Pharmacokinetic-Pharmacodynamic Modeling and Simulation of Merigolix, a Nonpeptide Gonadotropin-Releasing Hormone...

Gonadotropin-releasing hormone (GnRH) antagonists inhibit estrogen synthesis and secretion, making them promising treatment options for estrogen-dependent diseases, such as endometriosis. This study developed a population pharmacokinetic/pharmacodynamic (PK/PD) model for merigolix, a novel oral GnRH antagonist, to determine its optimal dosing in the treatment of endometriosis. Population PK/PD modeling was performed using NONMEM 7.4, incorporating data from phase I clinical studies involving single and multiple ascending dose (SAD and MAD) trials in healthy premenopausal volunteers. The PK profile was characterized using a two-compartment model incorporating first-order absorption and elimination processes. The temporal delay between merigolix concentration and subsequent estradiol (E2) suppression was described using an indirect response turnover model. The models were evaluated via visual predictive checks, goodness-of-fit plots, and bootstrap analysis. The PK model described merigolix concentrations across various doses (estimated clearance: 549 L/h, central volume of distribution: 1690 L). The PD model demonstrated dose-dependent E2 suppression (estimated maximum inhibitory effect [I_max]: 1, half-maximal inhibitory concentration [IC₅₀]: 0.209 ng/mL). Simulations suggested that, assuming a baseline E2 concentration of 100 pg/mL, daily doses of 120 and 160 mg achieved the clinically meaningful target E2 range of 20-40 pg/mL (partial suppression), while higher doses of 240 and 320 mg resulted in target E2 levels below 20 pg/mL (full suppression), effectively controlling symptoms and minimizing the risk of bone mineral density loss. This PK/PD model provides a quantitative framework for optimizing merigolix dosing and supports the selection of dosing regimens for future clinical trials, potentially offering a novel therapeutic option for endometriosis treatment.