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Antimicrobial Agents and Chemotherapy, March 2009, p. 926-934, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01032-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Robust Antiviral Efficacy upon Administration of a Nucleoside Analog to Hepatitis C Virus-Infected Chimpanzees{triangledown}

Steven S. Carroll,1* Steven Ludmerer,1 Larry Handt,2 Kenneth Koeplinger,3 Nanyan Rena Zhang,3 Donald Graham,1 Mary-Ellen Davies,4 Malcolm MacCoss,5 Daria Hazuda,1 and David B. Olsen1

Antiviral Research Department,1 Laboratory Animal Resources,2 Department of Drug Metabolism,3 Vaccines Biologics Research, Merck Research Laboratories, West Point, Pennsylvania 19486,4 Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 070655

Received 1 August 2008/ Returned for modification 8 October 2008/ Accepted 8 December 2008

Hepatitis C virus (HCV) infects an estimated 170 million individuals worldwide and is associated with an increased incidence of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Currently approved therapies to treat HCV infection consist of combinations of pegylated alpha interferon and ribavirin which result in a sustained viral response in 40 to 60% of patients. Efforts to develop improved therapies include the development of direct inhibitors of virally encoded enzymes such as the viral RNA-dependent RNA polymerase. A nucleoside analog, 2'-C-methyl-7-deaza-adenosine (MK-0608), has been shown to inhibit viral RNA replication in the subgenomic HCV genotype 1b replicon, with a 50% effective concentration (EC50) of 0.3 µM (EC90 = 1.3 µM). To determine efficacy in vivo, MK-0608 was administered to HCV-infected chimpanzees, resulting in dose- and time-dependent decreases in plasma viral loads. In separate experiments, chimpanzees dosed for 7 days with MK-0608 at 0.2 and 2 mg per kg of body weight per day by intravenous administration experienced average reductions in viral load of 1.0 and >5 log10 IU/ml, respectively. Two other HCV-infected chimpanzees received daily doses of 1 mg MK-0608 per kg via oral administration. After 37 days of oral dosing, one chimpanzee with a high starting viral load experienced a reduction in viral load of 4.6 log10, and the viral load in the other chimpanzee fell below the limit of quantification (LOQ) of the HCV TaqMan assay (20 IU/ml). Importantly, viral load remained below the LOQ throughout the duration of dosing and for at least 12 days after dosing ended. The results demonstrate a robust antiviral effect on the administration of MK-0608 to HCV-infected chimpanzees.

* Corresponding author. Mailing address: WP26A-3000, Merck Research Laboratories, West Point, PA 19486. Phone: (215) 652-4488. Fax: (215) 993-6842. E-mail: steve_carroll{at}merck.com

{triangledown} Published ahead of print on 15 December 2008.

Antimicrobial Agents and Chemotherapy, March 2009, p. 926-934, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01032-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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