Daridorexant

Daridorexant
Names
Trade namesQuviviq
Other namesNemorexant; ACT-541468, Daridorexant hydrochloride (USAN US)
IUPAC name
  • [(2S)-2-(5-Chloro-4-methyl-1H-benzimidazol-2-yl)-2-methylpyrrolidin-1-yl]-[5-methoxy-2-(triazol-2-yl)phenyl]methanone
Clinical data
Drug classOrexin receptor antagonist
Main usesTrouble sleeping.[1]
Side effectsHeadache, sleepiness, tiredness, depression, sleep paralysis, complex sleep behavior[2]
Addiction riskSome[3]
Routes of
use		By mouth[2]
Onset of actionTmax: 1–2 hours (delayed by 1.3 hours with food)[2]
Duration of action~8 hours (50 mg)[4]
Typical dose25 to 50 mg[2]
External links
AHFS/Drugs.comMonograph
Legal
License data
Legal status
Pharmacokinetics
Bioavailability62%[2]
Protein binding99.7%[2]
MetabolismExtensive (mainly CYP3A4 (89%))[2]
Elimination half-life8 hours (6–10 hours)[2][4]
ExcretionFeces: ~57%[2]
Urine: ~28%[2]
Chemical and physical data
FormulaC23H23ClN6O2
Molar mass450.93 g·mol−1
3D model (JSmol)
SMILES
  • CC1=C(C=CC2=C1N=C(N2)[C@@]3(CCCN3C(=O)C4=C(C=CC(=C4)OC)N5N=CC=N5)C)Cl
InChI
  • 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 a medication used to treat trouble sleeping.[1] It is used in those who have had problems for at least three months and is only recommended short term.[1] It is taken by mouth half an hour before bed.[2][1]

Common side effects include headache, sleepiness, and tiredness.[2] Other side effects may include depression, sleep paralysis, and complex sleep behavior.[2] It has a relatively low risk of misuse.[2][5] It should not be used in those with severe liver problems or narcolepsy.[2] Safety in pregnancy is unclear.[3] It is a dual orexin receptor antagonist (DORA) and works by blocking the action of orexin.[1] It is not a benzodiazepine or Z-drug.[6]

Daridorexant was approved for medical use in the United States and Europe in 2022.[2][1] In the United States a month of medication costs about 470 USD as of 2022.[7] It is not commercially available in the United Kingdom as of 2022.[8] It is a schedule IV controlled substance in the United States.[2]

Medical uses

Daridorexant is indicated for the treatment of adults with insomnia characterized by difficulties with sleep onset and/or sleep maintenance.[2] 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.[2] 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.[2] Daridorexant has also been found to improve daytime functioning at a dose of 50 mg but not at 25 mg.[9] It is the first insomnia medication to have been evaluated and shown effectiveness in improving not only nighttime symptoms but also daytime functioning.[10]

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.[11][12][13][14] 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 –0.01 to 0.48).[11] 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).[11] Benzodiazepines and Z-drugs generally showed larger effect sizes than orexin receptor antagonists (e.g., SMDs of 0.45 to 0.83).[11] 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.[11] 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.[11]

Orexin receptor antagonists are not used as first-line treatments for insomnia due to their costs and concerns about possible misuse liability.[12]

Available forms

Daridorexant is available in the form of 25 and 50 mg oral tablets.[2] 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).[2]

Contraindications

Daridorexant is contraindicated in people with narcolepsy.[2] It is not recommended in people with severe hepatic impairment, whereas a lower maximum dose is recommended in people with moderate hepatic impairment.[2] 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.[2]

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).[2] No residual effects have been found after administration of 25 mg daridorexant in the evening to either young or elderly individuals.[4] However, daridorexant may cause next-morning driving impairment at the start of treatment or in some individuals.[2] Orexin receptor antagonists like daridorexant may have less or no propensity for causing tolerance compared to other sedatives and hypnotics based on animal studies.[6][2] 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.[2][4] Loss of sleep-promoting effectiveness occurs rapidly upon discontinuation of daridorexant.[2] Preclinical research has suggested that orexin antagonists may reduce appetite, but daridorexant and other orexin antagonists have not been associated with weight loss in rigorous clinical trials.[15]

Orexin receptor antagonists can affect the reward system and produce drug-liking responses in humans.[16][17][15] 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.[2][18] 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).[2][18] 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).[19] No reports indicative of misuse liability were observed in large clinical trials with daridorexant, although these studies excluded participants with history of drug or alcohol misuse.[2][20][18]

Overdose

There is limited clinical experience with overdose of daridorexant.[2] 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, catalepsy-like symptoms, sleep paralysis, attention disturbances, fatigue, headache, and constipation.[2] There is no specific antidote to overdose of daridorexant.[2]

