The Effect of Food and the Proton Pump Inhibitor Rabeprazole on Binimetinib Pharmacokinetics in Healthy Participants

BACKGROUND: Binimetinib is a selective and potent MEK1/MEK2 inhibitor approved in combination with encorafenib for patients with BRAF-mutant melanoma and non-small cell lung cancer. Binimetinib is a basic amine with pH-dependent solubility in vitro, indicating that binimetinib may be susceptible to drug-drug interactions when coadministered with a proton pump inhibitor. OBJECTIVE: The primary objective of this study was to evaluate the effect of a low-fat meal and high-fat meal and, separately, of multiple doses of rabeprazole 20 mg, a proton pump inhibitor, on the pharmacokinetics of a single oral dose of binimetinib 45 mg in healthy subjects. METHODS: The food effect study was an open-label, randomized, three-treatment, three-period, six sequence, crossover study, and the proton pump inhibitor effect study was an open-label, two-period, two-treatment, fixed-sequence study. Both studies were conducted in healthy subjects. RESULTS: A total of 12 participants were enrolled in the study evaluating the effect of food on binimetinib pharmacokinetics and 15 participants were enrolled in the study evaluating the effect of concomitant proton pump inhibitor use on binimetinib pharmacokinetics. The area under the plasma concentration-time curve from 0 extrapolated to infinity for binimetinib did not change in the presence of either a low-fat meal or high-fat meal compared to in the fasted state. The geometric mean ratio peak plasma concentration increased 29% with a low-fat meal and decreased by 17.2% with a high-fat meal. The area under the plasma concentration-time curve from 0 extrapolated to infinity and maximum concentration geometric mean ratio values for binimetinib in the presence of oral rabeprazole versus binimetinib alone increased by 4% and decreased by 17.4%, respectively. There were no serious adverse events or patient discontinuations in either study. CONCLUSIONS: The results indicate that there were no clinically significant changes in pharmacokinetics or tolerability resulting from meals or proton pump inhibitor use during concomitant administration with binimetinib.