Abstract
PURPOSE: This study aims to compare the safety and tolerability of CABOMETYX(®) (commercial name of the marketed cabozantinib tablets) with a novel cabozantinib formulation, referred to hereafter as HND-039 (HP), in Wistar rats. METHODS: The research comprised several studies: a single-dose pharmacokinetic (PK) study comparing CABOMETYX(®) (R) to two versions of HP (T1 and T2) formulations; a dose tolerance study investigating various doses of CABOMETYX(®) in terms of adverse effects; and a safety and tolerability study comparing HP at 5 mg/kg/day to CABOMETYX(®) at 10 mg/kg/day and 7.5 mg/kg/day. Analytical methods included LC-MS/MS for sample analysis, non-compartmental analysis for pharmacokinetics, Kaplan-Meier plots for survival, and standard statistical tests for safety endpoints. RESULTS: In the single-dose PK study, the HP formulation demonstrated area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC(t)) and maximum observed plasma concentration (C(max)) values approximately 50% higher than those of CABOMETYX(®), indicating significantly enhanced bioavailability. The dose tolerance study revealed that doses ≥ 12 mg/kg/day of CABOMETYX(®) resulted in severe adverse effects and high mortality, while doses ≤ 6 mg/kg/day caused minimal adverse reactions. In the safety and tolerability study, HP demonstrated significantly lower incidence of diarrhea and mortality compared to both CABOMETYX(®) groups. Additionally, rats treated with HP exhibited attenuated body weight loss and a less pronounced reduction in food intake, along with favorable blood pressure measurements and organ weights. CONCLUSION: The HP exhibits enhanced bioavailability and superior safety and a favorable safety and tolerability profile in preclinical settings. These findings support further clinical development as a potentially safer alternative to CABOMETYX(®), that may reduce treatment-limiting adverse events.