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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01416337.

Keywords: bioavailability; intravenous; microtracer; pharmacokinetic; trametinib.

© 2014 The British Pharmacological Society.

Figures

Figure 1

(A) Individual plasma trametinib and [14C]-trametinib concentration vs. time profiles after oral (2 mg) and i.v. (5 μg) administration. Individual patients are denoted by symbols and colours. The dashed lines represent oral trametinib; the solid lines represent i.v. [14C]-trametinib. Inset shows detail from 0 to 24 h post-dose

Figure 2

Mean plasma [14C]-trametinib (solid line, ng ml−1) and total radioactivity (dashed line, ng equivalents of trametinib ml−1) concentration vs. time profile after i.v.; 5 μg administration (n = 4). Inset shows detail from 0 to 24 h post-dose. , [14C]-trametinib; , total radioactivity

Figure 3

Individual AUC(0,tlast) and Cmax values for a single 2 mg oral dose of trametinib (A,C) or a single 5 μg i.v. dose of [14C]-trametinib (B,D). Symbols denote male (triangles) and female (circles) subjects