Abstract:

A tablet consisting of direct-acting antiviral agents, ledipasvir (a NS5A protein inhibitor) and sofosbuvir (a NS5B polymerase inhibitor), is the first fixed-dose preparation used in the antiviral therapy of hepatitis C. A model-based meta-analysis of ledipasvir and GS331007, the primary metabolite of sofosbuvir, enabled the integration of pharmacokinetic (PK) information from separate clinical trials and the quantitative characterization of the population pharmacokinetics of these two drugs. A systematicpublication search was conducted for the clinical studies of ledipasvir and sofosbuvir. A total of 401 arm-level aggregate concentrations of GS331007 and 188 concentrations of ledipasvir were used for PK modeling. A two-compartment disposition model was used for both ledipasvir and GS331007. Zero-order absorption was applied for ledipasvir PK modeling, and a combined zero- and first-orderabsorption was used for the modeling of GS331007. Absorption lag was observed in concentration-time profiles of both ledipasvirand GS331007. To aid the development of direct-acting antiviral drugs, our established PK models provided a basis for the further PK-viral kinetic studies of ledipasvir and sofosbuvir.

Key words: Ledipasvir, Sofosbuvir, GS331007, Population pharmacokinetic modeling, Hepatitis C, Model-based meta-analysis