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Concomitant oral and intravenous pharmacokinetics of trametinib, a MEK inhibitor, in subjects with solid tumours.


ABSTRACT: The aim of this phase 1, single centre, open label study in four patients with solid tumours was to determine the absolute bioavailability of a 2?mg oral dose of trametinib. Trametinib is an orally bioavailable, reversible and selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity.A microtracer study approach, in which a 5??g radiolabelled i.v. microdose of trametinib was given concomitantly with an unlabelled 2?mg oral tablet formulation, was used to recover i.v. and oral pharmacokinetic parameters, simultaneously.The least-squares mean (90% confidence interval) absolute bioavailability of trametinib (2?mg tablet) was 72.3% (50.0%, 104.6%). Median tmax after oral administration was 1.5?h and the geometric mean terminal half-life was 11?days. The geometric mean clearance and volume of distribution after i.v. administration were 3.21?l?h(-1) and 976?l, respectively, resulting in a terminal elimination half-life of 11?days.Trametinib absolute bioavailability was moderate to high, whereas first pass metabolism was low.

SUBMITTER: Leonowens C 

PROVIDER: S-EPMC4243903 | BioStudies | 2014-01-01

REPOSITORIES: biostudies

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