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Safety and Antiviral Activity of NS5B Polymerase Inhibitor MK-3281in Genotype 1 and 3 HCV-Infected Patients
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Reported by Jules Levin
AASLD Nov 3 2009, Boston, MA
DM Brainard,1 MS Anderson,1 AS Petry,1 K Van Dyck,1 I De Lepeleire,1
K Sneddon,1 CE Cummings,1 RB Nachbar,1 RJO Barnard,1 P Sun,1 P Panorchan,1 E Udezue,2 B Sanderson,3 F Wagner,4M Iwamoto,1 JA Chodakewitz,1 JA Wagner1
1Merck & Co., Inc. Whitehouse Station, NJ; 2Chiltern Place, Slough, England; 3Chiltern (Early Phase) Limited, Dundee, Scotland; and 4Charite University Hospital, Berlin, Germany
Background
MK-3281 is a tetracyclic indole non-nucleoside hepatitis C virus · (HCV) NS5B polymerase inhibitor that binds in the thumb region and inhibits the enzyme prior to elongation.
MK-3281 demonstrates robust in vitro potency against genotypes
(GT) 1a/b and 3 HCV.
- EC50 GT1a (H77) in 10% FCS = 12 nM
- EC50 GT1b (con1) in 10% FCS = 41 nM
- EC50 GT3a in 10% FCS = 37 nM
MK-3281 exhibits >1000-fold selectivity over the human DNA · polymerases α, β, λ (IC50 >50 µM).
MK-3281 has been generally safe and well tolerated in healthy · male volunteers dosed for up to 10 days.1
Study Objectives
Evaluate the safety and tolerability of MK-3281 administered for 7 days to male patients infected with HCV genotypes 1 and 3.
Evaluate the pharmacokinetic profile of MK-3281 (e.g., AUC0-12hr, Cmax, C12hr, Tmax, apparent t1/2 and accumulation ratios) with multiple dose administration.
Evaluate the antiviral activity of MK-3281 administered as monotherapy for 7 days to male patients infected with HCV genotype 1 or 3.
RESULTS
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