Daridorexant

Last updated

Daridorexant
Daridorexant structure.svg
Clinical data
Trade names Quviviq
Other namesNemorexant; ACT-541468, Daridorexant hydrochloride (USAN US)
License data
Routes of
administration 		By mouth [1]
Drug class Dual orexin receptor antagonist; Hypnotic; Sedative
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 62% [1]
Protein binding 99.7% [1]
Metabolism Extensive (mainly CYP3A4 (89%)) [1]
Onset of action Tmax: 1–2 hours (delayed by 1.3 hours with food) [1]
Elimination half-life 8 hours (6–10 hours) [1] [5]
Duration of action ~8 hours (50 mg) [5]
Excretion Feces: ~57% [1]
Urine: ~28% [1]
Identifiers
  • [(2S)-2-(5-Chloro-4-methyl-1H-benzimidazol-2-yl)-2-methylpyrrolidin-1-yl]-[5-methoxy-2-(triazol-2-yl)phenyl]methanone
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.353.123 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C23H23ClN6O2
Molar mass 450.93 g·mol−1
3D model (JSmol)
  • CC1=C(C=CC2=C1N=C(N2)[C@@]3(CCCN3C(=O)C4=C(C=CC(=C4)OC)N5N=CC=N5)C)Cl
  • InChI=1S/C23H23ClN6O2/c1-14-17(24)6-7-18-20(14)28-22(27-18)23(2)9-4-12-29(23)21(31)16-13-15(32-3)5-8-19(16)30-25-10-11-26-30/h5-8,10-11,13H,4,9,12H2,1-3H3,(H,27,28)/t23-/m0/s1
  • Key:NBGABHGMJVIVBW-QHCPKHFHSA-N

Daridorexant, sold under the brand name Quviviq, is an orexin antagonist medication which is used for the treatment of insomnia. [1] [4] [6] [7] [8] Daridorexant is taken by mouth. [1] [4] [7]

Contents

Side effects of daridorexant include headache, somnolence, and fatigue. [1] [7] The medication is a dual orexin receptor antagonist (DORA). [9] [7] [10] [8] It acts as a selective dual antagonist of the orexin receptors OX1 and OX2. [9] [10] [8] Daridorexant has a relatively short elimination half-life of 8 hours and a time to peak of about 1 to 2 hours. [1] [7] [5] It is not a benzodiazepine or Z-drug and does not interact with GABA receptors, instead having a distinct mechanism of action. [8] [7]

Daridorexant was approved for medical use in the United States in January 2022 [1] [11] and became available in May 2022. [12] It was approved in the European Union in April 2022, and is the first orexin receptor antagonist to become available in European Union. [13] The medication is a schedule IV controlled substance in the United States and may have a modest potential for misuse. [1] [14] [15] Besides daridorexant, other orexin receptor antagonists, like suvorexant and lemborexant, have also been introduced. [16] [17]

Medical uses

Daridorexant is indicated for the treatment of adults with insomnia characterized by difficulties with sleep onset and/or sleep maintenance. [1] The medication has been found to significantly improve latency to persistent sleep (LPS), wake after sleep onset (WASO), and subjective total sleep time (TST) in regulatory clinical trials. [1] At doses of 25 to 50 mg and in terms of treatment–placebo difference, it reduces LPS by 6 to 12 minutes, reduces WASO by 10 to 23 minutes, and increases subjective TST by 10 to 22 minutes. [1] [18] Daridorexant has also been found to improve daytime functioning at a dose of 50 mg but not at 25 mg. [17]

Network meta-analyses have assessed the sleep-promoting effects of orexin receptor antagonists and have compared them between one another as well as to other sleep aids including benzodiazepines, Z-drugs, antihistamines, sedative antidepressants (e.g., trazodone, doxepin, amitriptyline, mirtazapine), and melatonin receptor agonists. [19] [20] [21] [22] A major systematic review and network meta-analysis of insomnia medications published in 2022 found that daridorexant had an effect size (standardized mean difference (SMD)) against placebo for treatment of insomnia at 4 weeks of 0.23 (95% CI Tooltip confidence interval –0.01 to 0.48). [19] This was similar to but numerically lower than the effect sizes at 4 weeks for suvorexant (SMD 0.31, 95% CI 0.01 to 0.62) and lemborexant (SMD 0.36, 95% CI 0.08 to 0.63). [19] Benzodiazepines and Z-drugs generally showed larger effect sizes than orexin receptor antagonists (e.g., SMDs of 0.45 to 0.83). [19] The review concluded on the basis of daridorexant's small effect size that it did not show an overall material benefit in the treatment of insomnia. [19] Conversely, it concluded that lemborexant—as well as the Z-drug eszopiclone—had the best profiles overall in terms of efficacy, tolerability, and acceptability among all of the assessed insomnia medications. [19]

