Skip to main content
SpringerLink
Log in

Daridorexant for the treatment of insomnia disorder: findings and implications

  • Review
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The involvement of the orexin system in the physiopathology of insomnia has been rapidly increasing in understanding. In this sense, daridorexant was the third orexin receptor antagonist approved by the FDA in January 2022. This review aims to summarize the chemistry, pharmacodynamics, pharmacokinetics, efficacy, safety, and tolerability profile of daridorexant for the treatment of insomnia disorder.

Methods

We performed a review of daridorexant for the treatment of insomnia disorder. The search was carried out in Medline via PubMed, Embase, and clinical trials, up to March 2022.

Results

Daridorexant 25 and 50 mg had more significant improvement for the wake after sleep onset (WASO), latency to persistent sleep (LPS), and subjective total sleep time (sTST) than placebo. In addition, daridorexant 50 mg was better for Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) than placebo. The most common adverse events were nasopharyngitis and headache.

Conclusion

Daridorexant was efficacious and safe. Studies that evaluate the long-term safety and compare daridorexant with benzodiazepines, benzodiazepine receptor agonists, sedative antidepressants, and other orexin receptor antagonists are required.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

Not applicable.

References

  1. Sateia MJ (2014) International classification of sleep disorders-third edition: highlights and modifications. Chest 146(5):1387–1394. https://doi.org/10.1378/chest.14-0970

    Article  PubMed  Google Scholar 

  2. Roth T (2007) Insomnia: definition, prevalence, etiology, and consequences. J Clin Sleep Med: JCSM: Official Pub Am Acad Sleep Med 3(5 Suppl):S7–S10

    Google Scholar 

  3. Ford ES, Cunningham TJ, Giles WH, Croft JB (2015) Trends in insomnia and excessive daytime sleepiness among U.S. adults from 2002 to 2012. Sleep Med 16(3), 372–378. https://doi.org/10.1016/j.sleep.2014.12.008

  4. Calem M, Bisla J, Begum A, Dewey M, Bebbington PE, Brugha T, Cooper C, Jenkins R, Lindesay J, McManus S, Meltzer H, Spiers N, Weich S, Stewart R (2012) Increased prevalence of insomnia and changes in hypnotics use in England over 15 years: analysis of the 1993, 2000, and 2007 National Psychiatric Morbidity Surveys. Sleep 35(3):377–384. https://doi.org/10.5665/sleep.1700

    Article  PubMed  PubMed Central  Google Scholar 

  5. Olfson M, Wall M, Liu SM, Morin CM, Blanco C (2018) Insomnia and impaired quality of life in the United States. J Clin Psych 79(5):17m12020. https://doi.org/10.4088/JCP.17m12020

  6. Edinger JD, Arnedt JT, Bertisch SM, Carney CE, Harrington JJ, Lichstein KL, Sateia MJ, Troxel WM, Zhou ES, Kazmi U, Heald JL, Martin JL (2021) Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med: JCSM: Official Pub Am Acad Sleep Med 17(2):255–262. https://doi.org/10.5664/jcsm.8986

    Article  Google Scholar 

  7. Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL (2017) Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med: JCSM: Official Pub Am Acad Sleep Med 13(2):307–349. https://doi.org/10.5664/jcsm.6470

    Article  Google Scholar 

  8. Equihua AC, De La Herrán-Arita AK, Drucker-Colin R (2013) Orexin receptor antagonists as therapeutic agents for insomnia. Front Pharmacol 4:163. https://doi.org/10.3389/fphar.2013.00163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Glass J, Lanctôt KL, Herrmann N, Sproule BA, Busto UE (2005) Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ (Clinical research ed) 331(7526):1169. https://doi.org/10.1136/bmj.38623.768588.47

    Article  Google Scholar 

  10. Panneman MJ, Goettsch WG, Kramarz P, Herings RM (2003) The costs of benzodiazepine-associated hospital-treated fall injuries in the EU: a Pharmo study. Drugs Aging 20(11):833–839. https://doi.org/10.2165/00002512-200320110-00004