Interactions

CYP3A4 inhibitors like ranitidine and diltiazem and CYP3A4 inducers like efavirenz can increase and decrease exposure to daridorexant, respectively.[2] 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.[2] Gastric pH modifiers like famotidine can decrease peak levels of daridorexant without affecting total exposure.[2] Alcohol and selective serotonin reuptake inhibitors (SSRIs) like citalopram have not shown significant pharmacokinetic interactions with daridorexant.[2] 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.[2] Daridorexant has not been found to significantly influence the pharmacokinetics of other drugs including midazolam (CYP3A4 substrate), rosuvastatin (BCRP substrate), and the SSRI citalopram.[2]

Pharmacology

Pharmacodynamics

Daridorexant acts as a selective dual antagonist of the orexin (hypocretin) receptors OX1 and OX2.[4] 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.[2] 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.[6] Hence, daridorexant is approximately equipotent in its antagonism of the orexin receptors.[6] Daridorexant is selective for the orexin receptors over many other targets.[6] In contrast to certain other sedatives and hypnotics, daridorexant is not a benzodiazepine or Z-drug and does not interact with GABA receptors.[6]

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.[21][15] Deficiency of orexin signaling is thought to be the primary cause of the sleep disorder narcolepsy.[21][15] Disturbances in orexin signaling may also be involved in insomnia.[21] Research suggests that orexin signaling may change with age, and this has been implicated in age-related sleep disturbances.[21] By blocking the actions of orexins and modulating sleep–wake cycles, orexin receptor antagonists like daridorexant reduce wakefulness and improve sleep.[21][15] 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.[15] 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.[21]

Pharmacokinetics

Daridorexant levels after a single oral dose of 50 to 150 mg daridorexant in healthy recreational sedative drug users.[18]

Absorption

The absolute bioavailability of daridorexant is 62%.[2] It reaches peak concentrations within 1 to 2 hours following a dose.[2] 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.[2]

Distribution

The volume of distribution of daridorexant is 31 L.[2] Its plasma protein binding is 99.7%.[2] The plasma-to-blood ratio of daridorexant is 0.64.[2] Daridorexant effectively crosses the blood–brain barrier in animals.[6]

Metabolism

Daridorexant is extensively metabolized primarily by CYP3A4 (89%).[2] Other cytochrome P450 enzymes contribute individually to less than 3% of the clearance of daridorexant.[2]

Elimination

Daridorexant is eliminated primarily by feces (57%) then by urine (28%).[2] It is excreted mainly in the form of metabolites, with only trace amounts of the parent compound identified.[2]

The medication has an elimination half-life of about 8 hours[2] or of 6 to 10 hours.[4] Its half-life is shorter than that of other orexin receptor antagonists such as suvorexant (12 hours) and lemborexant (~18–55 hours).[4] The relatively short half-life of daridorexant may allow for reduced daytime sedation.[4][15] The duration of action of daridorexant in terms of sedative effects is approximately 8 hours with a 50 mg dose.[4]

Chemistry

Daridorexant is a small-molecule compound.[6] 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.[22][2] Its molecular formula is C23H23N6O2Cl and its molecular weight is 450.93 g/mol (or 487.38 g/mol for the hydrochloride).[22][2] Daridorexant hydrochloride is a white to light yellowish powder and is very slightly soluble in water.[2]

History

Daridorexant was patented in 2013[23] and was first described in the scientific literature in 2017.[24][25][26] It was approved for medical use in the United States in January 2022[2][27] and became available in this country in May 2022.[28] 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.[1][29] On 29 April 2022, daridorexant was authorized for use in the European Union.[30] It was the first orexin receptor antagonist to become available for use in the European Union.[30][31] (The earlier orexin receptor antagonists suvorexant and lemborexant are not available in the European Union.)[32][33][34][35] Regulatory review is also ongoing in Canada and Switzerland and is planned for the United Kingdom.[9][36] Daridorexant was originated by Actelion Pharmaceuticals and was further developed by Idorsia.[1][36][29]

Society and culture

Daridorexant is a schedule IV controlled substance under the Controlled Substances Act in the United States.[2][37][5]

Daridorexant (Quviviq) was approved for medical use in the European Union in April 2022.[1]