Orexin receptor antagonists are not used as first-line treatments for insomnia due to their costs and concerns about possible misuse liability. [20]

Population pharmacokinetic modeling indicates that differences between subjects do not require dose adjustments, and that lean body weight and fat mass effect the pharmacokinetics of daridorexant better than other body size descriptors. [23]

Treatment with daridorexant is generally safe and well tolerated for up to one year, with improvements in sleep and daytime functioning persisting throughout treatment. [24]

The Department of Defense (DOD) is testing the effectiveness of daridorexant in patients with post-traumatic stress disorder (PTSD) as the link between insomnia and PTSD is well established. [25]

Available forms

In the United States and Canada, daridorexant is available in the form of 25 and 50 mg oral tablets. [1] It is provided as the salt daridorexant hydrochloride, with each tablet containing 27 or 54 mg of this substance (equivalent to 25 or 50 mg daridorexant). [1]

Contraindications

Daridorexant is contraindicated in people with narcolepsy. [1] It is not recommended in people with severe hepatic impairment, whereas a lower maximum dose is recommended in people with moderate hepatic impairment. [1] Concomitant use of daridorexant with strong CYP3A4 inhibitors and moderate to strong CYP3A4 inducers is not recommended and should be avoided due to unfavorable modification of daridorexant exposure. [1]

Side effects

Side effects of daridorexant include headache (6% at 25 mg vs. 7% at 50 mg vs. 5% for placebo), somnolence or fatigue (includes somnolence, sedation, fatigue, hypersomnia, and lethargy) (6% at 25 mg vs. 5% at 50 mg vs. 4% for placebo), dizziness (2% at 25 mg vs. 3% at 50 mg vs. 2% for placebo), and nausea (0% at 25 mg vs. 3% at 50 mg vs. 2% for placebo). [1] No residual effects have been found after administration of 25 mg daridorexant in the evening to either young or elderly individuals. [5] However, daridorexant may cause next-morning driving impairment at the start of treatment or in some individuals. [1] Orexin receptor antagonists like daridorexant may have less or no propensity for causing tolerance compared to other sedatives and hypnotics based on animal studies. [8] [1] Daridorexant did not produce signs of withdrawal or dependence upon discontinuation in animal studies and clinical trials, and orexin receptor antagonists are not associated with rebound insomnia. [1] [5] Loss of sleep-promoting effectiveness occurs rapidly upon discontinuation of daridorexant. [1] Preclinical research has suggested that orexin antagonists may reduce appetite, but daridorexant and other orexin antagonists have not been associated with weight loss in clinical trials. [16] Daridorexant may have a small risk of suicidal ideation. [26]

Orexin receptor antagonists can affect the reward system and produce drug-liking responses in humans. [27] [16] Daridorexant at a dose of 50 mg (the maximum recommended dose) showed significantly greater drug liking than placebo but significantly less drug liking than zolpidem (30 mg) and suvorexant (150 mg) in recreational sedative drug users. [1] [28] At higher doses of 100 and 150 mg (greater than the recommended maximum dose), drug liking with daridorexant was similar to that with zolpidem (30 mg) and suvorexant (150 mg). [1] [28] In other studies, suvorexant showed similar drug liking compared to zolpidem but lower misuse potential on other measures (e.g., overall rate of misuse potential adverse events of 58% for zolpidem and 31% for suvorexant in recreational drug users). [29] No reports indicative of misuse liability were observed in clinical trials with daridorexant, although these studies excluded participants with history of drug or alcohol misuse. [1] [30] [28]

Overdose

There is limited clinical experience with overdose of daridorexant. [1] Overdose of the medication at a dose of up to four times the maximum recommended dose may result in adverse effects including somnolence, muscle weakness, cataplexy-like symptoms, sleep paralysis, attention disturbances, fatigue, headache, and constipation. [1] There is no specific antidote to overdose of daridorexant. [1]

