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Orexin antagonist

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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.[1] Medical applications include treatment of sleep disorders such as insomnia.[2][3]

Examples

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Marketed

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  • Daridorexant (nemorexant; Quviviq) – dual OX1 and OX2 antagonist – approved for insomnia in January 2022,[4] formerly under development for sleep apnea[5] – half-life 8 hours[6]
  • Lemborexant (Dayvigo) – dual OX1 and OX2 antagonist – approved for insomnia in December 2019[4] and released June 1 2020, under development for circadian rhythm sleep disorders, chronic obstructive pulmonary disease, and sleep apnea – half-life 17–55 hours[7][8]
  • Suvorexant (Belsomra) – dual OX1 and OX2 antagonist – approved for insomnia in August 2014,[4] under development for delirium[9][10] – half-life 12 hours[7][11]

Under development

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  • Fazamorexant (YZJ-1139) – dual OX1 and OX2 antagonist – under development for insomnia, up to phase 3 [12]
  • Nivasorexant (ACT-539313) – selective OX1 antagonist – under development for binge eating disorder and previously for anxiety disorders, up to phase 2 – half-life 3–7 hours [13]
  • Seltorexant (MIN-202, JNJ-42847922, JNJ-922) – selective OX2 antagonist – under development for major depressive disorder, insomnia, and sleep apnea, up to phase 3 – half-life 2–3 hours [14]
  • Tebideutorexant (JNJ-61393215, JNJ-3215) – selective OX1 antagonist – under development for major depressive disorder, no development reported for anxiety disorders and panic disorder, up to phase 2[15]
  • Vornorexant (ORN-0829, TS-142) – dual OX1 and OX2 antagonist – under development for insomnia and sleep apnea, up to phase 3 in Japan – half-life 1.5–3 hours[16]

Not marketed

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  • ACT-335827 – selective OX1 antagonist
  • Almorexant (ACT-078573) – dual OX1 and OX2 antagonist – development of the drug was abandoned in January 2011 [17]
  • EMPA – selective OX2 antagonist
  • Filorexant (MK-6096) – dual OX1 and OX2 antagonist – development was discontinued in 2015 [18]
  • GSK-649868 (SB-649868) – dual OX1 and OX2 antagonist – was in development for potential use in sleep disorders
  • JNJ-10397049 – selective OX2 antagonist
  • RTIOX-276 – selective OX1 antagonist
  • SB-334867 – first non-peptide selective OX1 antagonist – has been shown to produce sedative and anorectic effects in animals[19]
  • SB-408124 – selective OX1 antagonist
  • TCS-OX2-29 – first non-peptide selective OX2 antagonist

Medical uses

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Insomnia

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Orexin receptor antagonists dose-dependently improve sleep parameters including latency to persistent sleep (LPS), wake after sleep onset (WASO), sleep efficiency (SE), total sleep time (TST), and sleep quality (SQ).[20][21][22][23][24]

Orexin receptor antagonists are not currently used as first-line treatments for insomnia due to cost and concerns about possible misuse liability.[25]

Delirium

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Suvorexant appears to be effective in the prevention of delirium.[9][10]

Side effects

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Side effects of orexin receptor antagonists include somnolence, daytime sleepiness and sedation, headache, abnormal dreams, fatigue, and dry mouth.[20][21][22][24][23]

Rates of somnolence or fatigue with orexin receptor antagonists in clinical trials were 7% (vs. 3% with placebo) for suvorexant 15 to 20 mg,[26] 7 to 10% (vs. 1.3% for placebo) for lemborexant 5 to 10 mg,[27] and 5 to 6% (vs. 4% with placebo) for daridorexant 25 to 50 mg.[28]

Contraindications

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Narcolepsy, a neurological disorder caused by orexin deficiency, is a contraindication to the use of orexin antagonists.[29]

Pharmacology

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Pharmacokinetics

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The elimination half-lives of clinically used orexin receptor antagonists are 12 hours for suvorexant, about 17 to 19 hours ("effective" half-life) or 55 hours (terminal elimination half-life) for lemborexant, and 6 to 10 hours for daridorexant.[8] The elimination half-lives of investigational orexin receptor antagonists are 2 to 3 hours for seltorexant and about 1.5 to 3 hours for vornorexant.[8][30]

The pharmacokinetics of suvorexant are significantly affected by age, sex, and other factors, leading to increased blood concentrations in female, obese, and older patients.[7] These factors do not significantly affect the pharmacokinetics of lemborexant[7] or daridorexant.[31]

All three marketed orexin antagonists do not need to be dose adjusted in patients with reduced renal function, as the pharmacokinetic profiles of these medications are not significantly affected.[32][31][33] In patients with moderate to severe hepatic impairment, dose adjustments of these medications may be necessary.[34]

