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Purpose <p>This study aims to compare the safety and tolerability of CABOMETYX<sup>®</sup> (commercial name of the marketed cabozantinib tablets) with a novel cabozantinib formulation, referred to hereafter as HND-039 (HP), in Wistar rats.</p> Methods <p>The research comprised several studies: a single-dose pharmacokinetic (PK) study comparing CABOMETYX<sup>®</sup> (R) to two versions of HP (T1 and T2) formulations; a dose tolerance study investigating various doses of CABOMETYX<sup>®</sup> in terms of adverse effects; and a safety and tolerability study comparing HP at 5&#xa0;mg/kg/day to CABOMETYX<sup>®</sup> at 10&#xa0;mg/kg/day and 7.5&#xa0;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.</p> Results <p>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<sub>t</sub>) and maximum observed plasma concentration (C<sub>max</sub>) values approximately 50% higher than those of CABOMETYX<sup>®</sup>, indicating significantly enhanced bioavailability. The dose tolerance study revealed that doses ≥ 12&#xa0;mg/kg/day of CABOMETYX<sup>®</sup> resulted in severe adverse effects and high mortality, while doses ≤ 6&#xa0;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<sup>®</sup> 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.</p> Conclusion <p>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<sup>®</sup>, that may reduce treatment-limiting adverse events.</p>

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A novel cabozantinib formulation with improved safety and bioavailability: preclinical validation in rats

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月14日

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  • Shangwei Qin,
  • Yu Zhang,
  • John Duan,
  • George Kraft,
  • Joanne Bowen

摘要

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 (AUCt) and maximum observed plasma concentration (Cmax) 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.