Biotransformation of obefazimod, a novel potential anthelmintic, in sheep and the target nematode Haemonchus contortus

Parasitic nematodes cause significant health issues in livestock, resulting in clinical complications and economic losses worldwide. As the efficacy of current anthelmintic drugs is being compromised by the emergence of drug resistance, a search for novel therapeutics with new modes of action is necessary. Obefazimod (ABX464) originally developed for human inflammatory diseases, has recently shown promising nematocidal activity against Haemonchus contortus and other parasitic nematodes. This study aimed to elucidate the biotransformation pathways of obefazimod in H. contortus and in its host, sheep. Adult nematodes (females and males separately) of drug-susceptible and drug-resistant strains and ovine liver models were used. Using a newly developed and optimized UHPLC-HRMS/MS method, we identified 13 metabolites formed via phase I and II metabolism. These findings provide the first insight into the metabolic fate of obefazimod in target parasites and host species.