Interactions

CYP3A4 inhibitors and inducers can increase and decrease exposure to daridorexant, respectively. [1] [17] [31] The weak CYP3A4 inhibitor ranitidine (150 mg) is predicted to increase overall exposure to daridorexant by 1.5-fold; the moderate CYP3A4 inhibitor diltiazem (240 mg) increased exposure to daridorexant by 2.4-fold; and the strong CYP3A4 inhibitor itraconazole, on the basis of physiologically-based pharmacokinetic modeling, would be expected to increase daridorexant exposure by more than 4-fold. [1] [17] [31] [7] Conversely, the moderate CYP3A4 inducer efavirenz (600 mg) decreased daridorexant overall exposure by 35 to 60% and the strong CYP3A4 inducer rifampin similarly decreased daridorexant exposure by more than 50%. [1] [31] [7] Concomitant use of daridorexant with strong CYP3A4 inhibitors or with moderate or strong CYP3A4 inducers should be avoided, while it is recommended that the maximum dose of daridorexant be reduced with moderate CYP3A4 inhibitors. [1] [7]

Examples of important CYP3A4 modulators which are expected to interact with daridorexant include the strong CYP3A4 inhibitors boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, and telithromycin (concomitant use not recommended); the moderate CYP3A4 inhibitors amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fosamprenavir, grapefruit juice, imatinib, and verapamil (lower doses of daridorexant recommended); and the strong CYP3A4 inducers apalutamide, carbamazepine, efavirenz, enzalutamide, phenytoin, rifampin, and St. John's wort (expected to decrease daridorexant effectiveness). [1] [32] [5]

Gastric pH modifiers like famotidine can decrease peak levels of daridorexant without affecting total exposure. [1] Alcohol and selective serotonin reuptake inhibitors (SSRIs) like citalopram have not shown significant pharmacokinetic interactions with daridorexant. [1] 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. [1] [7]

Daridorexant has not been found to significantly influence the pharmacokinetics of other drugs including midazolam (a CYP3A4 substrate), rosuvastatin (a BCRP substrate), and the SSRI citalopram (primarily a CYP2C19 substrate). [1] [7]

Pharmacology

Pharmacodynamics

Daridorexant acts as a selective dual antagonist of the orexin (hypocretin) receptors OX1 and OX2. [5] 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. [1] 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. [8] Hence, daridorexant is approximately equipotent in its antagonism of the orexin receptors. [8] Daridorexant is selective for the orexin receptors over many other targets. [8] In contrast to certain other sedatives and hypnotics, daridorexant is not a benzodiazepine or Z-drug and does not interact with GABA receptors. [8]

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. [33] [16] [7] Deficiency of orexin signaling is thought to be the primary cause of the sleep disorder narcolepsy. [33] [16] Disturbances in orexin signaling may also be involved in insomnia. [33] Research suggests that orexin signaling may change with age, and this has been implicated in age-related sleep disturbances. [33] By blocking the actions of orexins and modulating sleep–wake cycles, orexin receptor antagonists like daridorexant reduce wakefulness and improve sleep. [33] [16] [7] 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. [16] 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. [33]

Pharmacokinetics

Daridorexant levels after a single oral dose of 50 to 150 mg daridorexant in healthy recreational sedative drug users. Daridorexant levels after a single oral dose of 50 to 150 mg daridorexant in recreational sedative drug users.png
Daridorexant levels after a single oral dose of 50 to 150 mg daridorexant in healthy recreational sedative drug users.

Absorption

The absolute bioavailability of daridorexant is 62%. [1] [7] The poor aqueous solubility of daridorexant limits its bioavailability. [7] It reaches peak concentrations within 1 to 2 hours following a dose. [1] [7] Food prolonged the time to peak by 1.3 to 2 hours and decreased the peak concentrations by 16 to 24%, but did not affect area-under-the-curve concentrations. [1] [7]

Distribution

The volume of distribution of daridorexant is 31 L. [1] [7] Its plasma protein binding is 99.7%. [1] [7] The plasma-to-blood ratio of daridorexant is 0.64. [1] Daridorexant is a lipophilic molecule and effectively crosses the blood–brain barrier in animals. [8] [7]

Metabolism

Daridorexant is extensively metabolized primarily by CYP3A4 (89%). [1] [7] Other cytochrome P450 enzymes contribute individually to less than 3% of the clearance of daridorexant. [1] Daridorexant has 77 identified metabolites. [7] Its major metabolites are less active than daridorexant as orexin receptor antagonists. [7]

