Preclinical Metabolism and Disposition of an Orally Bioavailable Macrocyclic FXIa Inhibitor

Abstract

FXIa-6f is as a high affinity, orally bioavailable macrocyclic FXIa inhibitor with antithrombotic activity in preclinical species. The objectives of this study were to characterize the in vitro metabolism, determine circulating metabolites in pre-clinical species, and examine the disposition of the compound in a bile duct-cannulated rat study (BDC) study, to inform clinical development of the compound and the medicinal chemistry approach to identify molecules with improved properties. Across species, metabolic pathways included several oxidative metabolites, including hydroxylated metabolites on the macrocycle or P1 region, descarbamoylation of the methyl carbamate side chain, and a glutathione conjugate on the 2,6-difluoro-3-chlorophenyl ring. In BDC rat, the absorbed dose of [3H]FXIa-6f was cleared mainly by metabolism, with excretion of drug-related material in the bile, mostly as metabolites. In all preclinical species, the parent drug was the primary drug-related component in circulation, but the species differences in the metabolic pathways observed in vitro were reflected in the plasma, where M6 was more prominent in rat plasma, and M9 was more prominent in monkey plasma. Based on the available data, the human metabolism appears to be most similar to monkey.