It is a kinase inhibitor indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-,oxaliplatin- and irinotecan-based chemotherapy,an antiVEGF therapy,and,if KRAS wild type,an anti-EGFR therapy.
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.
Recommended Dose: 160 mg orally,once daily for the first 21 days of each 28-day cycle. ? Take It with food (a low-fat breakfast).
Effect of Strong CYP3A4 Inducers on Regora: Co-administration of a strong CYP3A4 inducer with Regora decreased the plasma concentrations of Regora, increased the plasma concentrations of the active metabolite M-5, and resulted in no change in the plasma concentrations of the active metabolite M-2 and may lead to decreased efficacy. Concomitant use of Regora with strong CYP3A4 inducers (e.g. Rifampin, Phenytoin, Carbamazepine, Phenobarbital, and St. John’s Wort) should be avoided.
Effect of Strong CYP3A4 Inhibitors on Regora: Co-administration of a strong CYP3A4 inhibitor with Regora increased the plasma concentrations of Regora and decreased the plasma concentrations of the active metabolites M-2 and M-5 and may lead to increased toxicity. Concomitant use of Regora with strong CYP3A4 inhibitors (e.g. Clarithromycin, Grapefruit juice, Itraconazole, Ketoconazole, Nefazodone, Posaconazole, Telithromycin, and Voriconazole) should be avoided.
Effect of Regora on Breast Cancer Resistance Protein (BCRP) Substrates: Co-administration of Regora with a BCRP substrate increased the plasma concentrations of the BCRP substrate Patients should be monitored closely for signs and symptoms of exposure related toxicity to the BCRP substrate(e.g. Methotrexate, Fluvastatin, Atorvastatin). Concomitant BCRP substrate product information should be consulted when considering administration of such products together with Regora.
Asthenia/fatigue,decreased appetite and food intake,hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia (PPE)],diarrhea,mucositis,weight loss,infection, hypertension,and dysphonia.
Pregnancy:Regorafenib can cause fetal harm when administered to a pregnant woman. There are no available data on Regorafenib use in pregnant women. Administration of regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose,with increased incidences of cardiovascular,genitourinary,and skeletal malformations. Advise pregnant women of the potential hazard to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population,the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 % and 15 to 20%,respectively.Nursing Mothers: Discontinue drug or nursing,taking into consideration the importance of the drug to the mother.
The highest dose of Regora studied clinically is 220 mg per day. The most frequently observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue. There is no known antidote for Regora overdose. In the event of suspected overdose, Regora should be interrupted, instituted supportive care, and observed until clinical stabilization.
Store below 30°C in a cool and dry place, away from sunlight. Keep out of the reach of children.
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