Tìm theo
Dabrafenib
Các tên gọi khác (2) :
  • Dabrafenib
  • GSK2118436a
Thuốc Gốc
Small Molecule
CTHH: C23H20F3N5O2S2
PTK: 519.562
Dabrafenib mesylate is a reversible ATP-competitive kinase inhibitor and targets the MAPK pathway. FDA approved on May 29, 2013.
Nhận Dạng Quốc Tế & Đặc Tính Hóa Học
Công thức hóa học
C23H20F3N5O2S2
Phân tử khối
519.562
Monoisotopic mass
519.101050904
InChI
InChI=1S/C23H20F3N5O2S2/c1-23(2,3)21-30-18(19(34-21)16-10-11-28-22(27)29-16)12-6-4-9-15(17(12)26)31-35(32,33)20-13(24)7-5-8-14(20)25/h4-11,31H,1-3H3,(H2,27,28,29)
InChI Key
InChIKey=BFSMGDJOXZAERB-UHFFFAOYSA-N
IUPAC Name
N-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene-1-sulfonamide
Traditional IUPAC Name
N-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide
SMILES
CC(C)(C)C1=NC(=C(S1)C1=NC(N)=NC=C1)C1=C(F)C(NS(=O)(=O)C2=C(F)C=CC=C2F)=CC=C1
Độ hòa tan
3.27e-03 g/l
logP
5.46
logS
-5.2
pKa (strongest acidic)
7.16
pKa (Strongest Basic)
2.91
PSA
110.86 Å2
Refractivity
127.51 m3·mol-1
Polarizability
49.71 Å3
Rotatable Bond Count
5
H Bond Acceptor Count
6
H Bond Donor Count
2
Physiological Charge
0
Number of Rings
4
Bioavailability
0
Dược Lực Học : Dabrafenib caused an inhibition of phosphorylated ERK. This indicates a decrease in cell proliferation. Furthermore, within 24 hours of administration, downstream mediators of the MAPK pathway were inhibited.
Cơ Chế Tác Dụng : Dabrafenib mesylate is a reversible ATP-competitive kinase inhibitor and targets the MAPK pathway. FDA approved on May 29, 2013. Dabrafenib is an inhibitor of some mutated forms of BRAF kinases with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. Dabrafenib also inhibits wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM, respectively, and other kinases such as SIK1, NEK11, and LIMK1 at higher concentrations. Some mutations in the BRAF gene, including those that result in BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth.
Dược Động Học :
▧ Absorption :
After oral administration, median time to achieve peak plasma concentration (Tmax) is 2 hours. Mean absolute bioavailability of oral dabrafenib is 95%.
▧ Volume of Distribution :
Apparent volume of distribution (Vd/F) = 70.3 L. Distribution to the brain is restricted because dabrafenib is a substrate and undergoes efflux by P-glycoprotein and breast cancer resistance protein.
▧ Protein binding :
99.7% bound to human plasma protein.
▧ Metabolism :
Dabrafenib is hepatically metabolized. The biotransformation process is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-debrafenib. This metabolite is further oxidized via CYP3A4 to form carboxy-dabrafenib and subsequently excreted in bile and urine. Carboxy-dabrafenib can also undergo decarboxylation to form desmethyl-dabrafenib, which may be reabsorbed from the gut. Desmethyl-dabrafenib is further metabolized by CYP3A4 to oxidative metabolites.
▧ Route of Elimination :
71% of the dose is excreted in feces. 23% of the dose is excreted in the urine as metabolites only.
▧ Half Life :
Dabrafenib = 8 hours; Hydroxy-dabrafenib = 10 hours; Carboxy-dabrafenib = 21-22 hours; Desmethyl-dabrafenib = 21- 22 hours.
▧ Clearance :
The apparent clearance of dabrafenib is 17.0 L/h after single dosing and 34.4 L/h after 2 weeks of twice daily dosing.
Độc Tính : Most common adverse reactions (≥20%) for dabrafenib are hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome.
Chỉ Định : Dabrafenib is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.
Tương Tác Thuốc :
  • Carbamazepine Strong CYP3A4 inducers may decrease levels of dabrafenib. Consider alternate therapy.
  • Clarithromycin Strong CYP3A4 inhibitors may increase levels of dabrafenib. Consider alternate therapy.
  • Gemfibrozil Strong CYP3A4 inhibitors may increase levels of dabrafenib. Consider alternate therapy.
  • Ketoconazole Strong CYP3A4 inhibitors may increase levels of dabrafenib. Consider alternate therapy.
  • Midazolam Dabrafenib decreased the maximum concentration (Cmax) and area under the curve (AUC) of midazolam (a substrate of CYP3A4) by 61% and 74%, respectively.
  • Nefazodone Strong CYP3A4 inhibitors may increase levels of dabrafenib. Consider alternate therapy.
  • Pantoprazole Proton pump inhibitors may alter the solubility of dabrafenib and reduce its bioavailability.
  • Phenobarbital Strong CYP3A4 inducers may decrease levels of dabrafenib. Consider alternate therapy.
  • Phenytoin Strong CYP3A4 inducers may decrease levels of dabrafenib. Consider alternate therapy.
  • Ranitidine H2-receptor antagonists may alter the solubility of dabrafenib and reduce its bioavailability.
  • Rifampicin Strong CYP3A4 inducers may decrease levels of dabrafenib. Consider alternate therapy.
Liều Lượng & Cách Dùng : Capsule - Oral - 50 mg, 75 mg
Dữ Kiện Thương Mại
Nhà Sản Xuất
Tài Liệu Tham Khảo Thêm
drugbank
http://www.drugbank.ca/drugs/DB08912
KEGG Drug
http://www.genome.jp/dbget-bin/www_bget?drug:D10064
National Drug Code Directory
http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/0173-0847-08
Wikipedia
http://en.wikipedia.org/wiki/Dabrafenib
RxList
http://www.rxlist.com/tafinlar-drug.htm
Drugs.com
http://www.drugs.com/tafinlar.html
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