title: Concomitant oral and intravenous pharmacokinetics of trametinib, a MEK inhibitor, in subjects with solid tumours.
abstract: OBJECTIVE
  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.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Cathrine
authors.initials: C
authors.lastname: Leonowens
authors.forename: Carolyn
authors.initials: C
authors.lastname: Pendry
authors.forename: John
authors.initials: J
authors.lastname: Bauman
authors.forename: Graeme C
authors.initials: GC
authors.lastname: Young
authors.forename: May
authors.initials: M
authors.lastname: Ho
authors.forename: Frank
authors.initials: F
authors.lastname: Henriquez
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.forename: Royce A
authors.initials: RA
authors.lastname: Morrison
authors.forename: Keith
authors.initials: K
authors.lastname: Orford
authors.forename: Daniele
authors.initials: D
authors.lastname: Ouellet
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001682:Biological Availability; D005260:Female; D006207:Half-Life; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011728:Pyridones / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2
keywords: bioavailability; intravenous; microtracer; pharmacokinetic; trametinib