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 (S1P(1,4,5)) in development for treatment of various immune-mediated inflammatory disorders. The disposition and mass balance of a single 2-mg [C-14]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.