Recently, a study was carried out using human liver microsomes reported that daridorexant underwent 3 reaction; hydroxylation at the methyl group of the benzimidazole moiety, oxidative O-demethylation of the anisole to the corresponding phenol, and hydroxylation to a 4-hydroxy piperidinol derivative. Researchers proved that the chemical structures of the benzylic alcohol and the phenol are products of standard CYP450 reactions; while the latter hydroxylation product was incompatible with the initially postulated hydroxylation of the pyrrolidine ring, hence they suggested that human monooxygenase CYP3A4 catalyzes the intramolecular rearrangement of daridorexant. In detail, they proposed the following mechanism, hydroxylation in 5-position of the pyrrolidine ring initially will yield a cyclic hemiaminal which subsequently will hydrolyze to a ring-open amino aldehyde. Afterwards, cyclization of the latter onto one of the nitrogen atoms of the benzimidazole moiety will yield the final 4-hydroxy piperidinol metabolite. [34]

Elimination

Daridorexant is eliminated primarily by feces (57%) then by urine (28%). [1] [7] It is excreted mainly in the form of metabolites, with only trace amounts of the parent compound identified. [1] [7]

The medication has an elimination half-life of about 8 hours [1] or of 6 to 10 hours. [5] [7] The half-life of daridorexant may be longer in elderly individuals compared to young adults (9–10 hours in the elderly versus 6 hours in young adults). [7] Its half-life is shorter than that of other orexin receptor antagonists such as suvorexant (12 hours) and lemborexant (~18–55 hours). [5] The relatively short half-life of daridorexant may allow for reduced daytime sedation. [5] [16] The duration of action of daridorexant in terms of sedative effects is approximately 8 hours with a 50 mg dose. [5]

Chemistry

Daridorexant is a small-molecule compound. [8] The chemical name of daridorexant is (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone. [35] [1] Its molecular formula is C23H23N6O2Cl and its molecular weight is 450.93 g/mol (or 487.38 g/mol for the hydrochloride). [35] [1] Daridorexant hydrochloride is a white to light yellowish powder. [1] Daridorexant is a lipophilic compound and daridorexant hydrochloride is very slightly soluble in water. [7] [1]

History

Daridorexant was originated by Actelion Pharmaceuticals and was further developed by Idorsia. [4] [9] [36] It was patented in 2013 [37] and was first described in the scientific literature in 2017. [38] [39] [40] It was in development for 25 years by the husband-wife team Jean-Paul and Martine Clozel. [41] Daridorexant was approved for medical use in the United States in January 2022 [1] [11] and became available in May 2022. [12]

On 24 February 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Quviviq, intended for the treatment of insomnia. [4] [36] On 29 April 2022, daridorexant was authorized for use in the European Union. [13] It was the first orexin receptor antagonist to become available for use in the European Union. [13] [42] (The earlier orexin receptor antagonists suvorexant and lemborexant are not available in the European Union.) [43] [44] [45] [46] Regulatory review is also ongoing in Canada and Switzerland and is planned for the United Kingdom. [17] [9] [ needs update ]

Society and culture

Daridorexant is a schedule IV controlled substance under the Controlled Substances Act in the United States. [1] [14] [15]

Daridorexant (Quviviq) was approved for medical use in the European Union in April 2022. [4] [47]

Daridorexant (Quviviq) was approved by Health Canada in April 2023. [48]

Related Research Articles

<span class="mw-page-title-main">Hypnotic</span> Drug whose use induces sleep

Hypnotic, or soporific drugs, commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to induce sleep and to treat insomnia (sleeplessness).

<span class="mw-page-title-main">Hydroxyzine</span> Antihistamine drug

Hydroxyzine, sold under the brand names Atarax and Vistaril among others, is an antihistamine medication. It is used in the treatment of itchiness, anxiety, insomnia, and nausea. It is used either by mouth or injection into a muscle.

<span class="mw-page-title-main">Eszopiclone</span> Hypnotic medication

Eszopiclone, sold under the brand name Lunesta among others, is a medication used in the treatment of insomnia. Evidence supports slight to moderate benefit up to six months. It is taken by mouth.

<span class="mw-page-title-main">Doxylamine</span> First-generation antihistamine used as a short-term sedative and hypnotic (sleep aid)

Doxylamine is an antihistamine medication used to treat insomnia and allergies, and—in combination with pyridoxine (vitamin B6)—to treat morning sickness in pregnant women. It is available over-the-counter and is typically sold under such brand names as Equate or Unisom, among others; and it is used in nighttime cold medicines (e.g., NyQuil) and pain medications containing acetaminophen and/or codeine to help with sleep. The medication is delivered chemically by the salt doxylamine succinate and is taken by mouth. Doxylamine and other first-generation antihistamines are the most widely used sleep medications in the world. Typical side effects of doxylamine (at recommended doses) include dizziness, drowsiness, grogginess, and dry mouth, among others.

