Comparative preclinical assessment of relugolix tablets and relugolix intravenous injection

Prostate cancer continues to represent a significant global health burden with androgen deprivation therapy (ADT) serving as the cornerstone of systemic management. Relugolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist has demonstrated rapid and sustained testosterone suppression compared with conventional ADT agents such as degarelix, which are primarily available as depot-based injectable formulations and are associated with delayed absorption, limited dose flexibility, and injection-site reactions. However, the clinical utility of relugolix is constrained by its low oral bioavailability (~ 12%), attributable to incomplete absorption and extensive first-pass metabolism. In this study, we developed and evaluated a citrate-buffered injectable formulation of relugolix to overcome these limitations. Pharmacokinetic assessment in a preclinical prostate cancer model revealed that intravenous administration achieved significantly higher systemic exposure compared to oral dosing, with a peak plasma concentration of ~ 4300 ng mL−1 at 5 min versus ~ 427 ng mL−1 at 3 h, corresponding to an approximately nine-fold increase in area under the curve (AUC). Enhanced systemic availability resulted in greater early-phase tumor drug accumulation. Therapeutic efficacy was evaluated in the Myc-CaP allograft model, where the injectable formulation demonstrated significantly improved tumor growth inhibition compared to oral administration. Safety evaluation indicated good tolerability, with no significant alterations in hematological, biochemical, or urinalysis parameters. Collectively, these findings demonstrate that parenteral delivery substantially enhances the pharmacokinetic and therapeutic performance of relugolix, supporting further translational development of injectable formulations for improved prostate cancer management.