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Concomitant oral and intravenous pharmacokinetics of trametinib, a MEK inhibitor, in subjects with solid tumours
Author(s) -
Leonowens Cathrine,
Pendry Carolyn,
Bauman John,
Young Graeme C.,
Ho May,
Henriquez Frank,
Fang Lei,
Morrison Royce A.,
Orford Keith,
Ouellet Daniele
Publication year - 2014
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12373
Subject(s) - trametinib , pharmacokinetics , bioavailability , pharmacology , concomitant , microdose , mek inhibitor , oral administration , half life , volume of distribution , medicine , chemistry , kinase , mapk/erk pathway , biochemistry
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 t max 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.