<span class="mw-page-title-main">Doxepin</span> Medication to treat depressive disorder, anxiety disorders, chronic hives, and trouble sleeping

Doxepin is a medication belonging to the tricyclic antidepressant (TCA) class of drugs used to treat major depressive disorder, anxiety disorders, chronic hives, and insomnia. For hives it is a less preferred alternative to antihistamines. It has a mild to moderate benefit for sleeping problems. It is used as a cream for itchiness due to atopic dermatitis or lichen simplex chronicus.

<span class="mw-page-title-main">Zaleplon</span> Medication used to treat insomnia

Zaleplon, sold under the brand name Sonata among others, is a sedative and hypnotic which is used to treat insomnia. It is a nonbenzodiazepine or Z-drug of the pyrazolopyrimidine class. It was developed by King Pharmaceuticals and approved for medical use in the United States in 1999.

<span class="mw-page-title-main">Nonbenzodiazepine</span> Class of psychoactive drugs

Nonbenzodiazepines, sometimes referred to colloquially as Z-drugs, are a class of psychoactive, depressant, sedative, hypnotic, anxiolytic drugs that are benzodiazepine-like in uses, such as for treating insomnia and anxiety.

<span class="mw-page-title-main">Ramelteon</span> Hypnotic medication

Ramelteon, sold under the brand name Rozerem among others, is a melatonin agonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset. It reduces the time taken to fall asleep, but the degree of clinical benefit is small. The medication is approved for long-term use. Ramelteon is taken by mouth.

<span class="mw-page-title-main">SB-649868</span> Chemical compound

SB-649868 is a dual orexin receptor antagonist that was being developed by GlaxoSmithKline as a treatment for insomnia.

The orexin receptor (also referred to as the hypocretin receptor) is a G-protein-coupled receptor that binds the neuropeptide orexin. There are two variants, OX1 and OX2, each encoded by a different gene (HCRTR1, HCRTR2).

<span class="mw-page-title-main">Almorexant</span> Orexin antagonist compound

Almorexant (INN), also known by its development code ACT-078573, is an orexin antagonist, acting as a competitive antagonist of the OX1 and OX2 orexin receptors, which was being developed by the pharmaceutical companies Actelion and GSK for the treatment of insomnia. Development of the drug was abandoned in January 2011 due to concerns over the hepatic safety of almorexant after transient increases in liver enzymes were observed in trials.

<span class="mw-page-title-main">Esmirtazapine</span> Drug formerly under development for treatment of menopause symptoms

Esmirtazapine (ORG-50,081) is a tetracyclic antidepressant drug that was under development by Organon for the treatment of insomnia and vasomotor symptoms (e.g., hot flashes) associated with menopause. Esmirtazapine is the (S)-(+)-enantiomer of mirtazapine and possesses similar overall pharmacology, including inverse agonist actions at H1 and 5-HT2 receptors and antagonist actions at α2-adrenergic receptors.

<span class="mw-page-title-main">Suvorexant</span> Medication used to treat insomnia

Suvorexant, sold under the brand name Belsomra, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maintenance in adults. Suvorexant helps with falling asleep faster, sleeping longer, being awake less in the middle of the night, and having better quality of sleep. Its effectiveness is modest, and is similar to that of other orexin antagonists, but is lower than that of benzodiazepines and Z-drugs. Suvorexant is taken by mouth.

An orexin receptor antagonist, or orexin antagonist, is a drug that inhibits the effect of orexin by acting as a receptor antagonist of one (selective orexin receptor antagonist or SORA) or both (dual orexin receptor antagonis or DORA) of the orexin receptors, OX1 and OX2. Medical applications include treatment of sleep disorders such as insomnia.

<span class="mw-page-title-main">Seltorexant</span> Experimental anti-insomnia drug

Seltorexant, also known by its developmental code names MIN-202 and JNJ-42847922, is an orexin antagonist medication which is under development for the treatment of depression and insomnia. It is a selective antagonist of the orexin OX2 receptor (2-SORA). The medication is taken by mouth.

<span class="mw-page-title-main">Lemborexant</span> Chemical compound

Lemborexant, sold under the brand name Dayvigo, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maintenance in adults. The medication is taken by mouth.