References

  1. 1 2 3 4 5 6 7 8 9 10 "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.
  2. 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 "Quviviq- daridorexant tablet, film coated". DailyMed. 23 March 2022. Archived from the original on 19 September 2022. Retrieved 18 September 2022.
  3. 1 2 "Daridorexant Monograph for Professionals". Drugs.com. Retrieved 10 December 2022.
  4. 1 2 3 4 5 6 7 8 9 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 Opin Drug Metab Toxicol. 16 (11): 1063–1078. doi:10.1080/17425255.2020.1817380. PMID 32901578. S2CID 221572078.
  5. 1 2 "Schedules of Controlled Substances: Placement of Daridorexant in Schedule IV". Archived from the original on 13 April 2022. Retrieved 13 April 2022. Public Domain This article incorporates text from this source, which is in the public domain.
  6. 1 2 3 4 5 6 7 8 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 (Berl). 238 (10): 2693–2708. doi:10.1007/s00213-021-05954-0. PMC 8455402. PMID 34415378.
  7. ↑ "Daridorexant". Retrieved 10 December 2022.
  8. ↑ "Daridorexant". SPS - Specialist Pharmacy Service. 13 April 2019. Archived from the original on 17 May 2022. Retrieved 10 December 2022.
  9. 1 2 Markham A (March 2022). "Daridorexant: First Approval". Drugs. 82 (5): 601–607. doi:10.1007/s40265-022-01699-y. PMC 9042981. PMID 35298826. S2CID 247501311.
  10. ↑ "The Lancet Neurology reports impact of daridorexant on both nighttime symptoms and daytime functioning in adults with insomnia". 20 January 2022. Archived from the original on 10 April 2022. Retrieved 10 April 2022.
  11. 1 2 3 4 5 6 De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, Kurtulmus A, Tomlinson A, Mitrova Z, Foti F, Del Giovane C, Quested DJ, Cowen PJ, Barbui C, Amato L, Efthimiou O, Cipriani A (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. PMID 35843245. S2CID 250536370.
  12. 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.
  13. ↑ 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. PMID 34121443.
  14. ↑ 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.
  15. 1 2 3 4 5 6 7 Jacobson LH, Hoyer D, de Lecea L (January 2022). "Hypocretins (orexins): The ultimate translational neuropeptides". J Intern Med. 291 (5): 533–556. doi:10.1111/joim.13406. PMID 35043499. S2CID 248119793.
  16. ↑ Calipari ES, España RA (2012). "Hypocretin/orexin regulation of dopamine signaling: implications for reward and reinforcement mechanisms". Front Behav Neurosci. 6: 54. doi:10.3389/fnbeh.2012.00054. PMC 3423791. PMID 22933994.
  17. ↑ Katzman MA, Katzman MP (January 2022). "Neurobiology of the Orexin System and Its Potential Role in the Regulation of Hedonic Tone". Brain Sci. 12 (2): 150. doi:10.3390/brainsci12020150. PMC 8870430. PMID 35203914.
  18. 1 2 3 4 Ufer M, Kelsh D, Schoedel KA, Dingemanse J (September 2021). "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.
  19. ↑ Patel KV, Aspesi AV, Evoy KE (April 2015). "Suvorexant: a dual orexin receptor antagonist for the treatment of sleep onset and sleep maintenance insomnia". Ann Pharmacother. 49 (4): 477–83. doi:10.1177/1060028015570467. PMID 25667197. S2CID 208871440.
  20. ↑ Mignot E, Mayleben D, Fietze I, Leger D, Zammit G, Bassetti CL, Pain S, Kinter DS, Roth T (February 2022). "Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials". Lancet Neurol. 21 (2): 125–139. doi:10.1016/S1474-4422(21)00436-1. PMID 35065036. S2CID 246054876.
  21. 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 Res Rev. 20: 63–73. doi:10.1016/j.arr.2014.11.001. PMC 4467809. PMID 25462194.
  22. 1 2 "Nemorexant". Pubchem.ncbi.nlm.nih.gov. Archived from the original on 27 January 2022. Retrieved 3 March 2022.
  23. ↑   "Archived copy". Archived from the original on 3 March 2022. Retrieved 3 March 2022.{{cite web}}: CS1 maint: archived copy as title (link) CS1 maint: bot: original URL status unknown (link)
  24. ↑ Treiber A, de Kanter R, Roch C, Gatfield J, Boss C, von Raumer M, Schindelholz B, Muehlan C, van Gerven J, Jenck F (September 2017). "The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468". J Pharmacol Exp Ther. 362 (3): 489–503. doi:10.1124/jpet.117.241596. PMID 28663311. S2CID 11503566.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ "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.
  28. ↑ "Idorsia's new treatment QUVIVIQ (Daridorexant) is now available in the US for adults living with insomnia". 2 May 2022. Archived from the original on 5 May 2022. Retrieved 5 May 2022.
  29. 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.
  30. 1 2 "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". Archived from the original on 5 May 2022. Retrieved 5 May 2022.
  31. ↑ "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.
  32. ↑ "Search Results - (Emc)". Archived from the original on 19 September 2022. Retrieved 8 April 2022.
  33. ↑ "Medicines". European Medicines Agency. 1 January 2021. Archived from the original on 21 August 2022. Retrieved 21 August 2022.
  34. ↑ "Home". MHRA Products. 30 October 2005. Archived from the original on 15 August 2022. Retrieved 21 August 2022.
  35. ↑ "Micromedex Products". Archived from the original on 23 May 2019. Retrieved 8 April 2022.
  36. 1 2 "Daridorexant - Idorsia Pharmaceuticals - AdisInsight". Archived from the original on 19 June 2018. Retrieved 19 June 2018.
  37. ↑ "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.

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