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Cobimetinib

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Cobimetinib
Clinical data
PronunciationKOE-bi-ME-ti-nib
Trade namesCotellic
Other namesGDC-0973, XL-518
AHFS/Drugs.comMonograph
MedlinePlusa615057
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth (tablets)[1]
ATC code
  • None
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailabilityreported from 28%[2] to 46%[1]
Protein binding95%[1]
MetabolismIntestinal and low hepatic clearance (mostly CYP3A4 oxidation and UGT2B7 glucuronidation)[1][2]
Elimination half-life44 hours (mean)[1]
ExcretionFeces (76–77%), urine (17.9–18%) (after oral and IV administration)[1][3]
Identifiers
  • (S)-[3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)phenyl][3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl] methanone
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H21F3IN3O2
Molar mass531.3 g/mol g·mol−1
3D model (JSmol)
  • 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
  • InChI=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
  • Key:BSMCAPRUBJMWDF-KRWDZBQOSA-N

Cobimetinib (trade name Cotellic) is a MEK inhibitor developed by Exelixis and Genentech. 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] A competing dual therapy, using dabrafenib along with trametinib, is also approved by the FDA,[6] and is reported to cost $15,300 monthly, or $183,600 per year.[5]

Medical use

Cobimetinib is approved for use in combination with vemurafenib (trade name Zelboraf) for the treatment of advanced melanoma that cannot be removed by surgery or which has spread to other parts of the body, provided that the melanoma has an abnormal gene, with a mutation of BRAF (either V600E or V600K).[1][7]

Adverse effects

Common adverse effects observed in cobimetinib and vemurafinib co-treated persons in clinical trials included diarrhea, nausea, vomiting, rash, photosensitivity, and pyrexia.[8]

Clinical trials

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 metastic 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][8]

References

  1. ^ a b c d e f g "Cotellic (cobimetinib) Tablets, for Oral Use. Full Prescribing Information" (PDF). Genentech USA, Inc., a Member of the Roche Group. 1 DNA Way, South San Francisco, CA 94080-4990. Retrieved 5 October 2016.
  2. ^ a b Takahashi, RH; Choo, EF; Ma, S; Wong, S; Halladay, J; Deng, Y; Rooney, I; Gates, M; Hop, CE; Khojasteh, SC; Dresser, MJ; Musib, L (January 2016). "Absorption, Metabolism, Excretion, and the Contribution of Intestinal Metabolism to the Oral Disposition of [14C]Cobimetinib, a MEK Inhibitor, in Humans". Drug Metabolism and Disposition: the Biological Fate of Chemicals. 44 (1): 28–39. doi:10.1124/dmd.115.066282. PMID 26451002. {{cite journal}}: |access-date= requires |url= (help)
  3. ^ Choo, E; Takahashi, R; Rooney, I; Gates, M; Deng, A; Musib, L (January 30, 2014). "Abstract B160: Assessing Human Absorption, Metabolism, Routes of Excretion and the Contribution of Intestinal Metabolism to the Oral Clearance of Cobimetinib, a MEK Inhibitor". Molecular Cancer Therapeutics. 12 (11 Supplement): B160. doi:10.1158/1535-7163.TARG-13-B160. {{cite journal}}: |access-date= requires |url= (help)
  4. ^ http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm472193.htm
  5. ^ a b c Staton, Tracy (11 November 2015). "Ready to rumble, Novartis? Roche targets melanoma-fighting combo market with new FDA nod". FiercePharma. FierceMarkets. Questex. Retrieved 2 December 2015.
  6. ^ http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm381451.htm
  7. ^ "FDA approves Cotellic as part of combination treatment for advanced melanoma". U.S. Food and Drug Administration. 10 November 2015. Retrieved 2 December 2015.
  8. ^ a b Larkin, James; Ascierto, Paolo A.; Dréno, Brigitte; Atkinson, Victoria; et al. (2014). "Combined Vemurafenib and Cobimetinib inBRAF-Mutated Melanoma". New England Journal of Medicine. 371 (20): 1867–1876. doi:10.1056/NEJMoa1408868. ISSN 0028-4793.
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