Regorafenib (Mechanism of Action)

In this article, we will discuss Regorafenib (Mechanism of Action). So, let’s get started.

Mechanism of Action


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, tumor angiogenesis, and maintenance of the tumor microenvironment. In 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, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E , SAPK2, PTK5, and Abl at concentrations of regorafenib that have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and inhibition of tumor growth as well as anti-metastatic activity in several mouse xenograft models including some for human colorectal carcinoma.

Pharmacokinetics

Absorption

Following a single 160 mg dose of Regorafenib in patients with advanced solid tumors, regorafenib reaches a geometric mean peak plasma level (Cmax) of 2.5 µg/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%.In a food-effect study, 24 healthy men received a single 160 mg dose of Regorafenib on three separate occasions: under a fasted state, with a high-fat meal and with a low-fat meal. A high-fat meal (945 calories and 54.6 g fat) increased the mean.

AUC of regorafenib by 48% and decreased the mean AUC of the M-2 and M-5 metabolites by 20% and 51%, respectively, as compared to the fasted state. A low-fat meal (319 calories and 8.2 g fat) increased the mean AUC of
regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively as compared to fasted conditions.

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.

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 of them having 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).

Elimination

Following a single 160 mg oral dose of Regorafenib, the geometric mean (range) 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 (range) elimination half-life of 51 hours (32 to 70 hours). 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.

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