Evaluation of the Absorption, Metabolism, and Excretion of a Single Oral 1 mg Dose of Tropifexor in Healthy Male Subjects and the Concentration Dependency of Tropifexor Metabolism.

Tropifexor (NVP-LJN452) is a highly potent, selective, non-steroidal, non-bile acid farnesoid X receptor (FXR) agonist for the treatment of nonalcoholic steatohepatitis (NASH). Its absorption, metabolism, and excretion were studied following a 1-mg oral dose of [14C]tropifexor to four healthy male subjects. Mass balance was achieved with ~94% of the administered dose recovered in excreta through 312 hours collection period. Fecal excretion of tropifexor-related radioactivity played a major role (~65% of the total dose). Tropifexor reached a maximum blood concentration (Cmax) of 33.5 ng/mL with a median Tmax of 4 hours and was eliminated with a plasma elimination half-life (T1/2) of 13.5 hours. Unchanged tropifexor was the principal drug-related component found in plasma (~92% of total radioactivity). Two minor oxidative metabolites, M11.6 and M22.4, were observed in circulation. Tropifexor was eliminated predominantly via metabolism with >68% of the dose recovered as metabolites in excreta. Oxidative metabolism appeared to be the major clearance pathway of tropifexor. Metabolites containing multiple oxidative modifications and combined oxidation and glucuronidation were also observed in human excreta. The involvement of direct glucuronidation could not be ruled out, based on previous in vitro and nonclinical in vivo studies indicating its contribution to tropifexor clearance. The relative contribution of the oxidation and glucuronidation pathways appeared to be dose-dependent upon further in vitro investigation. Due to these complexities and the instability of glucuronide metabolites in the gastrointestinal tract, the contribution of glucuronidation remained undefined in this study. Significance Statement Tropifexor was found to be primarily cleared from human body via oxidative metabolism. In vitro metabolism experiments revealed that the relative contribution of oxidation and glucuronidation was concentration-dependent with glucuronidation as the predominant pathway at higher concentrations while oxidative process becoming more important at lower concentrations near clinical exposure range. The body of work demonstrated the importance of carefully designed in vivo and in vitro experiments for better understanding of disposition processes during drug development.