Abstract 3766: Effects of a high-fat meal on the pharmacokinetics of orally administered GSK2118436 in patients with BRAF mutation-positive tumors

GSK2118436 is a potent and selective small-molecule inhibitor of BRAF kinase activity that is currently being developed for the treatment of BRAF mutation-positive tumors. This study evaluated the effect of a high-fat meal on the pharmacokinetics (PK) of a single 150 mg oral dose of GSK2118436 administered to patients with BRAF-mutant solid tumors. This was an open-label, randomized, two-period crossover study. In a cohort of 14 patients, GSK2118436 was administered under fasted state or with a high-fat meal, with a 1-week washout between periods. Blood samples were collected up to 96 hours post-dose to characterize the PK of GSK2118436 and its circulating metabolites. PK parameters were calculated by non-compartmental methods (WinNonlin 5.2). Geometric mean ratios (fed/fasted) for the point estimate and 90% CIs were calculated for Cmax and AUC0-α, and median difference (90% CI) was calculated for tmax using the Hodges-Lehmann non-parametric method. The absence of a food effect can be concluded if the 90% CIs are contained between 0.8 and 1.25 for Cmax and AUC0-α. Following administration of a high-fat meal, median Cmax concentrations were delayed by 3.7 h (90% CI: 2.4-5.0) compared with the fasted state. A high-fat meal decreased the exposure to GSK2118436, with geometric mean ratios (90% CI) for Cmax and AUC0-α of 0.49 (0.35-0.69) and 0.69 (0.57-0.85), respectively. Metabolite exposures were decreased to a similar extent. Based on the data generated in this study, it appears that there is a food effect for GSK2118436, as the 90% CI are not contained within the acceptable boundaries of 0.8 and 1.25. In clinical studies GSK2118436 has been administered on an empty stomach, and results from this study are consistent with these recommendations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3766. doi:1538-7445.AM2012-3766