<span class="mw-page-title-main">Vornorexant</span> Chemical compound

Vornorexant, also known by its developmental code names ORN-0829 and TS-142, is an orexin antagonist medication which is under development for the treatment of insomnia and sleep apnea. It is a dual orexin OX1 and OX2 receptor antagonist (DORA). The medication is taken by mouth. As of June 2021, vornorexant is in phase 2 clinical trials for insomnia and phase 1 trials for sleep apnea. It is under development by Taisho Pharmaceutical.

<span class="mw-page-title-main">ACT-462206</span> Chemical compound

ACT-462206 is a dual orexin receptor antagonist (IC50 for OX1 = 60nM, OX2 = 11nM) which has been investigated for the treatment of insomnia. In human trials, ACT-462206 produced dose-dependent sedative effects and was generally well tolerated, with residual sleepiness and headache being the most common adverse events.

<span class="mw-page-title-main">Somnifacient</span> Class of medications that induce sleep

Somnifacient, also known as sedatives or sleeping pills, is a class of medications that induces sleep. It is mainly used for treatment of insomnia. Examples of somnifacients include benzodiazepines, barbiturates and antihistamines.

<span class="mw-page-title-main">Fazamorexant</span> Orexin receptor antagonist

Fazamorexant is an orexin receptor antagonist which is under development for the treatment of insomnia. It is taken by mouth.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 "Quviviq- daridorexant tablet, film coated". DailyMed. 23 March 2022. Archived from the original on 19 September 2022. Retrieved 18 September 2022.
  2. ↑ "Summary Basis of Decision for Quviviq". Health Canada. 4 August 2023. Retrieved 4 October 2023.
  3. ↑ "Details for: Quviviq". Health Canada. 8 September 2023. Retrieved 4 October 2023.
  4. 1 2 3 4 5 6 "Quviviq EPAR". European Medicines Agency (EMA). 22 February 2022. Archived from the original on 4 May 2022. Retrieved 5 May 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  5. 1 2 3 4 5 6 7 8 9 10 11 Muehlan C, Vaillant C, Zenklusen I, Kraehenbuehl S, Dingemanse J (November 2020). "Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders". Expert Opinion on Drug Metabolism & Toxicology. 16 (11): 1063–1078. doi:10.1080/17425255.2020.1817380. PMID   32901578. S2CID   221572078.
  6. ↑ "Quviviq Product Information" (PDF). European Medicines Agency. 2022. Archived (PDF) from the original on 6 May 2022. Retrieved 5 May 2022.
  7. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Park J, Render PharmD KP, Cates PharmD DW (January 2023). "Daridorexant: Comprehensive Review of A New Oral Agent for the Treatment of Insomnia". The Annals of Pharmacotherapy. 57 (9): 1076–1087. doi:10.1177/10600280221143794. PMID   36602018. S2CID   255473890.
  8. 1 2 3 4 5 6 7 8 9 10 11 Roch C, Bergamini G, Steiner MA, Clozel M (October 2021). "Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia". Psychopharmacology. 238 (10): 2693–2708. doi:10.1007/s00213-021-05954-0. PMC   8455402 . PMID   34415378.
  9. 1 2 3 4 "Daridorexant - Idorsia Pharmaceuticals - AdisInsight". Archived from the original on 19 June 2018. Retrieved 19 June 2018.
  10. 1 2 Equihua-Benítez AC, Guzmán-Vásquez K, Drucker-Colín R (July 2017). "Understanding sleep-wake mechanisms and drug discovery". Expert Opinion on Drug Discovery. 12 (7): 643–657. doi:10.1080/17460441.2017.1329818. PMID   28511597. S2CID   3513546.
  11. 1 2 "Drug Approval Package: Quviviq". U.S. Food and Drug Administration (FDA). 14 February 2022. Archived from the original on 4 March 2022. Retrieved 4 March 2022.
  12. 1 2 "Idorsia's new treatment QUVIVIQ (Daridorexant) is now available in the US for adults living with insomnia" (Press release). 2 May 2022. Archived from the original on 5 May 2022. Retrieved 5 May 2022.
