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

• Published in: British journal of clinical pharmacology Vol. 78; no. 3; pp. 524 - 532
• Main Authors: Leonowens, Cathrine, Pendry, Carolyn, Bauman, John, Young, Graeme C., Ho, May, Henriquez, Frank, Fang, Lei, Morrison, Royce A., Orford, Keith, Ouellet, Daniele
• Format: Journal Article
• Language: English
• Published: England BlackWell Publishing Ltd 01.09.2014
• Subjects: Administration, Intravenous; Administration, Oral; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; bioavailability; Biological Availability; Female; Half-Life; Humans; intravenous; Male; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase 2 - antagonists & inhibitors; microtracer; Neoplasms - drug therapy; pharmacokinetic; Pharmacokinetics; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - therapeutic use; Pyridones - administration & dosage; Pyridones - pharmacokinetics; Pyridones - therapeutic use; Pyrimidinones - administration & dosage; Pyrimidinones - pharmacokinetics; Pyrimidinones - therapeutic use; Tissue Distribution; trametinib; trametinib; intravenous; pharmacokinetic; bioavailability; microtracer
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.12373

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.