    Article  PubMed  Google Scholar 

  11. Verster JC, Veldhuijzen DS, Patat A, Olivier B, Volkerts ER (2006) Hypnotics and driving safety: meta-analyses of randomized controlled trials applying the on-the-road driving test. Curr Drug Saf 1(1):63–71. https://doi.org/10.2174/157488606775252674

    Article  CAS  PubMed  Google Scholar 

  12. Lie JD, Tu KN, Shen DD, Wong BM (2015) Pharmacological treatment of insomnia. P & T: Peer-Rev J Formulary Manag 40(11):759–771

    Google Scholar 

  13. Huedo-Medina TB, Kirsch I, Middlemass J, Klonizakis M, Siriwardena AN (2012) Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration. BMJ (Clinical research ed) 345:e8343. https://doi.org/10.1136/bmj.e8343

    Article  CAS  Google Scholar 

  14. Scharner V, Hasieber L, Sönnichsen A, Mann E (2022) Efficacy and safety of Z-substances in the management of insomnia in older adults: a systematic review for the development of recommendations to reduce potentially inappropriate prescribing. BMC Geriatr 22(1):87. https://doi.org/10.1186/s12877-022-02757-6

    Article  PubMed  Google Scholar 

  15. Sun Y, Tisdale RK, Kilduff TS (2021) Hypocretin/orexin receptor pharmacology and sleep phases. Front Neurol Neurosci 45:22–37. https://doi.org/10.1159/000514963

    Article  PubMed  PubMed Central  Google Scholar 

  16. Hoever P, de Haas SL, Dorffner G, Chiossi E, van Gerven JM, Dingemanse J (2012) Orexin receptor antagonism: an ascending multiple-dose study with almorexant. J Psychopharmacol (Oxford, England) 26(8):1071–1080. https://doi.org/10.1177/0269881112448946

    Article  CAS  Google Scholar 

  17. Food And Drug Administration (2014) Suvorexant (Belsomra). https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204569s000lbledt.pdf. Accessed 20 Jan 2022

  18. Herring WJ, Connor KM, Ivgy-May N, Snyder E, Liu K, Snavely DB, Krystal AD, Walsh JK, Benca RM, Rosenberg R, Sangal RB, Budd K, Hutzelmann J, Leibensperger H, Froman S, Lines C, Roth T, Michelson D (2016) Suvorexant in patients with insomnia: results from two 3-month randomized controlled clinical trials. Biol Psychiat 79(2):136–148. https://doi.org/10.1016/j.biopsych.2014.10.003

    Article  CAS  PubMed  Google Scholar 

  19. Food And Drug Administration (2019) Lemborexant (Dayvigo). https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212028s000lbl.pdf. Accessed 20 Jan 2022

  20. Rosenberg R, Murphy P, Zammit G, Mayleben D, Kumar D, Dhadda S, Filippov G, LoPresti A, Moline M (2019) Comparison of lemborexant with placebo and zolpidem tartrate extended release for the treatment of older adults with insomnia disorder: a phase 3 randomized clinical trial. JAMA Netw Open 2(12):e1918254. https://doi.org/10.1001/jamanetworkopen.2019.18254

    Article  PubMed  PubMed Central  Google Scholar 

  21. Food And Drug Administration (2022) Daridorexant (Quviviq). https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214985s000lbl.pdf. Accessed 20 Jan 2022

  22. Mignot E, Mayleben D, Fietze I, Leger D, Zammit G, Bassetti C, Pain S, Kinter DS, Roth T, Investigators (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 Neurol 21(2):125–139. https://doi.org/10.1016/S1474-4422(21)00436-1

    Article  CAS  PubMed  Google Scholar 

  23. Daina A, Michielin O, Zoete V (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7:42717. https://doi.org/10.1038/srep42717

