Impact of Local Liver Irradiation Concurrent Versus Sequential with Lenvatinib on Pharmacokinetics and Biodistribution.

Concurrent and sequential regimens involving radiotherapy (RT) and lenvatinib were designed with off-target or stereotactic body radiation therapy (SBRT) doses in a freely moving rat model to evaluate the effect of RT on the pharmacokinetics (PK) of lenvatinib. Liver RT concurrent with lenvatinib decreased the area under the concentration-time curve of lenvatinib concentration (AUClenvatinib) by 51.1% with three fractions of 2 Gy (RT2Gy×3f'x, p = 0.03), and 48.9% with RT9Gy×3f'x (p = 0.03). The AUClenvatinib increased by 148.8% (p = 0.008) with RT2Gy×3f'x, and 68.9% (p = 0.009) with RT9Gy×3f'x in the sequential regimen compared to the concurrent regimen. There were no differences in the AUClenvatinib between RT2Gy×3f'x and RT9Gy×3f'x in the concurrent or sequential regimen. Both the RT2Gy×3f'x and RT9Gy×3f'x concurrent regimens markedly decreased the biodistribution of lenvatinib in the heart, liver, lung, spleen, and kidneys, which ranged from 31% to 100% for RT2Gy×3f'x, and 11% to 100% for RT9Gy×3f'x, compared to the sham regimen. The PK and biodistribution of lenvatinib can be modulated by simultaneous off-target irradiation and SBRT doses. The timing of lenvatinib administration with respect to RT, impacted the PK and biodistribution of the drug. Additionally, off-target and SBRT doses had a similar ability to modulate the effect of systemic therapy.