Pharmacokinetics, Food Effect, Ketoconazole Interaction, and Safety of JTK-853, a Novel Nonnucleoside HCV Polymerase Inhibitor, After Ascending Single and Multiple Doses in Healthy Subjects

Abstract

Pharmacokinetics, safety, and tolerability of JTK-853, a novel HCV polymerase inhibitor, were evaluated in single and multiple ascending dose (SAD, MAD) studies, with food- and ketoconazole-related effects on exposure to JTK-853 and its active (CYP3A4 mediated) metabolite M2. JTK-853 was safe and well tolerated in both studies. In the SAD study, at doses >1600 mg (with standard breakfast [SBF]), JTK-853 exposure did not increase further, was substantially higher (AUC_inf increase: 3- to 8-fold) with SBF (vs fasted), with a moderate increase in AUC_inf (approximately 1.5-fold [1600 mg]) with a high-fat breakfast (vs SBF). In the SAD study (400-1600 mg, SBF), mean effective half-life (t_1/2(eff) ) of JTK-853 was 8.3 to 10.9 hours, and 20.3 to 27.3 hours in the MAD study (twice daily dosing, fed condition), with 2- to 3-fold accumulation in exposure (AUC_tau ). At steady-state, AUC_tau increased dose proportionally, and was approximately 2-fold higher with ketoconazole coadministration. Metabolite M2 (equipotent to JTK-853 in vitro) did not contribute significantly to parent drug exposure and decreased with increase in dose, repeated dosing, and ketoconazole coadministration. Trial simulation-based ratios (n = 1000/dose level) of trough JTK-853 plasma concentrations to the in vitro EC₉₀ for HCV genotype 1b were assessed for dose selection in a separate proof-of-concept study in patients. The studies enabled delineation of key drug attributes for further assessments in the target population.

Keywords: JTK-853; first-in-human; genotype 1a and 1b; hepatitis C virus; nonnucleoside polymerase inhibitor.