Effect of conventional liver irradiation on the pharmacokinetics of sorafenib through p-glycoprotein: Results of concurrent and sequential strategy.

Abstract

338 Background: Sorafenib is a multi-kinase inhibitor that demonstrated a significant improved survival of patients with hepatocellular carcinoma (HCC). The efficacy of radiotherapy (RT) concurrent or sequential with sorafenib in unresectable HCC patients has better effects than single agent. However, the mechanism for local RT on sorafenib in the plasma system remains unclear. Here, we evaluate the mechanism of liver irradiation on the pharmacokinetics (PK) of sorafenib using rats as an experimental model. Methods: Free-moving rat model was used in the current study. Image-guided RT with 2 Gy was delivered to the whole liver of Sprague-Dawley rats. The experimental animals were randomized to (A) the sorafenib-only (40 mg/kg, p.o.) group and (B) pre-treated with cyclosporin A [CsA, p-glycoprotein (p-gp) inhibitor, 20mg/kg, i.p. 30 min before RT] group. In each group, the experimental animals were randomized to sham RT (0 Gy with sorafnib), concurrent (after RT 1 hour) and sequential group (after RT 24 hour), respectively. The PK of sorafenib in the plasma system was calculated. Each group’s data was collected from six rats Results: For sorafenib-only group, compared to the sham-irradiated controls, the area under the concentration versus time curve (AUC) of sorafenib was increased by 132% in concurrent group [719 versus (vs.) 1669 min*ug/mL, p = 0.046]. On the contrary, the AUC of sorafenib was decreased by 59% in sequential group (719 vs. 297 min*ug/mL, p = 0.036). Compared to the sorafenib-only group, the AUC of sorafenib in the concurrent group pre-treated with CsA was decreased by 83% (1669 vs. 278 min*ug/mL, p = 0.011). Interestingly, the AUC of sorafenib in the sequential group pre-treated with CsA was increased by 275% (297 vs. 1113 min*ug/mL, p = 0.023). Conclusions: P-pg plays an important role for the PK of sorafenib that was modulated by whole liver irradiation in rodent model. The strategy for modulating the RT-PK phenomenon of sorafenib through p-gp is worth to investigate in the future.