Local Liver Irradiation Concurrently Versus Sequentially with Cabozantinib on the Pharmacokinetics and Biodistribution in Rats

The aim of this study was to evaluate the radiotherapy (RT)-pharmacokinetics (PK) effect of cabozantinib in concurrent or sequential regimens with external beam radiotherapy (EBRT) or stereotactic body radiation therapy (SBRT). Concurrent and sequential regimens involving RT and cabozantinib were designed. The RT–drug interactions of cabozantinib under RT were confirmed in a free-moving rat model. The drugs were separated on an Agilent ZORBAX SB-phenyl column with a mobile phase consisting of 10 mM potassium dihydrogen phosphate (KH(2)PO(4))–methanol solution (27:73, v/v) for cabozantinib. There were no statistically significant differences in the concentration versus time curve of cabozantinib (AUC(cabozantinib)) between the control group and the RT(2Gy×3 f’x) and RT(9Gy×3 f’x) groups in the concurrent and the sequential regimens. However, compared to those in the control group, the T(max), T(1/2) and MRT decreased by 72.8% (p = 0.04), 49.0% (p = 0.04) and 48.5% (p = 0.04) with RT(2Gy×3 f’x) in the concurrent regimen, respectively. Additionally, the T(1/2) and MRT decreased by 58.8% (p = 0.01) and 57.8% (p = 0.01) in the concurrent RT(9Gy×3 f’x) group when compared with the control group, respectively. The biodistribution of cabozantinib in the heart increased by 271.4% (p = 0.04) and 120.0% (p = 0.04) with RT(2Gy×3 f’x) in the concurrent and sequential regimens compared to the concurrent regimen, respectively. Additionally, the biodistribution of cabozantinib in the heart increased by 107.1% (p = 0.01) with the RT(9Gy×3 f’x) sequential regimen. Compared to the RT(9Gy×3 f’x) concurrent regimen, the RT(9Gy×3 f’x) sequential regimen increased the biodistribution of cabozantinib in the heart (81.3%, p = 0.02), liver (110.5%, p = 0.02), lung (125%, p = 0.004) and kidneys (87.5%, p = 0.048). No cabozantinib was detected in the brain in any of the groups. The AUC of cabozantinib is not modulated by irradiation and is not affected by treatment strategies. However, the biodistribution of cabozantinib in the heart is modulated by off-target irradiation and SBRT doses simultaneously. The impact of the biodistribution of cabozantinib with RT(9Gy×3 f’x) is more significant with the sequential regimen than with the concurrent regimen.