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Antimicrob. Agents Chemother. doi:10.1128/AAC.00723-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Activity of a Potent HCV Polymerase Inhibitor in the Chimpanzee Model

Abbott Laboratories, Global Pharmaceutical Research and Development, Abbott Park, Illinois, USA; Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, Texas, USA

^* To whom correspondence should be addressed. Email: tami.pilot-matias{at}abbott.com.

	Abstract

A-837093 is a potent and specific non-nucleoside inhibitor of HCV NS5B RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 hours and bioavailability was >60%. In monkeys it had a half-life of 1.9 hours with 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg twice a day for 14 days followed by a 14-day post-treatment observation. Maximum viral load reductions of 1.4 and 2.5 log₁₀ copies RNA/ml for genotype 1a- and 1b-infected chimpanzees, respectively, were observed within 2 day after the initiation of treatment. After this initial drop in viral load, rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance mutations in both chimpanzees is consistent with in vitro selection studies in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazines HCV polymerase inhibitors in vivo.

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