• Cathrine Leonowens, Carolyn Pendry, John Bauman, Graeme C Young, May Ho, Frank Henriquez, Lei Fang, Royce A Morrison, Keith Orford, and Daniele Ouellet.
• GlaxoSmithKline, Research Triangle Park, NC, USA.
• Br J Clin Pharmacol. 2014 Sep 1;78(3):524-32.

AimsThe 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.MethodsA 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.ResultsThe 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.ConclusionsTrametinib absolute bioavailability was moderate to high, whereas first pass metabolism was low.© 2014 The British Pharmacological Society.

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