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 (AUC_lenvatinib) by 51.1% with three fractions of 2 Gy (RT_2Gy×3f’x, p = 0.03), and 48.9% with RT_9Gy×3f’x (p = 0.03). The AUC_lenvatinib increased by 148.8% (p = 0.008) with RT_2Gy×3f’x, and 68.9% (p = 0.009) with RT_9Gy×3f’x in the sequential regimen compared to the concurrent regimen. There were no differences in the AUC_lenvatinib between RT_2Gy×3f’x and RT_9Gy×3f’x in the concurrent or sequential regimen. Both the RT_2Gy×3f’x and RT_9Gy×3f’x concurrent regimens markedly decreased the biodis-tribution of lenvatinib in the heart, liver, lung, spleen, and kidneys, which ranged from 31% to 100% for RT_2Gy×3f’x, and 11% to 100% for RT_9Gy×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.