The metabolism of the dual orexin receptor antagonist daridorexant

Abstract

1. Daridorexant is a dual orexin receptor antagonist developed for the treatment of insomnia disorder and has shown improvement in sleep outcomes and daytime functioning. The present work describes its biotransformation pathways in vitro and in vivo and provides a cross-species comparison between the animal species used in preclinical safety assessments and man.

2. Daridorexant clearance is driven by metabolism along seven distinct pathways. Metabolic profiles were characterised by downstream products while primary metabolic products were of minor importance. The metabolic pattern differed between rodent species, with the rat reflecting the human pattern better than the mouse.

3. In rodents, daridorexant is mostly excreted via the bile after extensive metabolism while urinary excretion was negligible in the rat. Only traces of the parent drug were detected in urine, bile, or faeces.

4. Daridorexant has three major metabolites which are well covered in these preclinical safety species. All of them retain some residual affinity towards orexin receptors. However, none of these is considered to contribute to the pharmacological effect of daridorexant as their active concentrations in the human brain are too low.

Keywords:

• Insomnia
• daridorexant
• orexin
• clearance
• metabolism
• excretion
• rat
• mouse
• human
• metabolite

Acknowledgements

The authors thank Ali Selimi, Markus Schäuble, Marc Enzler, Fabienne Drouet, Celia Müller-Grandjean, and Jerome Segrestaa for their dedication and experimental contributions.

Disclosure statement

All authors are employees of Idorsia Pharmaceuticals Ltd.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.