The metabolism of the orexin-1 selective receptor antagonist nivasorexant

Abstract

Nivasorexant was the first orexin-1 selective receptor antagonist entering clinical development. Despite encouraging preclinical evidence in animal models, a proof-of-concept trial in binge-eating patients recently failed to demonstrate its clinical utility in this population. Across species, nivasorexant clearance was driven by metabolism along seven distinct pathways, five of which were hydroxylation reactions in various locations of the molecule. The exact sites of metabolism were identified by means of mass spectrometry, the use of deuterated analogues, and finally confirmed by chemical references. CYP3A4 was the main cytochrome P450 enzyme involved in nivasorexant metabolism in vitro and accounting for about 90% of turnover in liver microsomes. Minor roles were taken by CYP2C9 and CYP2C19 but individually did not exceed 3–7%. In the rat, nivasorexant was mostly excreted via the bile after extensive metabolism, while urinary excretion was negligible. Only traces of the parent drug were detected in urine, bile, or faeces.