>What is the difference between a nucleotide polymerase inhibitor and a nucleoside polymerase inhibitor?<
A nucleotide (right) consists of a nucleoside (left) and one-to-three phosphate groups. (The depiction below contains one phosphate group.)
Why does this distinction matter?
The nucleotide with three phosphates is the active agent for all nucleoside/nucleotide drugs. IDIX found that a major reason for the failure of NM283, a nucleoside, was the variability of the phosphorylation step to produce the nucleotide from the nucleoside. With IDX184, this variability is eliminated because the prodrug resolves directly to the nucleotide in vivo.
>I believe IDIX has the only one of the former [nucleotide]<
IDIX – Here’s the IDX184 abstract for EASL, which contains PK data from the phase-1/2 monotherapy trial in progress. The findings in this abstract support the raison d’etre of IDX184, which is to use a nucleotide prodrug to ensure high levels of the active triphosphate in the liver while minimizing systemic exposure to the parent drug and its byproducts. For background, see #msg-34771363 and #msg-26915921. (EASL = European Association for Study of the Liver.)
›IDX184, a Liver-Targeted Nucleotide HCV Polymerase Inhibitor: Results of a First-In-Man Safety and Pharmacokinetic Study
Background and aims: IDX184 is a liver-targeted nucleotide prodrug designed to enhance formation of its active triphosphate in the liver, while minimizing systemic exposure to the parent drug and its nucleoside metabolite (NM). Multilog viral load reductions were observed in HCV-infected chimpanzees receiving 10 mg/kg IDX184 for 3 days. This first-in-man study investigated single ascending dose safety and the pharmacokinetics of IDX184.
Methods: Single ascending oral doses of 5, 10, 25, 50, 75 and 100 mg IDX184 were administered sequentially to cohorts of 8 healthy subjects randomized 6:2, active:placebo. Plasma levels of IDX184 and NM were quantitated using a validated LC-MS/MS methodology.
Results: IDX184 was rapidly absorbed (median Tmax: 0.25-0.5 h) and eliminated (mean t½: 0.6-1 h). Plasma concentrations of NM increased gradually (median Tmax: 4-6 h). Plasma exposure of IDX184 and NM was low and dose-related: the respective mean Cmax values ranged from 1.1 to 17 and 1.7 to 19 ng/mL, and mean total AUC values ranged from 1.2 to 22.7 and 17.3 to 334 ng*h/mL. Mean NM plasma concentrations 24 h after dosing were 0.6-3 ng/mL for 25-100 mg doses. Mean t½ for NM ranged from 18 to 43 h for doses >= 25 mg. IDX184 was well tolerated with no discontinuations, SAEs, dose-limiting toxicities, or dose-dependence of AEs. Overall, the incidence of AEs and laboratory abnormalities was low and similar among subjects receiving IDX184 or placebo. Dizziness was the most common AE, which occurred more frequently in placebo subjects. All AEs were mild to moderate and resolved at the end of study.
Conclusions: IDX184 appeared to be safe and well tolerated in this study. Consistent with a liver-targeting approach, systemic exposure of parent drug and metabolite was low. Importantly, systemic levels of NM obtained with 25 to 100 mg doses of IDX184 in this study are comparable to those associated with potent antiviral effects in HCV-infected chimpanzees. The favorable safety and pharmacokinetic profiles warrant further clinical development of IDX184 in HCV-infected patients.‹
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