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Antimicrobial Agents and Chemotherapy, May 2005, p. 1813-1822, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1813-1822.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Clinical Pharmacokinetics of Alamifovir and Its Metabolites

Clark Chan,^1* Eyas Abu-Raddad,² Georg Golor,³ Hikari Watanabe,⁴ Akira Sasaki,⁴ Kwee Poo Yeo,¹ Danny Soon,¹ Vikram P. Sinha,² Shawn D. Flanagan,^2, Minxia M. He,² and Stephen D. Wise¹

Lilly-NUS Centre for Clinical Pharmacology, National University of Singapore, Singapore, Republic of Singapore,¹ Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana,² PAREXEL Institute of Clinical Pharmacology, Berlin, Germany,³ Mitsubishi Pharma Corporation, Tokyo, Japan⁴

Received 24 August 2004/ Returned for modification 15 November 2004/ Accepted 27 January 2005

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.

Present address: Ligand Pharmaceuticals, San Diego, CA 92121.