  13. 1 2 3 "Europe's first dual orexin receptor antagonist – Quviviq (Daridorexant) – granted approval to improve both nighttime symptoms and daytime functioning in adults with chronic insomnia disorder". 3 May 2022. Archived from the original on 5 May 2022. Retrieved 5 May 2022.
  14. 1 2 "Idorsia receives US FDA approval of Quviviq (daridorexant)" (Press release). Idorsia Pharmaceuticals. 10 January 2022. Archived from the original on 11 January 2022. Retrieved 11 January 2022– via GlobeNewswire.
  15. 1 2 "Schedules of Controlled Substances: Placement of Daridorexant in Schedule IV". Archived from the original on 13 April 2022. Retrieved 13 April 2022.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  16. 1 2 3 4 5 6 7 8 Jacobson LH, Hoyer D, de Lecea L (May 2022). "Hypocretins (orexins): The ultimate translational neuropeptides". Journal of Internal Medicine. 291 (5): 533–556. doi:10.1111/joim.13406. PMID   35043499. S2CID   248119793.
  17. 1 2 3 4 5 Markham A (April 2022). "Daridorexant: First Approval". Drugs. 82 (5): 601–607. doi:10.1007/s40265-022-01699-y. PMC   9042981 . PMID   35298826. S2CID   247501311.
  18. ↑ Albadrani MS, Albadrani MS, Fadlalmola HA, Elhusein AM, Abobaker RM, Merghani MM, et al. (January 2023). "Safety and efficacy of daridorexant in the treatment of insomnia: a systematic review and meta-analysis of randomized controlled trials". International Clinical Psychopharmacology. 38 (1): 57–65. doi:10.1097/YIC.0000000000000425. PMID   36473030. S2CID   254274701.
  19. 1 2 3 4 5 6 De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, et al. (July 2022). "Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis". Lancet. 400 (10347): 170–184. doi: 10.1016/S0140-6736(22)00878-9 . hdl: 11380/1288245 . PMID   35843245. S2CID   250536370.
  20. 1 2 Wang L, Pan Y, Ye C, Guo L, Luo S, Dai S, et al. (December 2021). "A network meta-analysis of the long- and short-term efficacy of sleep medicines in adults and older adults". Neuroscience and Biobehavioral Reviews. 131: 489–496. doi: 10.1016/j.neubiorev.2021.09.035 . PMID   34560134. S2CID   237589779.
  21. ↑ McElroy H, O'Leary B, Adena M, Campbell R, Monfared AA, Meier G (September 2021). "Comparative efficacy of lemborexant and other insomnia treatments: a network meta-analysis". Journal of Managed Care & Specialty Pharmacy. 27 (9): 1296–1308. doi: 10.18553/jmcp.2021.21011 . PMC   10394202 . PMID   34121443.
  22. ↑ Xue T, Wu X, Chen S, Yang Y, Yan Z, Song Z, et al. (February 2022). "The efficacy and safety of dual orexin receptor antagonists in primary insomnia: A systematic review and network meta-analysis". Sleep Medicine Reviews. 61: 101573. doi:10.1016/j.smrv.2021.101573. PMID   34902823. S2CID   244689706.
  23. ↑ Krause A, Lott D, Brussee JM, Muehlan C, Dingemanse J (January 2023). "Population pharmacokinetic modeling of daridorexant, a novel dual orexin receptor antagonist". CPT: Pharmacometrics & Systems Pharmacology. 12 (1): 74–86. doi:10.1002/psp4.12877. PMC   9835129 . PMID   36309969.
  24. ↑ Kunz D, Dauvilliers Y, Benes H, García-Borreguero D, Plazzi G, Seboek Kinter D, et al. (January 2023). "Long-Term Safety and Tolerability of Daridorexant in Patients with Insomnia Disorder". CNS Drugs. 37 (1): 93–106. doi:10.1007/s40263-022-00980-8. PMC   9829592 . PMID   36484969.
  25. ↑ Dunleavy, Kevin (10 May 2023). "Defense Department backs new study of Idorsia's Quviviq as a treatment for PTSD" . Retrieved 28 September 2023.
  26. ↑ Nobile B, Olié E, Courtet P (December 2022). "Possible Suicidal Risk With Daridorexant, a New Treatment for Insomnia". The Journal of Clinical Psychiatry. 84 (1). doi: 10.4088/JCP.22l14628 . PMID   36479953. S2CID   254315580.
  27. ↑ Katzman MA, Katzman MP (January 2022). "Neurobiology of the Orexin System and Its Potential Role in the Regulation of Hedonic Tone". Brain Sciences. 12 (2): 150. doi: 10.3390/brainsci12020150 . PMC   8870430 . PMID   35203914.
  28. 1 2 3 4 Ufer M, Kelsh D, Schoedel KA, Dingemanse J (March 2022). "Abuse potential assessment of the new dual orexin receptor antagonist daridorexant in recreational sedative drug users as compared to suvorexant and zolpidem". Sleep. 45 (3). doi: 10.1093/sleep/zsab224 . PMID   34480579.
