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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,{dagger} 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 (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.

* Corresponding author. Mailing address: Lilly-NUS Centre for Clinical Pharmacology, Level 6 Clinical Research Centre (MD11), National University of Singapore, 10 Medical Dr., Singapore 117597, Republic of Singapore. Phone: 65 6413 9802. Fax: 65 6779 0587. E-mail: clark_chan{at}lilly.com.

{dagger} Present address: Ligand Pharmaceuticals, San Diego, CA 92121.

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.





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