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

Author:

Huang Yu-Chuen12,Hsieh Pei-Ying3ORCID,Wang Li-Ying45,Tsai Tung-Hu6ORCID,Chen Yu-Jen1678ORCID,Hsieh Chen-Hsi6910ORCID

Affiliation:

1. Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan

2. School of Chinese Medicine, China Medical University, Taichung 404, Taiwan

3. Department of Oncology and Hematology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan

4. School and Graduate Institute of Physical Therapy, College of Medicine, National Taiwan University, Taipei 100, Taiwan

5. Physical Therapy Center, National Taiwan University Hospital, Taipei 100, Taiwan

6. Institute of Traditional Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan

7. Department of Radiation Oncology, Mackay Memorial Hospital, Taipei 104, Taiwan

8. Department of Artificial Intelligence and Medical Application, MacKay Junior College of Medicine, Nursing, and Management, Taipei 112, Taiwan

9. School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan

10. Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan

Abstract

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 (KH2PO4)–methanol solution (27:73, v/v) for cabozantinib. There were no statistically significant differences in the concentration versus time curve of cabozantinib (AUCcabozantinib) between the control group and the RT2Gy×3 f’x and RT9Gy×3 f’x groups in the concurrent and the sequential regimens. However, compared to those in the control group, the Tmax, T1/2 and MRT decreased by 72.8% (p = 0.04), 49.0% (p = 0.04) and 48.5% (p = 0.04) with RT2Gy×3 f’x in the concurrent regimen, respectively. Additionally, the T1/2 and MRT decreased by 58.8% (p = 0.01) and 57.8% (p = 0.01) in the concurrent RT9Gy×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 RT2Gy×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 RT9Gy×3 f’x sequential regimen. Compared to the RT9Gy×3 f’x concurrent regimen, the RT9Gy×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 RT9Gy×3 f’x is more significant with the sequential regimen than with the concurrent regimen.

Funder

Far Eastern Memorial Hospital

the Ministry of Science and Technology, Taiwan

NYMU-FEMH Joint Research Program

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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