Concomitant oral and intravenous pharmacokinetics of trametinib, a MEK inhibitor, in subjects with solid tumours. (September 2014)

• Record Type: Journal Article
• Authors: Leonowens, Cathrine; Pendry, Carolyn; Bauman, John; Young, Graeme C.; Ho, May; Henriquez, Frank; Fang, Lei; Morrison, Royce A.; Orford, Keith; Ouellet, Daniele
• Is Part Of: British journal of clinical pharmacology. Volume 78:Number 3(2014:Sep.)
• Page Start: 524
• Page End: 532
• Publication Date: 2014-09
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12373
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12373-sec-0001" sec-type="section"> <title>Aims</title> <p>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.</p> </sec> <sec id="bcp12373-sec-0002" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="bcp12373-sec-0003" sec-type="section"> <title>Results</title> <p>The least‐squares mean (90% confidence interval) absolute bioavailability of trametinib (2 mg tablet) was 72.3% (50.0%, 104.6%). Median <italic>t</italic><sub>max</sub> 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<sup>−1</sup> and 976 l, respectively, resulting in a terminal elimination half‐life of 11 days.</p> </sec> <sec id="bcp12373-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Trametinib absolute bioavailability was moderate to high, whereas first pass metabolism was low.</p> </sec> </abstract>