Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumorangiogenesis, metastasis and tumor immunity. In vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, Abl and CSF1R at concentrations of regorafenib that have been achieved clinically. In vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model and inhibition of tumor growth in several mouse xenograft models including some for human colorectal carcinoma, gastrointestinal stromal and hepatocellular carcinoma. Regorafenib also demonstrated anti-metastatic activity in a mouse xenograft model and two mouse orthotopic models of human colorectal carcinoma. The effect of multiple doses of Regorafenib (160 mg once daily for 21 days) on the QTc interval was evaluated in an open-label, single-armstudy in 25 patients with advanced solid tumors. No large changes in the mean QTc interval (i.e., >20 msec) were detected in the study.Absorption: Following a single 160 mg dose of Regorafenib in patients with advanced solid tumors, Regorafenib reaches geometric mean peak plasma level (Cmax) of 2.5 µ g/mL at a median time of 4 hours and a geometric mean area under the plasma concentration vs. time curve (AUC) of 70.4 µg*h/mL. The AUC of Regorafenib at steady-state increases less than dose proportionally at doses greater than 60 mg. At steady-state, regorafenib reaches a geometric mean Cmax of 3.9 µg/mL and a geometric mean AUC of 58.3 µg/h/mL. The coefficient of variation of AUC and Cmax is between 35% and 44%. The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%.Distribution: Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour dosing interval. Regorafenib is highly bound (99.5%) to human plasma proteins.Elimination: Following a single 160 mg oral dose of Regorafenib, the geometric mean (minimum to maximum) elimination half-lives for regorafenib and the M-2 metabolite in plasma are 28 hours (14 to 58 hours) and 25 hours (14 to 32 hours), respectively. M-5 has a longer mean (minimum to maximum) elimination half-life of 51 hours (32 to 70 hours).Metabolism: Regorafenib is metabolized by CYP3A4 and UGT1A9. The main circulating metabolites of Regorafenib measured at steady-state in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl). Both metabolites have similar in vitro pharmacological activity and steady-state concentrations as Regorafenib. M-2 and M-5 are highly protein bound (99.8% and 99.95%, respectively).Excretion: Approximately 71% of a radiolabeled dose was excreted in feces (47% as parent compound, 24% as metabolites) and 19% of the dose was excreted in urine (17% as glucuronides) within 12 days after administration of a radiolabeled oral solution at a dose of 120 mg.
