trametinib   Click here for help

GtoPdb Ligand ID: 6495

Synonyms: GSK1120212 | GSK1120212B | GSK212 | JTP 74057 | Mekinist® | trametinib dimethyl sulfoxide
Approved drug PDB Ligand
trametinib is an approved drug (FDA (2013), EMA (2014))
Compound class: Synthetic organic
Comment: Trametinib is a Type-3 kinase inhibitor. Marketed formulations contain trametinib dimethyl sulfoxide (PubChem CID 50992434).
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 6
Hydrogen bond donors 2
Rotatable bonds 6
Topological polar surface area 106.61
Molecular weight 615.08
XLogP 6.37
No. Lipinski's rules broken 1
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Canonical SMILES CC(=O)Nc1cccc(c1)n1c(=O)n(C2CC2)c(=O)c2c1c(C)c(=O)n(c2Nc1ccc(cc1F)I)C
Isomeric SMILES CC(=O)Nc1cccc(c1)n1c(=O)n(C2CC2)c(=O)c2c1c(C)c(=O)n(c2Nc1ccc(cc1F)I)C
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)
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Summary of Clinical Use Click here for help
Used to treat BRAF V600 mutation positive metastatic melanomas.
In April 2018, the FDA approved the use of dabrafenib in combination with trametinib for the adjuvant treatment of patients with BRAF V600E or V600K mutated melanoma (as detected by an FDA-approved test) and involvement of lymph node(s), following complete resection. Then in May, this same combination was approved (FDA) for the treatment of locally advanced/metastatic BRAF V600E +ve anaplastic thyroid cancer.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Trametinib inhibits MAP2K1 and MAP2K2 (aka MEK1 and 2) in the p42/p44 MAPK pathway, which is hyper-stimulated in cancers driven by constitutively active BRAF V600 mutations (eg in melanomas) and reduces cell growth in vitro and in vivo [1].
Pharmacokinetics Click here for help
Following oral administration (best administered in the fasted state), time to peak plasma concentration (Tmax) is 1.5 hours. Mean absolute bioavailability of a single 2mg oral dose of trametinib tablet is 72%. Trametinib is 97.4% bound to human plasma proteins.
After repeat dosing, in excess of 75% of drug-related material in plasma is the parent compound. Metabolism is predominantly via deacetylation, probably mediated by hydrolytic enzymes such as carboxyl-esterases or amidases.
Estimated elimination half-life is 3.9 to 4.8 days. Excretion of trametinib is primarily via the feces (>80%), with <20% recovered in the urine. The parent compound accounts for <0.1% of the recovered dose.
Population pharmacokinetics
There are no clinically relevant differences in exposure to trametinib associated with age, gender or race. Data to evaluate potential differences in the exposure of trametinib by race or ethnicity are lacking. No studies have been conducted to evaluate the pharmacokinetics of trametinib in pediatric patients.
Organ function impairment
Mild hepatic impairment has no clinically important effect on total exposure to trametinib. The pharmacokinetics of trametinib have not been studied in patients with moderate or severe hepatic impairment. Given the low level of renal excretion, renal impairment is unlikely to have a clinically relevant effect on total exposure to trametinib.
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