The metabolism of the orexin-1 selective receptor antagonist nivasorexant

Area of Science:

• Pharmacology
• Drug Metabolism
• Biochemistry

Background:

• Nivasorexant is the first orexin-1 selective receptor antagonist to enter clinical trials.
• Preclinical studies suggested potential utility, but a recent proof-of-concept trial in binge-eating disorder patients failed.

Purpose of the Study:

• To elucidate the metabolic pathways and clearance mechanisms of nivasorexant.
• To identify the primary enzymes and excretion routes involved in nivasorexant disposition.

Main Methods:

• Mass spectrometry and deuterated analogues were used to identify metabolic sites.
• In vitro studies utilized liver microsomes to determine the role of cytochrome P450 enzymes.
• Excretion patterns were investigated in rat models.

Main Results:

• Nivasorexant undergoes extensive metabolism via seven distinct pathways, predominantly hydroxylation.
• Cytochrome P450 3A4 (CYP3A4) is the main enzyme responsible for nivasorexant metabolism (approx. 90% turnover).
• The rat model showed predominant biliary excretion after metabolism, with negligible urinary excretion of the parent drug.

Conclusions:

• Nivasorexant's clearance is driven by extensive hepatic metabolism, primarily mediated by CYP3A4.
• The drug is extensively metabolized before excretion, mainly via bile, with minimal parent drug recovery in urine or feces.
• Understanding nivasorexant's metabolic profile is crucial despite its clinical trial outcome.