Robust combination of liver stereotactic body radiotherapy modulates pharmacokinetics of sorafenib toward preferable parameters

Abstract

To evaluate the effect and mechanism of radiotherapy (RT)-sorafenib pharmacokinetics (PK) in different regimens with conventional or high dose irradiation. Between February 2012 and December 2018, 43 patients with portal vein tumor thrombosis treated with sorafenib plus conventional RT (58%) or stereotactic body radiation therapy (SBRT, 42%) were retrospectively reviewed. In vivo and in vitro studies of concurrent and sequential RT with sorafenib were designed. SBRT resulted in a 3-fold increase in complete recanalization compared to conventional RT group (28% vs. 8%, p = 0.014). Compared to the control group, the area under the concentration vs. time curve (AUC) of sorafenib was increased in the concurrent Rt 2Gy and Rt 9Gy groups and the sequential RT 9Gy group by 132% (p = 0.046), 163% (p = 0.038) and 102% (p = 0.018), respectively; and was decreased by 59% in the sequential Rt 2Gy group (p = 0.036). Sequential RT 2Gy and Rt 9Gy increased CYP3A4 activity by 82% (p = 0.028) and 203% (p = 0.0004), respectively, compared to that with the corresponding concurrent regimen. SBRT produced better recanalization than conventional RT with sorafenib. The AUC of sorafenib was modulated by RT. P-gp expression was not influenced by RT. The sequential RT regimen increased CYP3A4 activity that may increase the RT-sorafenib synergy effect and overall sorafenib activity. The biodistribution of sorafenib was modulated by local RT with the different regimens.

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

“…Moreover, preclinical data from studies combining sorafenib and RT have suggested improved efficacy in HCC cell lines both in vitro and in vivo [ 21 , 22 ]. Additionally, the efficacy of RT with sorafenib in patients with unresectable HCC has been reported [ 7 , 8 ]. Moreover, the AUC of sorafenib can be modulated by RT [ 8 ].…”

“…A freely moving rat model was designed for the current study [ 8 ]. The rats were anesthetized and immobilized on a board while undergoing computed tomography to localize the whole liver or a central area measuring 1.5 cm × 1.5 cm for the SBRT technique.…”

“…Stereotactic body radiation therapy (SBRT) is an advanced external beam radiotherapy (EBRT) technique, which can be considered as an alternative to ablation/embolization techniques, or used when these techniques fail or are contraindicated for HCC [ 5 , 6 ]. Recently, impressive benefits have been reported for radiotherapy (RT) combined with sorafenib in patients with unresectable HCC [ 7 , 8 ], but severe adverse effects have also been reported [ 9 , 10 ]. Moreover, interactions between RT and sorafenib, regardless of the target or off-target radiation dose, were confirmed by pharmacokinetics (PK) in a freely moving rat model [ 8 ].…”

“…Recently, impressive benefits have been reported for radiotherapy (RT) combined with sorafenib in patients with unresectable HCC [ 7 , 8 ], but severe adverse effects have also been reported [ 9 , 10 ]. Moreover, interactions between RT and sorafenib, regardless of the target or off-target radiation dose, were confirmed by pharmacokinetics (PK) in a freely moving rat model [ 8 ].…”

“…NF-κB responds to environmental stress, including RT [ 13 ]. Additionally, the expression of CYP3A4 can be affected by RT [ 8 ]. Furthermore, lenvatinib targets: VEGFR1, 2, and 3; fibroblast growth factor receptor (FGFR) 1, 2, 3, and 4; PDGFR-alpha (α); the RET proto-oncogene; and c-kit [ 14 , 15 ], and is metabolized primarily in the liver, undergoing oxidative metabolism via CYP3A4 [ 16 ].…”