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Title: Clinical pharmacokinetics of alamifovir and its metabolites
Authors: Chan, C.
Abu-Raddad, E.
Golor, G.
Watanabe, H.
Sasaki, A.
Yeo, K.P. 
Soon, D.
Sinha, V.P.
Flanagan, S.D.
He, M.M.
Wise, S.D.
Issue Date: May-2005
Citation: Chan, C., Abu-Raddad, E., Golor, G., Watanabe, H., Sasaki, A., Yeo, K.P., Soon, D., Sinha, V.P., Flanagan, S.D., He, M.M., Wise, S.D. (2005-05). Clinical pharmacokinetics of alamifovir and its metabolites. Antimicrobial Agents and Chemotherapy 49 (5) : 1813-1822. ScholarBank@NUS Repository.
Abstract: 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 (Tmax) and declined with a 1- to 2-h terminal half-life (t1/2). Maximum concentrations of 602076 (Cmax) averaged 10% of the 602074 Cmax and reached Tmax in 2.5 h with a 4-h t1/2. 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. Copyright © 2005, American Society for Microbiology. All Rights Reserved.
Source Title: Antimicrobial Agents and Chemotherapy
ISSN: 00664804
DOI: 10.1128/AAC.49.5.1813-1822.2005
Appears in Collections:Staff Publications

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