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Synonyms: GSK1120212 | GSK1120212B | GSK212 | JTP 74057 | Mekinist® | trametinib dimethyl sulfoxide
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).
Ligand Activity Visualisation ChartsThese are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts. ✖
View more information in the IUPHAR Pharmacology Education Project: trametinib |
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| No information available. |
Summary of Clinical Use  |
| 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 |
| 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 |
| Absorption/Distribution |
| 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. |
| Biotransformation/Metabolism |
| 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. |
| Elimination |
| 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. |
| External links |
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For extended ADME data see the following: Electronic Medicines Compendium (eMC) Drugs.com European Medicines Agency (EMA) |
