Clinical pharmacokinetics of alamifovir and its metabolites.
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.
Chan
Clark
C
Lilly-NUS Centre for Clinical Pharmacology, Level 6 Clinical Research Centre, National University of Singapore, Singapore 117597, Republic of Singapore. clark_chan@lilly.com
Abu-Raddad
Eyas
E
Golor
Georg
G
Watanabe
Hikari
H
Sasaki
Akira
A
Yeo
Kwee Poo
KP
Soon
Danny
D
Sinha
Vikram P
VP
Flanagan
Shawn D
SD
He
Minxia M
MM
Wise
Stephen D
SD
D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
C461207:2-amino-6-(4-methoxyphenylthio)-9-(2-(phosphonomethoxy)ethyl)purine bis(2,2,2-trifluoroethyl) ester; D000998:Antiviral Agents; D011355:Prodrugs; D011687:Purines