  29. ↑ Patel KV, Aspesi AV, Evoy KE (April 2015). "Suvorexant: a dual orexin receptor antagonist for the treatment of sleep onset and sleep maintenance insomnia". The Annals of Pharmacotherapy. 49 (4): 477–483. doi:10.1177/1060028015570467. PMID   25667197. S2CID   208871440.
  30. ↑ Mignot E, Mayleben D, Fietze I, Leger D, Zammit G, Bassetti CL, et al. (February 2022). "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. 21 (2): 125–139. doi:10.1016/S1474-4422(21)00436-1. PMID   35065036. S2CID   246054876.
  31. 1 2 3 "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 4 March 2022.
  32. ↑ "Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers". fda.gov. U.S. Food and Drug Administration. 10 March 2020. Retrieved 5 April 2022.
  33. 1 2 3 4 5 6 Nixon JP, Mavanji V, Butterick TA, Billington CJ, Kotz CM, Teske JA (March 2015). "Sleep disorders, obesity, and aging: the role of orexin". Ageing Research Reviews. 20: 63–73. doi:10.1016/j.arr.2014.11.001. PMC   4467809 . PMID   25462194.
  34. ↑ Treiber A, Aissaoui H, Delahaye S, Glutz S, Grimont J, Müller C, et al. (May 2023). "CYP3A4 Catalyzes the Rearrangement of the Dual Orexin Receptor Antagonist Daridorexant to 4-Hydroxypiperidinol Metabolites". ChemMedChem. 18 (10): e202300030. doi:10.1002/cmdc.202300030. PMID   36892179. S2CID   257426668.
  35. 1 2 "Nemorexant". Pubchem.ncbi.nlm.nih.gov. Archived from the original on 27 January 2022. Retrieved 3 March 2022.
  36. 1 2 "Quviviq: Pending EC decision". European Medicines Agency. 24 February 2022. Archived from the original on 27 February 2022. Retrieved 27 February 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  37. ↑ WO 2013182972,Boss C, Brotschi C, Gude M, Heidmann B, Sifferlen T, Williams JT,"Benzimidazole-proline derivatives", assigned to Actelion Pharmaceuticals Ltd
  38. ↑ Treiber A, de Kanter R, Roch C, Gatfield J, Boss C, von Raumer M, et al. (September 2017). "The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468". The Journal of Pharmacology and Experimental Therapeutics. 362 (3): 489–503. doi: 10.1124/jpet.117.241596 . PMID   28663311. S2CID   11503566.
  39. ↑ Muehlan C, Juif PE, Van Gerven J, Heuberger J, Dingemanse J (February 2017). "First-in-human study of ACT-541468, a novel dual orexin receptor antagonist: characterization of its pharmacokinetics, pharmacodynamics, safety, and tolerability". Clinical Pharmacology & Therapeutics. 101 (S1): S80.
  40. ↑ Boehler M, Muehlan C, Juif PE, English S, van Gerven J, Peeters P, Heuberger J, Dingemanse J. "Mass balance and absolute bioavailability of ACT-541468, a dual orexin receptor antagonist, by administration of a microtracer dose and AMS analysis in a first-in-human study". Clinical Pharmacology & Therapeutics. 101 (S1): S57.
  41. ↑ Dunleavy, Kevin (7 April 2023). "Idorsia petitions DEA to de-schedule its insomnia drug—plus Merck and Eisai rivals". Fierce Pharma. Retrieved 31 August 2023.
  42. ↑ "Quviviq (Daridorexant) recommended for approval in Europe as a new treatment for adults with insomnia disorder" (Press release). 25 February 2022. Archived from the original on 8 April 2022. Retrieved 8 April 2022.
  43. ↑ "Search Results - (Emc)". Archived from the original on 19 September 2022. Retrieved 8 April 2022.
  44. ↑ "Medicines". European Medicines Agency. 1 January 2021. Archived from the original on 21 August 2022. Retrieved 21 August 2022.
  45. ↑ "Home". MHRA Products. 30 October 2005. Archived from the original on 15 August 2022. Retrieved 21 August 2022.
  46. ↑ "Micromedex Products". Archived from the original on 23 May 2019. Retrieved 8 April 2022.
  47. ↑ "Quviviq Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  48. ↑ "Idorsia | Media release". www.idorsia.com. Retrieved 5 March 2024.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.