Research

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Filorexant was studied for but was not found to be effective in the treatment of diabetic neuropathy, migraine, and major depressive disorder in phase 2 clinical trials.[35][36][37] Seltorexant is under development for treatment of major depressive disorder however and is in phase 3 trials for this indication.[38] Also, suvorexant is in a phase 4 trial for use as an adjunct to antidepressant therapy in people with major depressive disorder and residual insomnia.[38][39][40]

References

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  1. ^ Mogavero MP, Silvani A, Lanza G, DelRosso LM, Ferini-Strambi L, Ferri R (2023-01-22). "Targeting Orexin Receptors for the Treatment of Insomnia: From Physiological Mechanisms to Current Clinical Evidence and Recommendations". Nature and Science of Sleep (Review). 15: 17–38. doi:10.2147/NSS.S201994. PMC 9879039. PMID 36713640.
  2. ^ Roecker AJ, Coleman PJ (2008). "Orexin receptor antagonists: medicinal chemistry and therapeutic potential". Current Topics in Medicinal Chemistry. 8 (11): 977–987. doi:10.2174/156802608784936746. PMID 18673167.
  3. ^ Cao M, Guilleminault C (April 2011). "Hypocretin and its emerging role as a target for treatment of sleep disorders". Current Neurology and Neuroscience Reports. 11 (2): 227–234. doi:10.1007/s11910-010-0172-9. PMID 21170610. S2CID 42562238.
  4. ^ a b c Preskorn SH (January 2023). "Comparative Pharmacology of the 3 Marketed Dual Orexin Antagonists-Daridorexant, Lemborexant, and Suvorexant-Part 2. Principal Drug Metabolizing Enzyme, Drug-Drug Interactions, and Effects of Liver and Renal Impairment on Metabolism". Journal of Psychiatric Practice. 29 (1): 38–41. doi:10.1097/PRA.0000000000000690. PMID 36649550. S2CID 255944492.
  5. ^ "Daridorexant - Idorsia Pharmaceuticals". AdisInsight. Springer Nature Switzerland AG.
  6. ^ Ziemichód W, Grabowska K, Kurowska A, Biała G (September 2022). "A Comprehensive Review of Daridorexant, a Dual-Orexin Receptor Antagonist as New Approach for the Treatment of Insomnia". Molecules. 27 (18): 6041. doi:10.3390/molecules27186041. PMC 9502995. PMID 36144776.
  7. ^ a b c d Keks NA, Hope J (August 2022). "Lemborexant, an orexin receptor antagonist sedative-hypnotic: Is it useful for insomnia in psychiatric disorders?". Australasian Psychiatry. 30 (4): 530–532. doi:10.1177/10398562221092310. PMID 35491942. S2CID 248494625.
  8. ^ a b c 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.
  9. ^ a b Xu S, Cui Y, Shen J, Wang P (July 2020). "Suvorexant for the prevention of delirium: A meta-analysis". Medicine. 99 (30): e21043. doi:10.1097/MD.0000000000021043. PMC 7386982. PMID 32791676.
  10. ^ a b Tian Y, Qin Z, Han Y (March 2022). "Suvorexant with or without ramelteon to prevent delirium: a systematic review and meta-analysis". Psychogeriatrics. 22 (2): 259–268. doi:10.1111/psyg.12792. PMID 34881812. S2CID 245076331.
  11. ^ Sutton EL (2015-11-11). "Profile of suvorexant in the management of insomnia". Drug Design, Development and Therapy. 9: 6035–6042. doi:10.2147/DDDT.S73224. PMC 4651361. PMID 26648692.
  12. ^ "YZJ 1139". AdisInsight. 14 September 2022. Retrieved 31 October 2024.
  13. ^ "Nivasorexant - Idorsia Pharmaceuticals". AdisInsight. 5 November 2023. Retrieved 31 October 2024.
  14. ^ "Seltorexant - Janssen Research & Development/Minerva Neurosciences". AdisInsight. Springer Nature Switzerland AG.
  15. ^ "JNJ 61393215 - AdisInsight".
  16. ^ "Vornorexant - Taisho Pharmaceutical". AdisInsight. Springer Nature Switzerland AG.
  17. ^ "Almorexant". AdisInsight. Springer Nature Switzerland AG.
  18. ^ "Filorexant". AdisInsight. Springer Nature Switzerland AG.
  19. ^ Rodgers RJ, Halford JC, Nunes de Souza RL, Canto de Souza AL, Piper DC, Arch JR, et al. (April 2001). "SB-334867, a selective orexin-1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats". The European Journal of Neuroscience. 13 (7): 1444–1452. doi:10.1046/j.0953-816x.2001.01518.x. PMID 11298806. S2CID 24935644.
  20. ^ a b 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.
