Trametinib

Trametinib, sold under the brand name Mekinist among others, is an anticancer medication used for the treatment of melanoma.[2][3] It is a MEK inhibitor drug with anti-cancer activity.[4] It inhibits MEK1 and MEK2.[4] It is taken by mouth.[2][3]

Trametinib
Clinical data
Trade namesMekinist
Other namesGSK1120212
AHFS/Drugs.comMonograph
MedlinePlusa613040
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
  • N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.158.135
Chemical and physical data
FormulaC26H23FIN5O4
Molar mass615.404 g·mol−1
3D model (JSmol)
  • Ic1ccc(c(F)c1)N\C3=C\2/C(=O)N(C(=O)N(C/2=C(\C(=O)N3C)C)c4cccc(NC(=O)C)c4)C5CC5
  • InChI=1S/C26H23FIN5O4/c1-13-22-21(23(31(3)24(13)35)30-20-10-7-15(28)11-19(20)27)25(36)33(17-8-9-17)26(37)32(22)18-6-4-5-16(12-18)29-14(2)34/h4-7,10-12,17,30H,8-9H2,1-3H3,(H,29,34)
  • Key:LIRYPHYGHXZJBZ-UHFFFAOYSA-N

The most common side effects include rash, diarrhea, tiredness, peripheral edema (swelling, especially of ankles and feet), nausea and acneiform dermatitis (acne-like inflammation of the skin).[3] When taken in combination with dabrafenib the most common side effects include fever, tiredness, nausea, chills, headache, diarrhea, vomiting, joint pain and rash.[3]

In May 2013, trametinib was approved as a single-agent by the US Food and Drug Administration for the treatment of people with V600E mutated metastatic melanoma.[5][6] It was approved for medical use in the European Union in June 2014.[3]

History

Clinical trial data demonstrated that resistance to single-agent trametinib often occurs within 6 to 7 months.[7] To overcome this, trametinib was combined with the BRAF inhibitor dabrafenib.[7] As a result of this research, on 8 January 2014, the FDA approved the combination of dabrafenib and trametinib for the treatment of patients with BRAF V600E/K-mutant metastatic melanoma.[8] On 1 May 2018, the FDA approved the combination dabrafenib/trametinib as an adjuvant treatment for BRAF V600E-mutated, stage III melanoma after surgical resection based on the results of the COMBI-AD phase 3 study,[9] making it the first oral chemotherapy regimen that prevents cancer relapse for node positive, BRAF-mutated melanoma.[10]

Research

Trametinib had good results for metastatic melanoma carrying the BRAF V600E mutation in a phase III clinical trial. In this mutation, the amino acid valine (V) at position 600 within the BRAF protein has become replaced by glutamic acid (E) making the mutant BRAF protein constitutively active.[11]

References
  1. "Prescription medicines: registration of new chemical entities in Australia, 2014". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  2. "Mekinist- trametinib tablet, film coated". DailyMed. 22 June 2022. Archived from the original on 26 November 2022. Retrieved 3 January 2023.
  3. "Mekinist EPAR". European Medicines Agency. 17 September 2018. Archived from the original on 9 August 2021. Retrieved 27 February 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. "Trametinib". NCI Drug Dictionary. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Archived from the original on 3 January 2023. Retrieved 28 February 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  5. "Drug Approval Package: Mekinist (trametinib) Tablets NDA #204114". U.S. Food and Drug Administration (FDA). 8 July 2013. Archived from the original on 27 October 2022. Retrieved 27 February 2023.
  6. "GSK melanoma drugs add to tally of U.S. drug approvals". Reuters. 30 May 2013. Archived from the original on 24 September 2015. Retrieved 5 July 2021.
  7. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. (November 2012). "Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations". The New England Journal of Medicine. 367 (18): 1694–703. doi:10.1056/NEJMoa1210093. PMC 3549295. PMID 23020132.
  8. "Dabrafenib/Trametinib Combination Approved for Advanced Melanoma". OncLive. 9 January 2014. Archived from the original on 25 January 2014. Retrieved 20 January 2014.
  9. Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, et al. (November 2017). "Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma" (PDF). The New England Journal of Medicine. 377 (19): 1813–1823. doi:10.1056/NEJMoa1708539. PMID 28891408. S2CID 205102412. Archived (PDF) from the original on 29 August 2021. Retrieved 1 October 2019.
  10. "FDA Approves Adjuvant Combo for BRAF+ Melanoma". www.medscape.com. WebMD LLC. Archived from the original on 6 May 2018. Retrieved 2 May 2018.
  11. Robert C, Flaherty KT, Hersey P, Nathan PD, Garbe C, Milhem MM, et al. (31 January 2017). "METRIC phase III study: Efficacy of trametinib (T), a potent and selective MEK inhibitor (MEKi), in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy (C) in patients (pts) with BRAFV600E/K mutant advanced or metastatic melanoma (MM)". Journal of Clinical Oncology. 30 (18_suppl): LBA8509. doi:10.1200/jco.2012.30.18_suppl.lba8509.
  • "Trametinib". Drug Information Portal. U.S. National Library of Medicine.


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