Tìm theo
Regorafenib
Các tên gọi khác (2) :
  • BAY 73-4506
  • Regorafenibum
Thuốc điều trị ung thư
Thuốc Gốc
Small Molecule
CAS: 755037-03-7
ATC: L01XE21
CTHH: C21H15ClF4N4O3
PTK: 482.815
Regorafenib is an orally-administered inhibitor of multiple kinases. It is used for the treatment of metastatic colorectal cancer and advanced gastrointestinal stromal tumours. FDA approved on September 27, 2012.
Nhận Dạng Quốc Tế & Đặc Tính Hóa Học
Công thức hóa học
C21H15ClF4N4O3
Phân tử khối
482.815
Monoisotopic mass
482.076880893
InChI
InChI=1S/C21H15ClF4N4O3/c1-27-19(31)18-10-13(6-7-28-18)33-12-3-5-17(16(23)9-12)30-20(32)29-11-2-4-15(22)14(8-11)21(24,25)26/h2-10H,1H3,(H,27,31)(H2,29,30,32)
InChI Key
InChIKey=FNHKPVJBJVTLMP-UHFFFAOYSA-N
IUPAC Name
4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
Traditional IUPAC Name
regorafenib
SMILES
CNC(=O)C1=CC(OC2=CC(F)=C(NC(=O)NC3=CC=C(Cl)C(=C3)C(F)(F)F)C=C2)=CC=N1
Độ hòa tan
Insoluble
logP
4.49
logS
-5.7
pKa (strongest acidic)
10.52
pKa (Strongest Basic)
2.02
PSA
92.35 Å2
Refractivity
114.73 m3·mol-1
Polarizability
41.23 Å3
Rotatable Bond Count
6
H Bond Acceptor Count
3
H Bond Donor Count
3
Physiological Charge
0
Number of Rings
3
Bioavailability
1
Rule of Five
true
MDDR-Like Rule
true
Cơ Chế Tác Dụng : Regorafenib is an orally-administered inhibitor of multiple kinases. It is used for the treatment of metastatic colorectal cancer and advanced gastrointestinal stromal tumours. FDA approved on September 27, 2012. 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.
Dược Động Học :
▧ Absorption :
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%.
▧ Volume of Distribution :
Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour dosing interval.
▧ Protein binding :
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).
▧ Route of Elimination :
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.
▧ Half Life :
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);
Độc Tính : 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
Chỉ Định : 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 tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.
Tương Tác Thuốc :
  • Carbamazepine Strong CYP3A4 inducers may decrease levels of regorafenib.
  • Clarithromycin Strong CYP3A4 inhibitors may increase levels of regorafenib.
  • Irinotecan Regorafenib may increase levels of irinotecan, a UGT1A1 substrate.
  • Itraconazole Strong CYP3A4 inhibitors may increase levels of regorafenib.
  • Ketoconazole Strong CYP3A4 inhibitors may increase levels of regorafenib.
  • Phenobarbital Strong CYP3A4 inducers may decrease levels of regorafenib.
  • Phenytoin Strong CYP3A4 inducers may decrease levels of regorafenib.
  • Posaconazole Strong CYP3A4 inhibitors may increase levels of regorafenib.
  • Rifampicin Strong CYP3A4 inducers may decrease levels of regorafenib.
  • St. John's Wort Strong CYP3A4 inducers may decrease levels of regorafenib.
  • Telithromycin Strong CYP3A4 inhibitors may increase levels of regorafenib.
  • Voriconazole Strong CYP3A4 inhibitors may increase levels of regorafenib.
Liều Lượng & Cách Dùng : Tablet - Oral - 40 mg
Dữ Kiện Thương Mại
Nhà Sản Xuất
Tài Liệu Tham Khảo Thêm
drugbank
http://www.drugbank.ca/drugs/DB08896
KEGG Drug
http://www.genome.jp/dbget-bin/www_bget?drug:D10138
National Drug Code Directory
http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/50419-171-03
Wikipedia
http://en.wikipedia.org/wiki/Regorafenib
RxList
http://www.rxlist.com/stivarga-drug.htm
Drugs.com
http://www.drugs.com/cdi/regorafenib.html
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