    Article  PubMed  PubMed Central  Google Scholar 

  24. ClinicalTrials.gov (2022) Daridorexant. https://clinicaltrials.gov. Accessed 20 Jan 2022

  25. Laskowski RA, Swindells MB (2011) LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model 51(10):2778–2786. https://doi.org/10.1021/ci200227u

    Article  CAS  PubMed  Google Scholar 

  26. Schöning-Stierand K, Diedrich K, Fährrolfes R, Flachsenberg F, Meyder A, Nittinger E, Steinegger R, Rarey M (2020) ProteinsPlus: interactive analysis of protein-ligand binding interfaces. Nucleic Acids Res 48(W1):W48–W53. https://doi.org/10.1093/nar/gkaa235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rappas M, Ali A, Bennett KA, Brown JD, Bucknell SJ, Congreve M, Cooke RM, Cseke G, de Graaf C, Doré AS, Errey JC, Jazayeri A, Marshall FH, Mason JS, Mould R, Patel JC, Tehan BG, Weir M, Christopher JA (2020) Comparison of Orexin 1 and orexin 2 ligand binding modes using X-ray crystallography and computational analysis. J Med Chem 63(4):1528–1543. https://doi.org/10.1021/acs.jmedchem.9b01787

    Article  CAS  PubMed  Google Scholar 

  28. Boss C, Brotschi C, Heidmann B, Siffer-Len T, Von Raumer M, Williams JT, Inventors Actelion Pharmaceuticals Ltd, assignee (2015) Crystalline salt form of (S)-(2-(6-chloro-7-methyl-1H-benzo[d]idazol-2-yl)-2-methyl-pyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone. World Intellectual Property Organization WO2015/083071. https://patentimages.storage.googleapis.com/d5/d3/39/00652f0a716d1f/WO2015083071A1.pdf. Accessed 20 Jan 2022

  29. Muehlan C, Heuberger J, Juif PE, Croft M, van Gerven J, Dingemanse J (2018) Accelerated development of the dual orexin receptor antagonist ACT-541468: integration of a microtracer in a first-in-human study. Clin Pharmacol Ther 104(5):1022–1029. https://doi.org/10.1002/cpt.1046

    Article  CAS  PubMed  Google Scholar 

  30. Muehlan C, Brooks S, Zuiker R, van Gerven J, Dingemanse J (2019) Multiple-dose clinical pharmacology of ACT-541468, a novel dual orexin receptor antagonist, following repeated-dose morning and evening administration. Eur Neuropsychopharmacol: J Eur Coll Neuropsychopharmacol 29(7):847–857. https://doi.org/10.1016/j.euroneuro.2019.05.009

    Article  CAS  Google Scholar 

  31. European Medicines Agency (2022) Assessment report EMA/187589/2022. Quviviq. https://www.ema.europa.eu/en/documents/assessment-report/quviviq-epar-public-assessment-report_en.pdf. Accessed 26 Aug 2022

  32. Muehlan C, Zuiker R, Peeters P, Rowles R, Dingemanse J (2020) Pharmacokinetics and pharmacodynamics of the dual orexin receptor antagonist daridorexant in Japanese and Caucasian subjects. J Clin Psychopharmacol 40(2):157–166. https://doi.org/10.1097/JCP.0000000000001182

    Article  CAS  PubMed  Google Scholar 

  33. Muehlan C, Boehler M, Brooks S, Zuiker R, van Gerven J, Dingemanse J (2020) Clinical pharmacology of the dual orexin receptor antagonist ACT-541468 in elderly subjects: exploration of pharmacokinetics, pharmacodynamics and tolerability following single-dose morning and repeated-dose evening administration. J Psychopharmacol (Oxford, England) 34(3):326–335. https://doi.org/10.1177/0269881119882854

    Article  Google Scholar 

  34. Berger B, Dingemanse J, Sabattini G, Delahaye S, Duthaler U, Muehlan C, Krähenbühl S (2021) Effect of liver cirrhosis on the pharmacokinetics, metabolism, and tolerability of daridorexant, a novel dual orexin receptor antagonist. Clin Pharmacokinet 60(10):1349–1360. https://doi.org/10.1007/s40262-021-01028-8

