Regorafenib

482.815

482.82

24T2A1DOYB

DTXSID60226441

C78204

L01XE21|L - Antineoplastic and immunomodulating agents

29242990

92.35000

4.2

1.5±0.1 g/cm3

206.0 to 210.0 °C

513.4±50.0 °C at 760 mmHg

264.3±30.1 °C

1.616

Insoluble

P201, P202, P260, P263, P264, P270, P273, P281, P308+P313, P314, P391, P405, P501

H360

|Danger|H302 (98.9%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P263, P264, P270, P273, P281, P301+P312, P308+P313, P314, P330, P391, P405, and P501|Aggregated GHS information provided by 91 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The most common adverse reactions (≥20%) are asthenia/fatigue, HFSR, diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, and infection, pain (not otherwise specified), decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea

In large clinical trials of regorafenib, elevations in serum aminotransferase levels were common, occurring in 39% to 45% of patients, and were greater than 5 times the upper limit of normal (ULN) in 3% to 6%. In addition, there have been several reports of clinically apparent liver injury arising during regorafenib therapy which was often severe and occasionally fatal, estimated to occur in 0.3% of treated subjects. For these reasons, routine monitoring of liver enzymes is recommended. Regorafenib induced liver injury can present in several different patterns or phenotypes. Some patients present within a few days of starting regorafenib with acute hepatic necrosis, high levels of serum aminotransferase and lactic dehydrogenase with mild jaundice, but prolongation of INR and signs of hepatic failure. The injury can be severe but is generally self-limited and recovery is rapid and complete. Other patients present with an acute viral hepatitis like pattern, hepatocelllar (or mixed) serum enzyme elevations and jaundice that can be prolonged and has been fatal in several instances. Autoimmune and immunoallergic features are uncommon. In addition, rare instances of regorafenib associated liver injury have presented with a sinusoidal obstruction-like syndrome or pseudocirrhosis, with marked hepatic nodularity and ascites that eventually improves or resolves. Finally, regorafenib, like other multi-kinase inhibitors [sunitinib, imatinib, sorafenib], has also been associated with episodes of hyperammonemic coma generally arising within a few days or weeks of starting and with rapid reversal upon stopping treatment.

Regorafenib is highly bound (99.5%) to human plasma proteins.

Regorafenib is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. Regorafenib is also indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumour (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. Regorafenib is also indicated for the treatment of patients with hepatocellular carcinoma (HCC) previously treated with sorafenib.|FDA Label|Stivarga is indicated as monotherapy for the treatment of adult patients with:metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies - these include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy;unresectable or metastatic gastrointestinal stromal tumors (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib;hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.|Treatment of all conditions contained in the category of malignant neoplasms (except haematopoietic and lymphoid tissue)|Drug: Regorafenib

Regorafenib is an oral multi-kinase inhibitor that is used in the therapy of refractory metastatic colorectal cancer, hepatocellular carcinoma and gastrointestinal stromal tumor. Regorafenib has been associated with frequent serum aminotransferase elevations during therapy and with rare, but sometimes severe and even fatal instances of clinically apparent liver injury.

Antineoplastic Agents

Cmax = 2.5 μg/mL; Tmax = 4 hours; AUC = 70.4 μg*h/mL; Cmax, steady-state = 3.9 μg/mL; AUC, steady-state = 58.3 μg*h/mL; The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%.|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.|Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour dosing interval.

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). Regorafenib is an inhibitor of P-glycoprotein, while its active metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) are substrates of P-glycoprotein.

Regorafenib, 160 mg oral dose = 28 hours (14 - 58 hours); M2 metabolite, 160 mg oral dose = 25 hours (14-32 hours); M5 metabolite, 160 mg oral dose = 51 hours (32-72 hours);

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, TrkA, 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.

4-(4-(((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)amino)-3-fluorophenoxy)-n-methylpyridine-2-carboxamide

Human drugs -> Stivarga -> EMA Drug Category|Antineoplastic agents, Protein kinase inhibitors -> Human pharmacotherapeutic group|Human drugs -> Rare disease (orphan)|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients