Evaluation of the Effects of Food on the Single‐Dose Pharmacokinetics of Trametinib, a First‐in‐Class MEK Inhibitor, in Patients with Cancer. (25th July 2013)

• Record Type: Journal Article
• Authors: Cox, Donna S.; Papdopoulos, Kyri; Fang, Lei; Bauman, John; LoRusso, Patricia; Tolcher, Anthony; Patnaik, Amita; Pendry, Carolyn; Orford, Keith; Ouellet, Daniele
• Is Part Of: Journal of clinical pharmacology. Volume 53:Number 9(2013:Sep.)
• Page Start: 946
• Page End: 954
• Publication Date: 2013-07-25
• Subjects: Pharmacology -- Periodicals; Pharmacology -- Periodicals; Pharmacology, Clinical -- Periodicals; 615.1
• DOI: 10.1002/jcph.115
• Languages: English
• ISSNs: 0091-2700

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="jcph115-sec-0001" sec-type="section"> <p>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.</p> </sec> </abstract>