    Article  CAS  PubMed  Google Scholar 

  35. Berger B, Muehlan C, Klein G, Dingemanse J (2021) Pharmacokinetics of daridorexant, a dual orexin receptor antagonist, are not affected by renal impairment. Clin Transl Sci 14(6):2132–2138. https://doi.org/10.1111/cts.13079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gehin M, Wierdak J, Sabattini G, Sidharta PN, Dingemanse J (2022) Effect of gastric pH and of a moderate CYP3A4 inducer on the pharmacokinetics of daridorexant, a dual orexin receptor antagonist. Br J Clin Pharmacol 88(2):810–819. https://doi.org/10.1111/bcp.15029

    Article  CAS  PubMed  Google Scholar 

  37. Berger B, Brooks S, Zuiker R, Richard M, Muehlan C, Dingemanse J (2020) Pharmacological Interactions between the dual orexin receptor antagonist daridorexant and ethanol in a double-blind, randomized, placebo-controlled, double-dummy, Four-Way Crossover Phase I Study in Healthy Subjects. CNS Drugs 34(12):1253–1266. https://doi.org/10.1007/s40263-020-00768-8

    Article  CAS  PubMed  Google Scholar 

  38. Zenklusen I, Muehlan C, Ulc I, Liška J, Dingemanse J (2020) The dual orexin receptor antagonist daridorexant does not affect the pharmacokinetics of the BCRP substrate rosuvastatin. Clin Exp Pharmacol Physiol 47(11):1843–1849. https://doi.org/10.1111/1440-1681.13370

    Article  CAS  PubMed  Google Scholar 

  39. Berger B, Kornberger R, Dingemanse J (2021) Pharmacokinetic and pharmacodynamic interactions between daridorexant, a dual orexin receptor antagonist, and citalopram in healthy subjects. Eur Neuropsychopharmacol: J Eur Coll Neuropsychopharmacol 51:90–104. https://doi.org/10.1016/j.euroneuro.2021.05.005

    Article  CAS  Google Scholar 

  40. Dauvilliers Y, Zammit G, Fietze I, Mayleben D, Seboek Kinter D, Pain S, Hedner J (2020) Daridorexant, a new dual orexin receptor antagonist to treat insomnia disorder. Ann Neurol 87(3):347–356. https://doi.org/10.1002/ana.25680

    Article  CAS  PubMed  Google Scholar 

  41. Zammit G, Dauvilliers Y, Pain S, Sebök Kinter D, Mansour Y, Kunz D (2020) Daridorexant, a new dual orexin receptor antagonist, in elderly subjects with insomnia disorder. Neurology 94(21):e2222–e2232. https://doi.org/10.1212/WNL.0000000000009475

    Article  CAS  PubMed  Google Scholar 

  42. Schilling U, Henrich A, Muehlan C, Krause A, Dingemanse J, Ufer M (2021) Impact of daridorexant, a dual orexin receptor antagonist, on cardiac repolarization following bedtime dosing: results from a thorough QT study using concentration-QT analysis. Clin Drug Investig 41(8):711–721. https://doi.org/10.1007/s40261-021-01062-1

    Article  CAS  PubMed  Google Scholar 

  43. Boof ML, Dingemanse J, Lederer K, Fietze I, Ufer M (2021) Effect of the new dual orexin receptor antagonist daridorexant on nighttime respiratory function and sleep in patients with mild and moderate obstructive sleep apnea. Sleep 44(6):zsaa275. https://doi.org/10.1093/sleep/zsaa275

  44. Boof ML, Dingemanse J, Brunke M, Esselmann A, Heymer P, Kestermann O, Lederer K, Fietze I, Ufer M (2021) Effect of the novel dual orexin receptor antagonist daridorexant on night-time respiratory function and sleep in patients with moderate chronic obstructive pulmonary disease. J Sleep Res 30(4):e13248. https://doi.org/10.1111/jsr.13248

