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examined in the Huh-7 cell line. The RT-PK phenomenon and biodistribution of

regorafenib under RT were confirmed in the free-moving rat model.

Results: Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent

manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib

treatment. Local liver irradiation in the concurrent regimen decreased the AUCplasm of

regorafenib by 33.0% at RT2Gy (p=0.356) and 35.2% at RT9Gy (p=0.405). The

AUCplasm of regorafenib was increased by 182.8% at RT2Gy (p=0.011) and 213.2% at

RT9Gy (p=0.016) in the sequential regimens. Additionally, compared to the concurrent

group, the AUCplasm of regorafenib was increased by 322.4% at RT2Gy (p=0.005) and

383.7% at RT9Gy (p=0.01) in the sequential group. The sequential regimen increased

the biodistribution of regorafenib more than the concurrent regimen at both dose

levels. The most influenced organs were liver, heart and lungs. The liver and renal

function stay normal no matter in the concurrent or sequential regimen.

Conclusions: The PK of regorafenib can be modulated by irradiation and may be

correlated with the effect and toxicity. The timing of the application of regorafenib

and RT influences the AUC and biodistribution during treatment. Additionally,

off-target and SBRT doses possess similar ability to modulate systemic therapy.