There is no specific antidote to overdose of daridorexant. Interactions
CYP3A4 inhibitors like ranitidine and diltiazem and CYP3A4 inducers like efavirenz can increase and decrease exposure to daridorexant, respectively. Concomitant use of daridorexant with strong CYP3A4 inhibitors or moderate or strong CYP3A4 inducers should be avoided, while it is recommended that the maximum dose of daridorexant be limited with moderate CYP3A4 inhibitors. Gastric pH modifiers like famotidine can decrease peak levels of daridorexant without affecting total exposure. Alcohol and selective serotonin reuptake inhibitors (SSRIs) like citalopram have not shown significant pharmacokinetic interactions with daridorexant. Coadministration of daridorexant with other sedatives like benzodiazepines, opioids, tricyclic antidepressants, and alcohol may increase the risk of central nervous system depression and daytime impairment. Daridorexant has not been found to significantly influence the pharmacokinetics of other drugs including midazolam (CYP3A4 substrate), rosuvastatin (BCRP substrate), and the SSRI citalopram. Pharmacology
Pharmacodynamics
Daridorexant acts as a selective dual antagonist of the orexin (hypocretin) receptors OX1 and OX2. The affinities (Ki) of daridorexant for the orexin receptors are 0.47 nM for the OX1 receptor and 0.93 nM for the OX2 receptor. Its Kb values for the human orexin receptors have been reported to be 0.5 nM for the OX1 receptor and 0.8 nM for the OX2 receptor. Hence, daridorexant is approximately equipotent in its antagonism of the orexin receptors. Daridorexant is selective for the orexin receptors over many other targets. In contrast to certain other sedatives and hypnotics, daridorexant is not a benzodiazepine or Z-drug and does not interact with GABA receptors.
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%).