Mechanism of action
The endogenous orexin neuropeptides, orexin A and orexin B, are involved in the regulation of sleep–wake cycles and act to promote wakefulness. Deficiency of orexin signaling is thought to be the primary cause of the sleep disorder narcolepsy. Disturbances in orexin signaling may also be involved in insomnia. Research suggests that orexin signaling may change with age, and this has been implicated in age-related sleep disturbances. By blocking the actions of orexins and modulating sleep–wake cycles, orexin receptor antagonists like daridorexant reduce wakefulness and improve sleep. The sleep-promoting effects of dual orexin receptor antagonists are thought to be mediated specifically by blockade of the OX2 receptor in the lateral hypothalamus. Although narcoleptic symptoms were a theoretical concern during the development of orexin receptor antagonists, this has not been observed in clinical trials of these agents. Pharmacokinetics
Absorption
The absolute bioavailability of daridorexant is 62%. It reaches peak concentrations within 1 to 2 hours following a dose. Food prolonged the time to peak by 1.3 hours and decreased the peak concentrations by 16%, but did not affect area-under-the-curve concentrations. Distribution
The volume of distribution of daridorexant is 31 L. Its plasma protein binding is 99.7%. The plasma-to-blood ratio of daridorexant is 0.64. Daridorexant effectively crosses the blood–brain barrier in animals. Metabolism
Daridorexant is extensively metabolized primarily by CYP3A4 (89%). Other cytochrome P450 enzymes contribute individually to less than 3% of the clearance of daridorexant. Elimination
Daridorexant is eliminated primarily by feces (57%) then by urine (28%).
Regulatory review is also ongoing in Canada and Switzerland and is planned for the United Kingdom. Daridorexant was originated by Actelion Pharmaceuticals and was further developed by Idorsia. Society and culture
Legal status
Daridorexant is a schedule IV controlled substance under the Controlled Substances Act in the United States.Daridorexant (Quviviq) was approved for medical use in the European Union in April 2022. References
Further reading
"Application Number: 214985Orig1s000. Integrated Review. Daridorexant (Quviviq) for Insomnia" (PDF). Center for Drug Evaluation and Research (Food and Drug Administration). 2022. Archived from the original (PDF) on 22 April 2022. "Quviviq (Daridorexant) Assessment Report. Procedure No. EMEA/H/C/005634/0000" (PDF). Committee for Medicinal Products for Human Use (European Medicines Agency). 24 February 2022. External links
"Daridorexant". Drug Information Portal. U.S. National Library of Medicine.