Daridorexant

Daridorexant (formerly known as nemorexant) is used to treat adult patients with insomnia who have difficulty falling asleep and/or staying asleep. [1,2] It was authorized by Food and Drug Administration (FDA) for insomnia management on 7 January 2022. This drug effectively reduces insomnia symptoms, increases daytime functioning, and improves the overall quality of sleep. [3] 

Pharmacological Class: Selective dual orexin receptor antagonist [1] 

Daridorexant is indicated for the management of adult insomnia patients who had trouble staying asleep or falling asleep. [1,2]

The complex interactions between systems that promote sleep, such as inhibitory gamma-aminobutyric acid (GABA) activity, and systems that promote wakefulness, such as acetylcholine, orexins, and monoaminergic systems, control the sleep-wake cycle. Orexin, commonly known as hypocretin, is a neuropeptide that promotes wakefulness. By stimulating orexin neurons, which are least active during sleep and most active during active wakefulness, orexin stabilizes alertness. The orexin neurons usually project to other wake-promoting neurons such as cholinergic neurons of basal forebrain, pedunculopontine, and laterodorsal tegmental nuclei, dopaminergic neurons of ventral tegmental area, serotoninergic neurons of dorsal raphe, noradrenergic neurons of locus coeruleus, and histaminergic neurons of tuberomammillary nucleus that also express G-protein coupled orexin receptors.

These wake-promoting neurons are a fundamental component of the ascending reticular activating system, which controls the sleep-wake cycle through a feedback loop. Orexin type 1 receptor (OX1R) and Orexin type 2 receptor (OX2R) bind to two distinct kinds of orexin (OXA and OXB). OX2R has a dual affinity for OXA and OXB, whereas OXA binds more selectively to OX1R. [1]  Daridorexant's mode of action is presumed to be through antagonism of the orexin receptors since the orexin neuropeptide signalling is implicated in wakefulness. [2]

Daridorexant inhibits the binding of orexins (wake-promoting neuropeptides) to the orexin receptors OX1R and OX2R. This, in turn, reduces the wake drive. It selectively targets orexin neurons and suppresses downstream neuronal pathways which elicit wakefulness. But, it is not known to influence neuronal pathways that trigger adverse effects commonly noted in the positive allosteric GABA-A receptor modulators. [1]

• 25 mg to 50 mg dosage is recommended to be given orally once every night, within 30 minutes before going to bed, and at least 7 hours before the intended wakeup
• If used with or right after a meal, the sleep onset time may be delayed
• In people with hepatic impairment, the suggested dosage is as follows:

                (a) Severe hepatic impairment: Not recommended

                (b) Moderate hepatic impairment: The maximum dose that is advised is 25 mg, not to be taken more than once per night [2]

Absorption

Within one to two hours, it achieves peak plasma concentrations. Its absolute bioavailability is 62%. In healthy participants, the total exposure remained unaffected despite a high-calorie, high-fat meal delaying the Tmax by 1.3 hours and lowering the Cmax by 16%.

Volume of distribution

Volume of distribution of Daridorexant is 31 L. With blood to plasma ratio of 0.64, blood-brain barrier is efficiently crossed.

Protein binding

99.7% of Daridorexant is bound to plasma proteins.

Metabolism

The extensive metabolism of Daridorexant is predominantly handled by Cytochromes P450 (CYP) 3A4 (89%), mostly by oxidative transformations. Less than 3% of Daridorexant's metabolic clearance is accounted by the other CYP enzymes individually.

Route of elimination

Feces, which account for around 57% of drug excretion, is the main mode of excretion. Approximately 28% of drug is eliminated via urine, majorly in the form of metabolites. Feces and urine both contained trace quantities of the parent medication.

Half-life

The terminal half-life is around eight hours.