  21. ^ a b Kuriyama A, Tabata H (October 2017). "Suvorexant for the treatment of primary insomnia: A systematic review and meta-analysis". Sleep Medicine Reviews. 35: 1–7. doi:10.1016/j.smrv.2016.09.004. PMID 28365447.
  22. ^ a b Kishi T, Matsunaga S, Iwata N (2015). "Suvorexant for Primary Insomnia: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials". PLOS ONE. 10 (8): e0136910. Bibcode:2015PLoSO..1036910K. doi:10.1371/journal.pone.0136910. PMC 4552781. PMID 26317363.
  23. ^ a b Kishi T, Nomura I, Matsuda Y, Sakuma K, Okuya M, Ikuta T, et al. (September 2020). "Lemborexant vs suvorexant for insomnia: A systematic review and network meta-analysis". Journal of Psychiatric Research. 128: 68–74. doi:10.1016/j.jpsychires.2020.05.025. PMID 32531478. S2CID 219620600.
  24. ^ a b 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.
  25. ^ 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.
  26. ^ "Belsomra- suvorexant tablet, film coated". DailyMed. U.S. National Library of Medicine. Retrieved 30 January 2020.
  27. ^ "Dayvigo- lemborexant tablet, film coated". DailyMed. U.S. National Library of Medicine. Retrieved 17 June 2021.
  28. ^ "Quviviq (daridorexant) tablets, for oral use, [controlled substance schedule pending]" (PDF). U.S. Food and Drug Administration (FDA). Retrieved 3 March 2022.
  29. ^ Earl DC, Van Tyle KM (November 2020). "New pharmacologic agents for insomnia and hypersomnia". Current Opinion in Pulmonary Medicine. 26 (6): 629–633. doi:10.1097/MCP.0000000000000722. PMID 32890017. S2CID 221511561.
  30. ^ Uchiyama M, Kambe D, Imadera Y, Sunaga H, Hasegawa S, Nogi T, et al. (April 2020). "0146 Efficacy and Safety of Single Dose of TS-142, a Novel and Potent Dual Orexin Receptor Antagonist, in Insomnia Patients". Sleep. 43 (Supplement 1): A58. doi:10.1093/sleep/zsaa056.144. eISSN 1550-9109. ISSN 0161-8105.
  31. ^ a b Ziemichód W, Grabowska K, Kurowska A, Biała G (September 2022). "A Comprehensive Review of Daridorexant, a Dual-Orexin Receptor Antagonist as New Approach for the Treatment of Insomnia". Molecules. 27 (18): 6041. doi:10.3390/molecules27186041. PMC 9502995. PMID 36144776.
  32. ^ Preskorn SH (January 2023). "Comparative Pharmacology of the 3 Marketed Dual Orexin Antagonists-Daridorexant, Lemborexant, and Suvorexant-Part 2. Principal Drug Metabolizing Enzyme, Drug-Drug Interactions, and Effects of Liver and Renal Impairment on Metabolism". Journal of Psychiatric Practice. 29 (1): 38–41. doi:10.1097/PRA.0000000000000690. PMID 36649550. S2CID 255944492.
  33. ^ Sutton EL (2015-11-11). "Profile of suvorexant in the management of insomnia". Drug Design, Development and Therapy. 9: 6035–6042. doi:10.2147/DDDT.S73224. PMC 4651361. PMID 26648692.
  34. ^ 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.
  35. ^ Janto K, Prichard JR, Pusalavidyasagar S (August 2018). "An Update on Dual Orexin Receptor Antagonists and Their Potential Role in Insomnia Therapeutics". Journal of Clinical Sleep Medicine. 14 (8): 1399–1408. doi:10.5664/jcsm.7282. PMC 6086961. PMID 30092886.
  36. ^ Summers CH, Yaeger JD, Staton CD, Arendt DH, Summers TR (March 2020). "Orexin/hypocretin receptor modulation of anxiolytic and antidepressive responses during social stress and decision-making: Potential for therapy". Brain Research. 1731: 146085. doi:10.1016/j.brainres.2018.12.036. PMC 6591110. PMID 30590027.
  37. ^ Han Y, Yuan K, Zheng Y, Lu L (April 2020). "Orexin Receptor Antagonists as Emerging Treatments for Psychiatric Disorders". Neuroscience Bulletin. 36 (4): 432–448. doi:10.1007/s12264-019-00447-9. PMC 7142186. PMID 31782044.
  38. ^ a b 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.
  39. ^ Shariq AS, Rosenblat JD, Alageel A, Mansur RB, Rong C, Ho RC, et al. (June 2019). "Evaluating the role of orexins in the pathophysiology and treatment of depression: A comprehensive review". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 92: 1–7. doi:10.1016/j.pnpbp.2018.12.008. PMID 30576764. S2CID 56482209.
  40. ^ Clinical trial number NCT02669030 for "A Six Week, Randomized, Double-Blind Placebo-Controlled, Suvorexant Augmentation Study of Antidepressant Treatment of Major Depressive Disorder With Residual Insomnia" at ClinicalTrials.gov
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