Disposition and Mass Balance of Etrasimod in Healthy Subjects and In Vitro Determination of the Enzymes Responsible for Its Oxidative Metabolism

Etrasimod (APD334) is an investigational, once‐daily, oral, selective sphingosine 1‐phosphate receptor 1,4,5 modulator (S1P1,4,5) in development for treatment of various immune‐mediated inflammatory disorders. The disposition and mass balance of a single 2‐mg [14C]etrasimod dose were evaluated in 8 healthy males. An in vitro study was also conducted to identify etrasimod's oxidative metabolizing enzymes. Peak concentrations of etrasimod and total radioactivity in plasma and whole blood were typically reached 4–7 hours postdose. Etrasimod constituted 49.3% of total radioactivity plasma exposure, with multiple minor/trace metabolites making up the remainder. Etrasimod was slowly cleared mainly via biotransformation, predominantly by oxidative metabolism, with unchanged etrasimod recovered in feces accounting for only 11.2% of the dose and none in urine. The mean apparent terminal half‐lives of etrasimod and total radioactivity in plasma were 37.8 and 89.0 hours, respectively. Mean cumulative recovery of radioactivity in excreta over 336 hours was 86.9% of the dose, mostly in feces. The prevalent metabolites eliminated in feces were M3 (hydroxy‐etrasimod) and M36 (oxy‐etrasimod sulfate), accounting for 22.1% and 18.9% of the dose, respectively. From in vitro reaction phenotyping, the predominant enzymes involved in the oxidation of etrasimod were CYP2C8, CYP2C9, and CYP3A4, with minor contributions from CYP2C19 and CYP2J2.