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

Aims 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. Methods A microtracer study approach, in which a 5 μg 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. Results 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. Conclusions Trametinib absolute bioavailability was moderate to high, whereas first pass metabolism was low.