Evaluation of the Mass Balance and Metabolic Profile of Futibatinib in Healthy Participants

Abstract

AbstractFutibatinib, a selective, irreversible fibroblast growth factor receptor 1–4 inhibitor, was recently approved for FGFR2 rearrangement–positive cholangiocarcinoma. This Phase I study evaluated the mass balance and metabolic profile of 14C‐futibatinib single oral 20‐mg dose in healthy participants (n = 6). Futibatinib was rapidly absorbed; median time to peak drug concentration was 1.0 hours. The mean elimination half‐life in plasma was 2.3 hours for futibatinib, and 11.9 hours for total radioactivity. Mean recovery of total radioactivity was 70% of the dose, with 64% recovered in feces and 6% in urine. The major excretion route was fecal; negligible levels were excreted as parent futibatinib. Futibatinib was the most abundant plasma component, comprising 59% of circulating radioactivity (CRA). The most abundant metabolites were cysteinylglycine‐conjugated futibatinib in plasma (13% CRA) and reduction of desmethyl futibatinib in feces (17% of dose). In human hepatocytes, 14C‐futibatinib metabolites included glucuronide and sulfate of desmethyl futibatinib, whose formation was inhibited by 1‐aminobenzotriazole (a pan‐cytochrome P450 inhibitor), and glutathione‐ and cysteine‐conjugated futibatinib. These data indicate the primary metabolic pathways of futibatinib are O‐desmethylation and glutathione conjugation, with cytochrome P450 enzyme‐mediated desmethylation as the main oxidation pathway. 14C‐futibatinib was well tolerated in this Phase 1 study.