Clearance

There is not much data available about clearance. [1]

• Patients with narcolepsy should not use Daridorexant. [2]

• Concomitant use of strong CYP3A4 inhibitors must be evaded.
• The maximum advised dosage for moderate CYP3A4 inhibitors is 25 mg.
• Concurrent usage with strong or moderate CYP3A4 inducers must be avoided.
• Concomitant usage of alcohol or other central nervous system (CNS) depressants can trigger additive damage to psychomotor performance and escalate CNS depression risk. [2] 

The most commonly reported adverse effects are:

• Headache
• Somnolence
• Fatigue
• Nasopharyngitis
• Dizziness
• Nausea [2,3]

• CNS-depressant effects and daytime disability: Daridorexant use may impair motor coordination and alertness, incorporating morning impairment. It must be used with prudence in people receiving CNS depressants. When given along with other central nervous system depressants, the risk magnifies. Driving should be avoided after taking Daridorexant. In people engaging in tasks that call for 100% mental alertness, Daridorexant must be cautiously used.
• Worsening of suicidal ideation or depression: Suicidal ideation or depression could get worse.
• Hypnagogic/hypnopompic hallucinations, sleep paralysis, and cataplexy-like symptoms: Daridorexant usage may result in sleep paralysis, hypnagogic/hypnopompic hallucinations, and cataplexy-like symptoms.
• Complex sleep behaviors: These encompass sleep-driving, sleep-walking, and performing other tasks while partially awake. Daridorexant must be discontinued if there is an occurrence of  complex sleep behavior.
• Compromised Respiratory Function: The impact on breathing should be taken into account.
• Requirement to assess for Comorbid Diagnoses: If sleeplessness continues after 7 to 10 days, a re-evaluation must be done. [2]

Efficacy, Safety, and Tolerability of Daridorexant for Insomnia Management

A recent review indicated that Daridorexant is safe and efficacious for treatment of insomnia disorder. Compared to placebo, Daridorexant 25 and 50 mg exhibited remarkable improvements in latency to persistent sleep (LPS), subjective total sleep time (sTST), and wake after sleep onset (WASO). Furthermore, 50 mg Daridorexant was better for Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) in comparison with placebo. [4]

Daridorexant was shown to be well tolerated in the elderly population when used to treat insomnia, according to a phase 2 study conducted by Zammit G et al. In this trial, insomnia patients between the ages of 65 and 85 years were randomly assigned to receive five treatments of 5, 10, 25, and 50 mg of the drug, and a placebo, over the course of five treatment periods lasting two nights, followed by a washout period lasting 5 to 12 days. Following administration of Daridorexant, the LPS and WASO dose-dependently decreased from baseline to days 1 and 2. Contrasted to placebo, reductions were clinically meaningful for Daridorexant dosages ≥ 10 mg. [5,6]

According to the results from two multicentre, placebo-controlled, double-blind, randomized, phase 3 trials in insomnia patients (aged ≥18 years), Daridorexant 25 mg led to remarkable improvements in sleep outcomes, while Daridorexant 50 mg elicited improvements in sleep outcomes and daytime functioning, with a favourable safety profile. For about three months, participants received 50 mg Daridorexant, 25 mg Daridorexant, or placebo (study 1) or 25 mg Daridorexant,10 mg Daridorexant, or placebo (study 2) every evening.

(a) Study 1: After 1 and 3 months, patients taking 50 mg and 25 mg of Daridorexant compared to the placebo-recipients had substantially lower LPS and WASO levels. Compared to placebo, volunteers in 50 mg of Daridorexant exhibited better self-reported sleep time, and improved IDSIQ sleepiness domain scores in the first and third months. The self-reported TST of volunteers receiving 25 mg of Daridorexant enhanced in the first and third months, but not in the IDSIQ drowsiness domain.

(b) Study 2: After 1 and 3 months of treatment with 25 mg of Daridorexant, WASO was dramatically decreased, but there were no variations in LPS when compared to placebo-recipients. Patients also noted betterment in their self-reported TST scores, but not in their IDSIQ sleepiness domain scores. Regarding self-reported TST, LPS, WASO, or IDSIQ sleepiness domain scores, no appreciable changes were there between the Daridorexant 10 mg and placebo. [6,7]

