Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation
Journal
Pharmaceutics
Journal Volume
13
Journal Issue
3
Date Issued
2021-03-13
Author(s)
Abstract
This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT-PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. 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. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f'x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f'x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f'x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f'x group. Both concurrent regimens, RT2Gy × 3 f'x and RT9Gy × 3 f'x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f'x and RT9Gy × 3 f'x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).
Subjects
biodistribution; pharmacokinetics; radiotherapy; regorafenib; stereotactic body radiation therapy (SBRT)
Biodistribution; Pharmacokinetics; Radiotherapy; Regorafenib; Stereotactic body radiation therapy (SBRT)
SDGs
Other Subjects
regorafenib; sorafenib; adult; animal experiment; apoptosis; area under the curve; Article; cancer incidence; cancer radiotherapy; cell viability; conformal radiotherapy; controlled study; disease exacerbation; drug dose sequence; external beam radiotherapy; HA22T/VGH cell line; heart; Hep-G2 cell line; in vitro study; in vivo study; intensity modulated radiation therapy; irradiation; kidney; liver; liver cell carcinoma; lung; male; nonhuman; rat; stereotactic body radiation therapy
Publisher
MDPI
Type
journal article