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In Vitro activity and pharmacological properties of IDX375, a novel HCV non-nucleoside inhibitor
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Reported by Jules Levin
AASLD Liver Meeting, San Francisco, CA Nov 4 2008
JP Bilello, DN Standring, C Dousson, J-F Griffon, M La Cola, L Lallos, M Liuzi, A-G Loi, J McCarville, J-L Papin, C Pierra, A Roland, M Seifer, D Surleraux, Idenix Pharmaceuticals
AUTHOR Conclusions
IDX375 is a potent and selective noncompetitive inhibitor that targets the palm domain of the HCV NS5B enzyme.
IDX375 inhibited HCV replication in an in vitro replicon assay with an EC50 value of 2.3 nM and a selectivivity index of >43,000.
IDX375 was not cytotoxic in test cell lines.
Treatment of replicon cells with 20x EC50 of IDX375 for 14 days resulted in a 3 log10 reduction in HCV relpicon RNA and reduced the number of replicon-containing foci in cell culture.
The PK profile of IDX375 in the rat and the cynomolgus monkey shows adequate drug exposure in the sestemic circulation. Moreover, the drug selectively concentrated in the liver.
The preclinical PK profile of IDX375 suggests the potential for once-a-day dosing. After 24 h, the plasma levels remained 10- to 30- fold above the EC50 in both rats and monkeys given single 10 mg/kg oral doses.
Based on the in vitro antiviral potency and the exposure seen in animal PK studies, IDX375 is a promising candidate for clinical evaluation.
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