To develop population pharmacokinetic (PopPK) and pharmacodynamics (PopPD) models of SIM0295 and explore potential covariates to inform dosing regimen.
Data from four phase I studies, including healthy Korean and Chinese subjects, and two phase IIa studies, including Korean gout patients with hyperuricemia. PopPK and popPD models of SIM0295 were developed using nonlinear mixed effects modeling.
A total of 195 subjects and 5852 plasma concentrations of SIM0295 were included to perform the PopPK model, and 147 subjects and 3781 concentrations of serum uric acid (sUA) samples were included in the PopPK/PD study. SIM0295 pharmacokinetic was described by the two-compartment model with a four transit compartments absorption and linear elimination, in which the PK parameters were corrected with body weight via an empirical allometric model. Food and food types were identified as factors that significantly affect the absorption rate. PopPK/PD study shown that the final model was investigated using an Emax model with a semi-mechanism of inhibition of sUA reabsorption. The subject status was found significantly influence the volume of distribution of serum uric acid (VU). Compared to healthy subjects, patients have a half lower VU, 246.54L and 144.72L respectively. Monte Carlo simulations demonstrated that food and food types had no significant influence on the efficacy of SIM0295 in patients.
The popPK/PD model quantified characterization of the dose-exposure-response relationship for SIM0295 in patient and healthy subjects. The model may be used to inform dose selection and design of subsequent studies that aim to define SIM0295 safety and efficacy in patients.