t 1/2 . Food appeared to decrease the extent of absorption of the compound. Multiple dosing resulted in minimal accumulation, and the concentrations following multiple doses could be predicted using the single-dose data. Alamifovir was well tolerated and the pharmacokinetics were characterized in these studies.
Materialart:
Online-Ressource
ISSN:
0066-4804
,
1098-6596
DOI:
10.1128/AAC.49.5.1813-1822.2005
Sprache:
Englisch
Verlag:
American Society for Microbiology
Publikationsdatum:
2005
ZDB Id:
1496156-8
SSG:
12
SSG:
15,3
