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.

A Phase 1/1b Study Evaluating Trametinib Plus Docetaxel or Pemetrexed in Patients With Advanced Non–Small Cell Lung Cancer

“…14 The trametinib exposure and demographics of patients with NSCLC from a previous study were similar to those in this study, and data were pooled across studies. 23 The final analysis contained 1826 observations. 14,15,24 The population PK database included trametinib plasma concentration versus time data and covariates such as age, race, sex, and ethnicity.…”

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

“…administration were 11 and 10 days, respectively. The half‐life determined in the food effect study (MEK113709 ) was approximately 5 days, likely due the shorter sampling period (up to 7 days) while the accumulation half‐life was only 4 days. Using a population PK model, estimated terminal half‐lives were 3.9 and 4.8 days for male and female subjects, respectively, and were consistent with the effective half‐life .…”

Effect of Food on the Pharmacokinetics of Quizartinib

“…Exposure to several oral tyrosine kinase inhibitors is affected by the presence of food, necessitating guidance regarding whether to dose these medications with or without food. [17][18][19][20][21][22][23] For example, midostaurin, an FLT3 inhibitor that also targets multiple kinases, is recommended to be administered with food. The effect of food on the PK of midostaurin was evaluated in an open-label, randomized, parallelgroup study following a single 50-mg dose of a final market image formulation in healthy subjects (n = 48); exposure to midostaurin increases 1.2-fold when it is administered with a standard meal (450 calories, 25% fat content) and 1.6-fold when it is administered with a high-fat meal (900-1000 calories, 50% fat content).…”