A phase I, single‐center, open‐label study to investigate the absorption, distribution, metabolism and excretion of encorafenib following a single oral dose of 100 mg [ (14)C] encorafenib in healthy male subjects

Encorafenib is a novel kinase inhibitor of BRAF V600E as well as wild‐type BRAF and CRAF and has received approval, in combination with binimetinib, to treat BRAF V600E or V600K mutation‐positive unresectable or metastatic melanoma or in combination with cetuximab to treat BRAF V600E mutation‐positive colorectal cancer. The absorption, distribution, metabolism and excretion (ADME) of encorafenib was studied by administering [(14)C] encorafenib (100 mg containing 90 μCi of radiolabeled material) to 4 healthy male subjects (NCT01436656). Following a single oral 100‐mg dose of [(14)C] encorafenib to healthy male subjects, the overall recovery of radioactivity in the excreta was ≥93.9% in all four subjects, indicating that good mass balance was achieved. An equal mean of 47.2% for the radioactivity dose was eliminated in the feces and urine. The percentage of the dose eliminated in the feces (5.0%) and urine (1.8%) as unchanged encorafenib was minor. Metabolism was found to be the major clearance pathway (~88% of the recovered radioactive dose) for encorafenib in humans and is predominantly mediated through N‐dealkylation of the isopropyl carbamic acid methyl ester to form the primary phase 1 direct metabolite M42.5 (LHY746). Oral absorption was estimated from the radioactive dose recovered in the urine (47.2%) and the total radioactive dose recovered in the feces as metabolites (39%). Based on these values and the assumptions that encorafenib and its metabolites are stable in feces, the fraction of oral absorption was estimated to be at least ~86%.