Regorafenib Monohydrate

Regorafenib is a small molecule that blocks many kinases, both those in the cell membrane and those inside the cell. These kinases are involved in normal cell functions and also in disease processes such as oncogenesis, tumor angiogenesis, metastasis and tumor immunity. In vitro biochemical or cellular assays showed that 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. This happened at concentrations that have been reached in patients. In vivo, the drug showed anti-angiogenic activity in a rat tumor model and inhibited tumor growth in several mouse xenograft models, including some for human colorectal carcinoma, gastrointestinal stromal and hepatocellular carcinoma. It also showed anti-metastatic activity in a mouse xenograft model and in two mouse orthotopic models of human colorectal carcinoma.

The effect of multiple doses (160 mg once daily for 21 days) on the QTc interval was studied in an open-label, single-arm study of 25 patients with advanced solid tumors. The study found no large changes in the mean QTc interval (that is, more than 20 msec).

Absorption: After a single 160 mg dose in patients with advanced solid tumors, the geometric mean peak plasma level (Cmax) is 2.5 µg/mL, reached at a median time of 4 hours. The geometric mean area under the plasma concentration vs. time curve (AUC) is 70.4 µg*h/mL. At steady-state, the AUC increases less than dose proportionally at doses greater than 60 mg. The geometric mean Cmax at steady-state is 3.9 µg/mL and the geometric mean AUC is 58.3 µg/h/mL. The coefficient of variation of AUC and Cmax is between 35% and 44%. Compared with an oral solution, the mean relative bioavailability of the tablets is 69% to 83%.

Distribution: The medicine undergoes enterohepatic circulation, so several plasma concentration peaks are seen across the 24-hour dosing interval. It is highly bound (99.5%) to human plasma proteins.

Elimination: After a single 160 mg oral dose, the geometric mean (minimum to maximum) elimination half-life in plasma is 28 hours (14 to 58 hours) for regorafenib and 25 hours (14 to 32 hours) for the M-2 metabolite. M-5 has a longer mean (minimum to maximum) elimination half-life of 51 hours (32 to 70 hours).

Metabolism: CYP3A4 and UGT1A9 metabolize the drug. The main metabolites circulating in human plasma at steady-state are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl). Both have in vitro pharmacological activity and steady-state concentrations similar to the parent drug. M-2 and M-5 are highly protein bound (99.8% and 99.95%, respectively).

Excretion: In a study using a radiolabeled oral solution at a dose of 120 mg, about 71% of the dose was excreted in feces within 12 days after administration (47% as parent compound, 24% as metabolites). About 19% of the dose was excreted in urine (17% as glucuronides) in the same period.