Pharmacokinetics of the Antiviral Agent β- d -2′-Deoxy-2′-Fluoro-2′- C -Methylcytidine in Rhesus Monkeys

Abstract

ABSTRACT β- d -2′-Deoxy-2′-fluoro-2′- C -methylcytidine (PSI-6130) is an effective inhibitor of hepatitis C virus (HCV) replication in vitro. The purpose of this study was to evaluate the single-dose pharmacokinetics of PSΙ-6130 in rhesus monkeys following intravenous (i.v.) and oral administration. Noncompartmental analysis of the serum data obtained following oral and i.v. administration was performed. Pharmacokinetic studies with rhesus monkeys indicated slow and incomplete absorption with a mean absorption time (MAT) of 4.6 h and an oral bioavailability of 24.0% ± 14.3% (mean ± standard deviation), with comparable mean apparent half-lives following i.v. (4.54 ± 3.98 h) and oral (5.64 ± 1.13 h) administrations. The average percentages of the total dose recovered unchanged and in deaminated form in the urine were 32.9% ± 12.6% and 18.9% ± 6.6% (i.v.) and 6.0% ± 3.9% and 3.9% ± 1.0% (oral), respectively. The total bioavailability, taking into account the parent drug and its deaminated metabolite 2′-deoxy-2′-fluoro-2′- C -methyluridine (PSI-6206), was 64% ± 26%. PSI-6130 was present in the cerebrospinal fluid after oral and i.v. dosing. However, no deamination of radiolabeled PSI-6130 was detected after 8 h of incubation in monkey and human whole blood. An N 4 -modified prodrug of PSI-6130 (PSI-6419) was orally administered to monkeys, but it failed to improve the oral bioavailability of PSI-6130. Further studies are warranted to improve the oral bioavailability and reduce the deamination of PSI-6130 in order to explore the potential of this drug for the treatment of HCV-infected individuals.