588 in Vitro Antiviral Activity and Pharmacology of Idx184, a Novel and Potent Inhibitor of HCV Replication

Safety and Pharmacokinetics of IDX184, a Liver-Targeted Nucleotide Polymerase Inhibitor of Hepatitis C Virus, in Healthy Subjects

“…In vitro experiments showed that the metabolism of IDX184 to 2Ј-MeG-MP takes place predominantly in liver cells and involves both cytochrome P450 (CYP450)-dependent and -independent processes (S. Good, unpublished data). 2Ј-MeG-TP is a potent inhibitor of the HCV polymerase NS5B, and IDX184 has demonstrated antiviral activity against HCV in vitro and in chimpanzees (1,6,7).The enhanced formation of active intracellular 2Ј-MeG-TP with IDX184 was demonstrated in vitro. In primary human and animal hepatocytes exposed to IDX184 and the nucleoside 2Ј-MeG, the formation of 2Ј-MeG-TP was about 100-fold higher with IDX184 than with 2Ј-MeG (S. Good, unpublished data).…”

“…In addition, many patients are not good candidates for treatment with these agents due to advanced liver disease or concurrent medical conditions, and many patients show poor tolerance of these treatments. Therefore, there is a need for new anti-HCV therapies, particularly for patients with genotype 1 HCV or those who have failed to respond to the available treatment options.While nucleoside HCV polymerase inhibitors have a higher genetic barrier to resistance and have demonstrated clinical anti-HCV activity, early nucleoside analogs have wide systemic exposure and inefficient phosphorylation of their 5Ј-monophosphate (MP) metabolite, resulting in limited formation of the active 5Ј-triphosphate (TP) in the liver, the site of HCV replication (1,3,5). In that context, IDX184 (Fig.…”

“…While nucleoside HCV polymerase inhibitors have a higher genetic barrier to resistance and have demonstrated clinical anti-HCV activity, early nucleoside analogs have wide systemic exposure and inefficient phosphorylation of their 5Ј-monophosphate (MP) metabolite, resulting in limited formation of the active 5Ј-triphosphate (TP) in the liver, the site of HCV replication (1,3,5). In that context, IDX184 (Fig.…”

“…In vitro experiments showed that the metabolism of IDX184 to 2Ј-MeG-MP takes place predominantly in liver cells and involves both cytochrome P450 (CYP450)-dependent and -independent processes (S. Good, unpublished data). 2Ј-MeG-TP is a potent inhibitor of the HCV polymerase NS5B, and IDX184 has demonstrated antiviral activity against HCV in vitro and in chimpanzees (1,6,7).…”

New developments in small molecular compounds for anti-hepatitis C virus (HCV) therapy

“…Unlike the first generation HCV nucleoside inhibitors, IDX184 is a "liver-target" prodrug, which theoretically will provide increased anti-HCV efficacy and safety. Preliminary studies in monkeys have shown approximately 95% hepatic extraction of orally administered IDX184 with low systemic IDX184 and nucleoside metabolite levels (Cretton-Scott et al, 2008). In chimpanzees infected with HCV-1, oral administration of 10 mg/kg BW QD produced a mean viral load reduction of 2.3 log 10 IU/ml after 4 d of dosing.…”