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

SIMPLE SUMMARY: Lenvatinib is a systemic treatment for patients with advanced hepatocellular carcinoma (HCC). Stereotactic body radiation therapy (SBRT) is an advanced technique of hypofractionated external beam radiotherapy (EBRT) that can be applied in patients with HCC. The current study showed that the area under the concentration–time curve of lenvatinib concentration (AUC(lenvatinib)) increased by 148.8% with radiotherapy (RT)(2Gy×3f’x) (EBRT for the whole liver), and 68.9% with RT(9Gy×3f’×) (SBRT targeting a 1.5 × 1.5 cm region in the center of the liver) in the sequential regimen compared to the concurrent regimen in rats. Additionally, the AUC(lenvatinib) was decreased by 50% in the concurrent regimen of both RT techniques with lenvatinib compared to the control group. The biodistribution of lenvatinib in the organs at risk was markedly decreased in the concurrent regimens. The radiation–drug interactions were between lenvatinib and RT, and showed sequential preferably. ABSTRACT: 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 biodistribution 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.