able source), sodium lauryl sulfate, colloidal silicon dioxide. Coating: hypromellose, titanium dioxide, polyethylene glycol, polysorbate 80 (2-mg tablets), iron oxide yellow (0.5-mg tablets), iron oxide red (2-mg tablets).
Mekinist - Clinical Pharmacology
Mechanism of Action
Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. Trametinib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo.
Pharmacodynamics
Administration of 1 mg and 2 mg trametinib to patients with BRAF V600 mutation-positive melanoma resulted in dose-dependent changes in tumor biomarkers including inhibition of phosphorylated ERK, inhibition of Ki67 (a marker of cell proliferation), and increases in p27 (a marker of apoptosis).
Pharmacokinetics
The pharmacokinetics (PK) of trametinib were characterized following single- and repeat-oral administration in patients with solid tumors and BRAF V600 mutation-positive metastatic melanoma.
Absorption: After oral administration, the median time to achieve peak plasma concentrations (Tmax) is 1.5 hours post-dose. The mean absolute bioavailability of a single 2-mg oral dose of trametinib tablet is 72%. The increase in Cmax was dose proportional after a single dose of 0.125 to 10 mg while the increase in AUC was greater than dose proportional. After repeat doses of 0.125 to 4 mg daily, both Cmax and AUC increase proportionally with dose. Inter-subject variability in AUC and Cmax at steady state is 22% and 28%, respectively.
Administration of a single dose of trametinib with a high-fat, high-calorie meal decreased AUC by 24%, Cmax by 70%, and delayed Tmax by approximately 4 hours as compared to fasted conditions [see Dosage and Administration (2.2)].
Distribution: Trametinib is 97.4% bound to human plasma proteins. The apparent volume of distribution (Vc/F) is 214 L.
Metabolism: Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways in vitro. Deacetylation is likely mediated by hydrolytic enzymes, such as carboxyl-esterases or amidases.
Following a single dose of [14C]-trametinib, approximately 50% of circulating radioactivity is represented as the parent compound. However, based on metabolite profiling after repeat dosing of trametinib, ≥75% of drug-related material in plasma is the parent compound.
Elimination: The estimated elimination half-life based on the population PK model is 3.9 to 4.8 days. The apparent clearance is 4.9 L/h.
Following oral administration of [14C]-trametinib, >80% of excreted radioactivity was recovered in the feces while <20% of excreted radioactivity was recovered in the urine with <0.1% of the excreted dose as parent.
Specific Populations: Based on a population pharmacokinetic analysis, age, gender, and body weight do not have a clinically important effect on the exposure of trametinib. There are insufficient data to eva luate potential differences in the exposure of trametinib by race or ethnicity.
Hepatic Impairment: Based on a population pharmacokinetic analysi |