    Article  PubMed  Google Scholar 

  45. Ufer M, Kelsh D, Schoedel KA. Dingemanse J (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):zsab224. https://doi.org/10.1093/sleep/zsab224

  46. Bollu PC, Kaur H (2019) Sleep medicine: insomnia and sleep. Mo Med 116(1):68–75

    PubMed  PubMed Central  Google Scholar 

  47. Sutton EL (2015) Profile of suvorexant in the management of insomnia. Drug Des Dev Ther 9:6035–6042. https://doi.org/10.2147/DDDT.S73224

    Article  CAS  Google Scholar 

  48. Kuriyama A, Tabata H (2017) Suvorexant for the treatment of primary insomnia: a systematic review and meta-analysis. Sleep Med Rev 35:1–7. https://doi.org/10.1016/j.smrv.2016.09.004

    Article  PubMed  Google Scholar 

  49. Jacobson LH, Callander GE, Hoyer D (2014) Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol 7(6):711–730. https://doi.org/10.1586/17512433.2014.966813

    Article  CAS  PubMed  Google Scholar 

  50. Waters K (2022) Review of the Efficacy and safety of lemborexant, a dual receptor orexin antagonist (DORA), in the treatment of adults with insomnia disorder. Ann Pharmacother 56(2):213–221. https://doi.org/10.1177/10600280211008492

    Article  CAS  PubMed  Google Scholar 

  51. Kishi T, Nomura I, Matsuda Y, Sakuma K, Okuya M, Ikuta T, Iwata N (2020) Lemborexant vs suvorexant for insomnia: a systematic review and network meta-analysis. J Psychiatr Res 128:68–74. https://doi.org/10.1016/j.jpsychires.2020.05.025

    Article  PubMed  Google Scholar 

  52. Spiegelhalder K, Feige B, Riemann D, Kyle SD (2022) Daridorexant for insomnia disorder. The Lancet Neurology 21(2):104–105. https://doi.org/10.1016/S1474-4422(22)00007-2

    Article  CAS  PubMed  Google Scholar 

  53. Riemann D, Baglioni C, Bassetti C, Bjorvatn B, Dolenc Groselj L, Ellis JG, Espie CA, Garcia-Borreguero D, Gjerstad M, Gonçalves M, Hertenstein E, Jansson-Fröjmark M, Jennum PJ, Leger D, Nissen C, Parrino L, Paunio T, Pevernagie D, Verbraecken J, Weeß HG, Spiegelhalder K (2017) European guideline for the diagnosis and treatment of insomnia. J Sleep Res 26(6):675–700. https://doi.org/10.1111/jsr.12594

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Health Technology Assessment and Economy Group, Center for Exact, Natural and Health Sciences, Federal University of Espírito Santo, Alto Universitário S/N, Guararema, Alegre, Espírito Santo, 29500-000, Brazil

    Jéssica Barreto Ribeiro dos Santos & Michael Ruberson Ribeiro da Silva

Authors
  1. Jéssica Barreto Ribeiro dos Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Ruberson Ribeiro da Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the conception for the work, literature search, interpretation of data, and drafted and critically revised the work. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Michael Ruberson Ribeiro da Silva.

Ethics declarations

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Key messages

• Daridorexant is the third oral orexin receptor antagonist approved for the treatment of insomnia disorder in adults. It was approved for use on 07 January 2022 by the United States Food and Drug Administration.

• Daridorexant was effective for sleep maintenance and sleep onset in the treatment of insomnia disorder. The drug was safe and well tolerated.

• Studies that evaluate the long-term safety and compare daridorexant with benzodiazepines, benzodiazepine receptor agonists, sedative antidepressants, and other orexin receptor antagonists are required.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

dos Santos, J.B.R., da Silva, M.R.R. Daridorexant for the treatment of insomnia disorder: findings and implications. Eur J Clin Pharmacol 78, 1749–1761 (2022). https://doi.org/10.1007/s00228-022-03381-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-022-03381-4

Keywords

Search

Navigation