In a multi-center, double-blind trial, individuals (18 to 64 years old) and older people (≥ 65 years old) suffering from insomnia were randomly allocated (1:1:1) to get administered Daridorexant 25 mg, 50 mg or placebo orally every evening for three months. Daridorexant was proven to be effective in improving daytime functioning and sleep in older persons. The WASO, LPS, sTST, and IDSIQ sleepiness domain changes from baseline at Month 3 in older adults for Daridorexant 25 mg and 50 mg, respectively, were -17.0 and -19.6 mins, -7.8 and -14.9 mins, 18.7 and 30.6 mins, and -0.6 and -2.6. No significant safety concerns were noted. [8]

Another study by Dauvilliers Y et al was carried out to explore the dose-response association of Daridorexant on sleep variables in people (≤64 years) suffering from insomnia disorder. The recruited volunteers were randomized to orally get 10 mg zolpidem, Daridorexant (5, 10, 25, or 50 mg), and placebo for 30 days. Daridorexant reduced wake time after sleep commencement in a dose-dependent manner. The decrease of wake after sleep onset and delay to persistent sleep from baseline to first and second day with Daridorexant was shown to have a substantial dose-response link. These reductions were reported to sustain through to days 28 and 29. Similar dose-dependent connections were noted for subjective latency to sleep onset and subjective wake after sleep onset. No significant treatment-related serious adverse events were witnessed. [9]

According to research by Zammit G et al., Daridorexant at any dose and each greater than placebo raised TST in individuals with insomnia in a dose-dependent manner with no alteration in proportion of all sleep phases. Subjects were randomly assigned to get 10 mg Daridorexant, 25 mg Daridorexant, or placebo in Trial 2 (N=924), and 25 mg Daridorexant, 50 mg Daridorexant or placebo in Trial 1 (N=930). Over the course of a three-month double-blind treatment phase, oral medication was given every night. Daridorexant elevated TST (minutes) from baseline to third month in a dose-dependent manner (25 mg, 55±56; 50mg, 61±53; placebo, 40±56 in Trial 1 and 10mg, 37±57; 25mg, 50±53; placebo, 35±56 in Trial 2 respectively). [10]

1. Daridorexant. Drug Bank. Accession Number DB15031. Available online from: https://go.drugbank.com/drugs/DB15031 [Last accessed on: 21 September 2022]

2. Daridorexant. FDA LABEL. Available online from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214985s000lbl.pdf [Last accessed on: 21 September 2022]

3. Robinson CL, Supra R, Downs E, Kataria S, Parker K, Kaye A et al. Daridorexant for the Treatment of Insomnia. Health Psychol Res. 2022 Aug 30;10(3):37400.

4. Dos Santos JBR, da Silva MRR. Daridorexant for the treatment of insomnia disorder: findings and implications. Eur J Clin Pharmacol. 2022 Sep 13.

5. Zammit G, Dauvilliers Y, Pain S, Kinter DS, Mansour Y, Kunz D. Daridorexant, a new dual orexin receptor antagonist, in elderly subjects with insomnia disorder. Neurology. 2020 May 26;94(21):e2222-32.

6. Robinson CL, Supra R, Downs E, Kataria S, Parker K, Kaye A et al. Daridorexant for the Treatment of Insomnia. Health Psychology Research. 2022 Aug 30;10(3).

7. Mignot E, Mayleben D, Fietze I, Leger D, Zammit G, Bassetti CL et al. Safety and efficacy of Daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. The Lancet Neurology. 2022 Feb 1;21(2):125-39.

8. Fietze I, Bassetti C, Mayleben D, Gimona A, Pain S, McCall W et al. Effects of Daridorexant on sleep and daytime functioning in older adults with insomnia. The American Journal of Geriatric Psychiatry. 2022 Apr 1;30(4):S69-70.

9. Dauvilliers Y, Zammit G, Fietze I, Mayleben D, Seboek Kinter D, Pain S et al. Daridorexant, a new dual orexin receptor antagonist to treat insomnia disorder. Annals of Neurology. 2020 Mar;87(3):347-56.

10. Zammit G, Mayleben D, Fietze I, Pain S, Kinter DS, Gimona A et al. 344 Daridorexant Improves Total Sleep Time (TST) in Insomnia Patients Without Altering the Proportion of Sleep Stages. Sleep. 2021 May;44(Supplement_2):A137-8.