Model Informed Development of SIM0295 in Patients with Gout and Hyperuricemia and Healthy Volunteers Using a Population Pharmacokinetics/ Pharmacodynamics Approach.

BACKGROUND

SIM0295, a novel inhibitor of human uric acid transporter 1 (hURAT1), is used to treat patients with gout and hyperuricemia. This study aimed to develop population pharmacokinetics and pharmacodynamics (popPK/PD) models of SIM0295 and explore potential covariates to inform clinical drug development.

RESEARCH DESIGN AND

METHODS

Data were obtained from four phase I studies conducted in healthy Korean and Chinese subjects and two phase II studies conducted in Korean patients with gout and hyperuricemia. The popPK/PD model of SIM0295 was developed using nonlinear mixed effects modeling.

RESULTS

SIM0295 pharmacokinetics was described using a two-compartment model with the absorption of four transit compartments and first-order elimination. PK parameters were normalized to weight via allometric scaling. Food was identified as a factor significantly affecting the absorption rate, with no clinical relevance. The sigmoid Emax model with a semi-mechanism of inhibition of serum uric acid (sUA) reabsorption was used to describe the exposure-response relationship. Additionally, Monte Carlo simulations demonstrated that approimately 9 mg/day of SIM0295 for 7 days could achieve the maximum decrease in sUA.

CONCLUSION

The established popPK/PD model characterized the dose-exposure-response relationship for SIM0295 in healthy subjects and patients with gout and hyperuricemia and could be used to inform the drug development.