| 词条 | Cobimetinib |
| 释义 |
| drug_name = | IUPAC_name = (S)-[3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)phenyl][3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl] methanone | image = Cobimetinib.svg | alt = | caption = | pronounce = {{IPAc-en|ˌ|k|oʊ|b|ɪ|ˈ|m|ɛ|t|ɪ|n|ɪ|b}} {{respell|KOH|bim|ET|i-nib}} | tradename = Cotellic | Drugs.com = {{Drugs.com|monograph|cotellic}} | MedlinePlus = a615057 | licence_EU = yes | licence_US = Cobimetinib | pregnancy_AU = D | pregnancy_US = | pregnancy_category = | legal_AU = S4 | legal_CA = Rx-only | legal_UK = POM | legal_US = Rx-only | legal_status = Rx-only | routes_of_administration = By mouth (tablets)[1] | bioavailability = reported from 28%[2] to 46%[1] | protein_bound = 95%[1] | metabolism = Intestinal and low hepatic clearance (mostly CYP3A4 oxidation and UGT2B7 glucuronidation)[1][2] | elimination_half-life = 44 hours (mean)[1] | excretion = Feces (76–77%), urine (17.9–18%) (after oral and IV administration)[1][3] | CAS_number = 934660-93-2 | ATCvet = | ATC_prefix = L01 | ATC_suffix = XE38 | PubChem = 16222096 | IUPHAR_ligand = 7626 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB05239 | ChemSpiderID = 17349374 | UNII = ER29L26N1X | KEGG = D10405 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 90851 | ChEMBL = 2146883 | synonyms = GDC-0973, XL-518 | C=21 | H=21 | F=3 | I=1 | N=3 | O=2 | molecular_weight = 531.3 g/mol | smiles = C1CCN[C@@H](C1)C2(CN(C2)C(=O)C3=C(C(=C(C=C3)F)F)NC4=C(C=C(C=C4)I)F)O | StdInChI=1S/C21H21F3IN3O2/c22-14-6-5-13(19(18(14)24)27-16-7-4-12(25)9-15(16)23)20(29)28-10-21(30,11-28)17-3-1-2-8-26-17/h4-7,9,17,26-27,30H,1-3,8,10-11H2/t17-/m0/s1 | StdInChIKey = BSMCAPRUBJMWDF-KRWDZBQOSA-N }}Cobimetinib (trade name Cotellic) is a MEK inhibitor developed by Exelixis and Genentech (Roche). It is used in combination with vemurafenib, a BRAF inhibitor, to treat melanoma. In November 2015, the U.S. Food and Drug Administration approved cobimetinib for unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib (Zelboraf). Cobimetinib is not indicated for treatment of patients with wild-type BRAF melanoma.[4] Cobimetinib in combination with vemurafenib is reportedly priced at $17,600 per month, or about $211,000 per year.[5] Medical useCobimetinib is approved for use in combination with vemurafenib (Zelboraf) for the treatment of advanced melanoma with BRAF mutation (either V600E or V600K) that cannot be removed by surgery or which has metastasized.[1][6] Adverse effectsCommon adverse effects observed in cobimetinib and vemurafenib co-treated persons in clinical trials included diarrhea, nausea, vomiting, rash, photosensitivity, and pyrexia.[14] Clinical trialsCobimetinib was awarded orphan drug status by the FDA for malignant melanoma with BRAFV600 mutation in 2014. Acquired resistance to BRAF inhibitors, such as vemurafenib and dabrafenib, commonly occurs after a several months of progression-free tumor response. Preclinical data indicated the involvement of MAPK pathways and MAPK-independent signaling in the developed resistance, suggesting dual inhibition of MEK and BRAF kinase as a strategy for increasing the longevity of tumor response seen with BRAF inhibition alone. In phase III clinical trials, the combination of cobimetinib and vemurafenib was tested in patients with BRAFV600-mutated metastatic melanoma, which resulted in significant improvement in progression-free survival in patients, but also produced some increase in toxicity. The combination increased progression-free survival to an average of 12.3 months, compared to 7.2 months for vemurafenib alone. This clinical data also showed that the combination treatment resulted in 65% survival rate of patients 17 months after beginning the treatment, increased rates from the 50% of patients on vemurafenib treatment alone. Adding cobimetinib also increased the median overall survival to 25.6 months, compared to the 18 months for vemurafenib alone.