trametinib

Ligand id: 6495

Name: trametinib

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Structure and Physico-chemical Properties

2D Structure
Calculated Physico-chemical Properties
Hydrogen bond acceptors 9
Hydrogen bond donors 2
Rotatable bonds 6
Topological polar surface area 102.06
Molecular weight 615.08
XLogP 4.39
No. Lipinski's rules broken 0

Molecular properties generated using the CDK

No information available.
Summary of Clinical Use
Used to treat BRAF V600 mutation positive metastatic melanomas.
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.
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