Population PK and Semimechanistic PK/PD Modeling and Simulation of Relugolix Effects on Testosterone Suppression in Men with Prostate Cancer

Relugolix, the first orally active, nonpeptide gonadotropin‐releasing hormone receptor antagonist, is approved in the United States and the European Union for the treatment of adult patients with advanced prostate cancer. The recommended dosing regimen is a 360‐mg loading dose followed by a 120‐mg daily dose. Relugolix and testosterone concentration data and clinical information from two phase I studies, two phase II studies, and the phase III safety and efficacy study (HERO) were used to develop a population pharmacokinetic (PopPK) model and a semimechanistic population pharmacokinetic/pharmacodynamic (PopPK/PD) model that characterized relugolix exposure and its relationship to testosterone concentrations. Age, body weight, and Black/African American race had at most minimal effects on relugolix exposure or testosterone concentrations with no clinical relevance. Simulations using the PopPK/PD model confirmed the recommended dosing regimen of relugolix, with the median simulated testosterone concentrations predicted to achieve castration levels (< 50 ng/dL) and profound castration levels (< 20 ng/dL) by day 2 and day 9, respectively, and demonstrated that 97.3% and 85.5% of the patients remained at castration levels (< 50 ng/dL) upon temporary interruption of treatment for 7 days and 14 days, respectively. Collectively, simulations based on the PopPK and PopPK/PD models were consistent with actual data from clinical studies, reflecting the high predictiveness of the models and supporting the reliability of model‐based simulations. These models can be used to provide guidance regarding dosing recommendations under various circumstances (e.g., temporary interruption of treatment, if needed) for relugolix.