title: Evaluation of the effects of food on the single-dose pharmacokinetics of trametinib, a first-in-class MEK inhibitor, in patients with cancer.
abstract: The aim of this study was to estimate the effect of a high-fat, high-calorie meal on the single-dose pharmacokinetics (PK) of trametinib, a MEK inhibitor. The design of this 2 treatment, 2 period crossover, incomplete wash-out study was influenced by the subject population, long half-life and PK variability; 24 subjects were randomized to a single, oral 2 mg trametinib dose administered in a fed/fasted state, followed by 7 days of serial PK sampling. Period 2 PK parameters were adjusted based on residual Period 1 concentrations. Geometric least square mean ratios of fed:fasted were 0.30, 0.76, and 0.90 for corrected maximum concentration (C(max)), area under concentration-time curve from time 0 to last quantifiable sample (AUC(0-last)) and AUC from time 0 extrapolated to infinity (AUC(0-α)), respectively. Median half-life was 6.3 and 5.3 days for fed and fasted regimens, respectively. Uncorrected PK parameters were consistent with these results. Food delayed absorption and had a mean difference in time of maximum concentration (t(max)) of 3.9 hours. Both oral trametinib doses were well-tolerated. Single-dose trametinib administration with food decreased the rate and, to a lesser degree, the extent of absorption, supporting the recommendation to administer trametinib 1 hour before or 2 hours after a meal.
authors.affiliation: GlaxoSmithKline, Philadelphia, PA 19406, USA.
authors.forename: Donna S
authors.initials: DS
authors.lastname: Cox
authors.forename: Kyri
authors.initials: K
authors.lastname: Papadopoulos
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.forename: John
authors.initials: J
authors.lastname: Bauman
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.forename: Anthony
authors.initials: A
authors.lastname: Tolcher
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Carolyn
authors.initials: C
authors.lastname: Pendry
authors.forename: Keith
authors.initials: K
authors.lastname: Orford
authors.forename: Daniele
authors.initials: D
authors.lastname: Ouellet
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D059305:Diet, High-Fat; D005215:Fasting / Q000378:metabolism; D005260:Female; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D011728:Pyridones / Q000097:blood / Q000493:pharmacokinetics*; D011744:Pyrimidinones / Q000097:blood / Q000493:pharmacokinetics*
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: MEK inhibitor; bioavailability; food-effect; long half-life; pharmacokinetics; trametinib