[5][7] Another phase III trial is comparing cobimetinib with atezolizumab and regorafenib for treatment of advanced colorectal cancer.[8] Roche has announced a planned phase III trial of atezolizumab in combination with cobimetinib and vemurafenib for BRAF-mutated melanoma. A phase II trial of cobimetinib with vemurafenib for melanoma with brain metastases was terminated in 2016.[9] Cobimetinib in combination with paclitaxel is in a phase II trial for the treatment of metastatic triple-negative breast cancer. References1. ^1 2 3 4 5 6 {{cite web|title=Cotellic (cobimetinib) Tablets, for Oral Use. Full Prescribing Information|url=http://www.gene.com/download/pdf/cotellic_prescribing.pdf|publisher=Genentech USA, Inc., a Member of the Roche Group. 1 DNA Way, South San Francisco, CA 94080-4990|accessdate=5 October 2016}} 2. ^1 {{cite journal|last1=Takahashi|first1=RH|last2=Choo|first2=EF|last3=Ma|first3=S|last4=Wong|first4=S|last5=Halladay|first5=J|last6=Deng|first6=Y|last7=Rooney|first7=I|last8=Gates|first8=M|last9=Hop|first9=CE|last10=Khojasteh|first10=SC|last11=Dresser|first11=MJ|last12=Musib|first12=L|title=Absorption, Metabolism, Excretion, and the Contribution of Intestinal Metabolism to the Oral Disposition of [14C]Cobimetinib, a MEK Inhibitor, in Humans|journal=Drug Metabolism and Disposition|date=January 2016|volume=44|issue=1|pages=28–39|doi=10.1124/dmd.115.066282|pmid=26451002}} 3. ^{{cite journal|last1=Choo|first1=E|last2=Takahashi|first2=R|last3=Rooney|first3=I|last4=Gates|first4=M|last5=Deng|first5=A|last6=Musib|first6=L|title=Abstract B160: Assessing Human Absorption, Metabolism, Routes of Excretion and the Contribution of Intestinal Metabolism to the Oral Clearance of Cobimetinib, a MEK Inhibitor|journal=Molecular Cancer Therapeutics|date=January 30, 2014|volume=12|issue=11 Supplement|pages=B160|doi=10.1158/1535-7163.TARG-13-B160}} 4. ^http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm472193.htm 5. ^1 {{cite news|last1=Staton|first1=Tracy|title=Ready to rumble, Novartis? Roche targets melanoma-fighting combo market with new FDA nod|url=http://www.fiercepharma.com/story/ready-rumble-novartis-roche-targets-melanoma-fighting-combo-market-new-fda/2015-11-11|accessdate=2 December 2015|work=FiercePharma|agency=Questex|publisher=FierceMarkets|date=11 November 2015}} 6. ^{{cite web |url=http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm471934.htm |title=FDA approves Cotellic as part of combination treatment for advanced melanoma |date=10 November 2015 |website=U.S. Food and Drug Administration |access-date=2 December 2015}} 7. ^1 {{cite journal|last1=Larkin|first1=James|last2=Ascierto|first2=Paolo A.|last3=Dréno|first3=Brigitte|last4=Atkinson|first4=Victoria|title=Combined Vemurafenib and Cobimetinib inBRAF-Mutated Melanoma|journal=New England Journal of Medicine|volume=371|issue=20|year=2014|pages=1867–1876|issn=0028-4793|doi=10.1056/NEJMoa1408868|display-authors=etal|pmid=25265494}} 8. ^https://clinicaltrials.gov/ct2/show/NCT02788279 9. ^https://clinicaltrials.gov/ct2/show/NCT02230306 External links
9 : Azetidines|Benzamides|Experimental cancer drugs|Fluoroarenes|Iodoarenes|MEK inhibitors|Piperidines|Protein kinase inhibitors|Genentech |
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