A pharmacokinetic/viral kinetic model to evaluate treatment of chronic hepatitis C virus infection with a non-nucleoside polymerase inhibitor

摘要

Viral kinetic models have proven useful in characterizing treatment effectiveness during HCV therapy with interferon (IFN) as well as with direct acting antivirals (DAAs). Here we use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with setrobuvir, a non-nucleosidic inhibitor of the HCV NS5B polymerase enzyme. Using PK data from 3 studies in healthy volunteers and PK and VK data from a phase 1 study, where setrobuvir was administered for 3 days, we fitted a two-compartment PK model with first-order absorption and lag-time, an Emax pharmacodynamics model and a standard biphasic viral kinetic model. Setrobuvir’s EC50 and Hill coefficient and the viral clearance rate were significantly different (P=0.014, P<0.001 and P=0.004, respectively) between patients infected with HCV subtypes 1b and 1a, leading to an increased viral load decline in patients infected with genotype 1b virus. Understanding the combined effects of PK/VK on the performance of a nonnucleoside polymerase inhibitor such as setrobuvir could provide valuable insights into their use in combination with other DAAs as well as to optimize future therapy. Further, our work suggests that patients infected with subtype 1a would need higher doses than those infected with subtype 1b to achieve the same effectiveness. Whether this is true for other non-nucleoside polymerase inhibitors needs to be examined.