Population Pharmacokinetics of AL-335 and Its Two Main Metabolites (ALS-022399, ALS-022227) in Monotherapy and in Combination with Odalasvir and/or Simeprevir.

Abstract

The aim of the current study was to characterize the time course of plasma concentrations of AL-335 and its main metabolites (ALS-022399 and ALS-022227) after oral administration in healthy and hepatitis C virus (HCV)-infected subjects, in monotherapy as well as in combination with simeprevir and/or odalasvir. AL-335, ALS-022399, and ALS-022227 plasma concentrations from subjects receiving 800mg of AL-335 orally once daily (qd) as monotherapy or in combination were pooled and analyzed using a nonlinear mixed effect modeling approach. The typical values (between subject variability) of AL-335 and ALS-022399 apparent linear clearances were 3300L/h (33.9%) and 1910L/h (30.0%), respectively. ALS-022227 elimination was characterized as a nonlinear process, with typical values of Vmax,ALS-022227 and Km,ALS-022227 estimated to be 84,799ng/h (14.9%) and 450.2ng/mL, respectively. AL-335 and ALS-022399 plasma concentrations were increased more than 2-fold in presence of simeprevir and/or odalasvir, while the effect on ALS-022227 plasma concentrations was limited. The effect of simeprevir and/or odalasvir might be explained by their capacity to inhibit P-glycoprotein. Internal evaluation confirmed that the population pharmacokinetic model developed was deemed appropriate to describe the time course of AL-335, ALS-022399, and ALS-022227 plasma concentrations and their associated variability in both healthy and HCV-infected subjects, as well as the interaction effect of simeprevir and/or odalasvir over AL-335 and its metabolites in healthy subjects. This model can be used as a starting point to evaluate drug-drug interaction processes in HCV-infected patients and support the development of a direct-acting antiviral (DAA) combination.