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

Abstract

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. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Following oral dosing of 2 mg trametinib, median tmax was 1.5 h and the mean effective half-life (t1/2) was approximately 4 days. Trametinib is greater than 95% protein bound. Trametinib accumulates about six-fold with repeat daily dosing, and the concentration-time profiles showed a flat profile at steady-state with a low peak : trough ratio.• The absolute bioavailability of trametinib has not been previously reported.• The microtracer approach has been used previously to recover i.v. and oral pharmacokinetic parameters, simultaneously, which are used to estimate absolute bioavailability.• Determination of absolute bioavailability improves our understanding of the clinical pharmacology of a compound. WHAT THIS STUDY ADDS• Trametinib has moderate to high bioavailability (72.3%) following oral administration of a 2 mg tablet.• The i.v. microtracer study approach revealed the contribution of high oral bioavailability with low first pass metabolism and a prolonged terminal elimination phase to the pharmacokinetics of trametinib.

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Adding value through accelerator mass spectrometry‐enabled first in human studies

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Approaches to intravenous clinical pharmacokinetics: Recent developments with isotopic microtracers

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