The orexin 1-selective receptor antagonist nivasorexant is a time-dependent inhibitor of CYP2C19 and CYP3A4

Nivasorexant was the first orexin 1-selective receptor antagonist entering into clinical development as an exploratory treatment for eating disorders.Drug-drug interactions were observed with markers of CYP2C9, CYP2C19, and CYP3A4. While the interaction with CYP2C19 was expected based on in vitro inhibition data, standard P450 inhibition screening assays according to regulatory guidelines failed to predict the interactions with CYP2C9 and CYP3A4.Mechanistic studies on the circulating metabolites of nivasorexant revealed a heterogeneous picture for the three P450 enzymes with covalent binding as a common denominator. For CYP3A4, the secondary didehydromorpholine metabolite <b>M30</b> was identified as the major origin for enzyme inactivation. Epoxidation of its double bond might yield a bicyclic reactive metabolite which subsequently binds within the CYP3A4 active site.Nivasorexant and virtually all its circulating metabolites were strong competitive or time-dependent inhibitors of CYP2C19. Some of them are initially produced by CYP3A4 and only exert their inhibitory potential after diffusion into the CYP2C19 active site. CYP2C9 and CYP2C19 both produce the 6-hydroxymorpholine metabolite <b>M25</b>, which exists in equilibrium with its open-chain amino aldehyde form. The latter is chemically reactive and might at least in part explain the covalent binding of nivasorexant to both P450 enzymes. Nivasorexant was the first orexin 1-selective receptor antagonist entering into clinical development as an exploratory treatment for eating disorders. Drug-drug interactions were observed with markers of CYP2C9, CYP2C19, and CYP3A4. While the interaction with CYP2C19 was expected based on in vitro inhibition data, standard P450 inhibition screening assays according to regulatory guidelines failed to predict the interactions with CYP2C9 and CYP3A4. Mechanistic studies on the circulating metabolites of nivasorexant revealed a heterogeneous picture for the three P450 enzymes with covalent binding as a common denominator. For CYP3A4, the secondary didehydromorpholine metabolite <b>M30</b> was identified as the major origin for enzyme inactivation. Epoxidation of its double bond might yield a bicyclic reactive metabolite which subsequently binds within the CYP3A4 active site. Nivasorexant and virtually all its circulating metabolites were strong competitive or time-dependent inhibitors of CYP2C19. Some of them are initially produced by CYP3A4 and only exert their inhibitory potential after diffusion into the CYP2C19 active site. CYP2C9 and CYP2C19 both produce the 6-hydroxymorpholine metabolite <b>M25</b>, which exists in equilibrium with its open-chain amino aldehyde form. The latter is chemically reactive and might at least in part explain the covalent binding of nivasorexant to both P450 enzymes.