Trametinib

Trametinib
Names
Trade namesMekinist
Other namesGSK1120212, trametinib dimethyl sulfoxide (DMSO)
IUPAC name
  • 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
Clinical data
Drug classMEK inhibitor[1]
Main usesMelanoma, non-small cell lung cancer, anaplastic thyroid cancer[2][3]
Side effectsRash, diarrhea, tiredness, swelling, nausea, fever[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • US: D (Evidence of risk)
    Routes of
    use    		By mouth[2]
    Typical dose2mg OD[2]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa613040
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • US: ℞-only
    Chemical and physical data
    FormulaC26H23FIN5O4
    Molar mass615.404 g·mol−1
    3D model (JSmol)
    SMILES
    • 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
    • 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

    Trametinib, sold under the trade name Mekinist, is a medication used to treat certain types of melanoma, non-small cell lung cancer, and anaplastic thyroid cancer.[2][3] Specifically it is used for cancers with the BRAF V600E mutation.[2] It is taken by mouth.[2]

    Common side effects include rash, diarrhea, tiredness, swelling, nausea, and fever.[2] Other side effects may include new cancers, bleeding, colitis, blood clots, and heart failure.[3] Use during pregnancy may harm the baby.[3] It is a MEK inhibitor and blocks both MEK1 and MEK2.[1]

    Trametinib was approved for medical use in the United States in 2013 and Europe in 2014.[3][2] In the United Kingdom a month of medication costs the NHS about £4,800 as of 2021.[4] This amount in the United States costs about 13,200 USD.[5]

    Medical uses

    It is used in melanoma with a specific mutation. 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.

    Other uses

    In a person with a sequence variant in the ARAF gene, trametinib helped the lymphatic system to remodel toward a healthier state, reducing lymphatic edema.[6] This benefit would not occur in most people because it is specific to genomes similar to the reported one, but it is potentially lifesaving for the few people with such genomes.[6] This case provides an example of what precision medicine can accomplish.[6]

    Dosage

    It is taken at a dose of 2mg per day.[2]

    History

    In May 2013, trametinib was approved as a single-agent by the Food and Drug Administration for the treatment of patients with V600E mutated metastatic melanoma.[7] Clinical trial data demonstrated that resistance to single-agent trametinib often occurs within 6 to 7 months.[8] To overcome this, trametinib was combined with the BRAF inhibitor dabrafenib.[8] As a result of this research, on January 8, 2014, the FDA approved the combination of dabrafenib and trametinib for the treatment of patients with BRAF V600E/K-mutant metastatic melanoma.[9] On May 1, 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,[10] making it the first oral chemotherapy regimen that prevents cancer relapse for node positive, BRAF-mutated melanoma.[11]

    References

    1. 1 2 "Trametinib". NCI Drug Dictionary. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Archived from the original on 2015-05-11. Retrieved 2021-07-21.
    2. 1 2 3 4 5 6 7 8 9 10 "Mekinist". Archived from the original on 9 August 2021. Retrieved 8 October 2021.
    3. 1 2 3 4 5 "Trametinib Dimethyl Sulfoxide Monograph for Professionals". Drugs.com. Archived from the original on 11 April 2020. Retrieved 8 October 2021.
    4. ↑ BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 1060. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    5. ↑ "Mekinist Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 11 April 2021. Retrieved 8 October 2021.
    6. 1 2 3 Li, Dong; March, Michael E; Gutierrez-Uzquiza, Alvaro; Kao, Charlly; et al. (2019), "ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor", Nature Medicine, 25 (7): 1116–1122, doi:10.1038/s41591-019-0479-2, PMID 31263281, S2CID 195766663.
    7. ↑ "GSK melanoma drugs add to tally of U.S. drug approvals". Reuters. May 30, 2013. Archived from the original on September 24, 2015. Retrieved July 21, 2021.
    8. 1 2 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.
    9. ↑ "Dabrafenib/Trametinib Combination Approved for Advanced Melanoma". OncLive. January 9, 2014. Archived from the original on January 25, 2014. Retrieved July 21, 2021.
    10. ↑ 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 2021-08-29. Retrieved 2021-07-21.
    11. ↑ "FDA Approves Adjuvant Combo for BRAF+ Melanoma". www.medscape.com. WebMD LLC. Archived from the original on 6 May 2018. Retrieved 2 May 2018.
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