Clinical pharmacokinetics of alamifovir and its metabolites.

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Chan C, Abu-Raddad E, Golor G, Watanabe H, Sasaki A, Yeo KP, Soon D, Sinha VP, Flanagan SD, He MM, Wise SD

Clinical pharmacokinetics of alamifovir and its metabolites.

Antimicrob Agents Chemother. 2005 May;49(5):1813-22.

PubMed ID
15855501 [ View in PubMed
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Abstract

Alamifovir, a purine nucleotide analogue prodrug, and its hydrolyzed derivatives have shown preclinical 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.

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