Orexin antagonist explained

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

Marketed

Under development

Not marketed

Medical uses

Insomnia

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).[14]

Orexin receptor antagonists are not currently used as first-line treatments for insomnia due to cost and concerns about possible misuse liability.[15]

Delirium

Suvorexant appears to be effective in the prevention of delirium.[16] [17]

Side effects

Side effects of orexin receptor antagonists include somnolence, daytime sleepiness and sedation, headache, abnormal dreams, fatigue, and dry mouth.[18] [19] [20] [21]

Rates of somnolence or fatigue with orexin receptor antagonists in clinical trials were 7% (vs. 3% with placebo) for suvorexant 15 to 20mg,[22] 7 to 10% (vs. 1.3% for placebo) for lemborexant 5 to 10mg,[23] and 5 to 6% (vs. 4% with placebo) for daridorexant 25 to 50mg.[24]

Contraindications

Narcolepsy, a neurological disorder caused by orexin deficiency, is a contraindication to the use of orexin antagonists.[25]

Pharmacology

Pharmacokinetics

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.[26] 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.[27]

The pharmacokinetics of suvorexant are significantly affected by age, sex, and other factors, leading to increased blood concentrations in female, obese, and older patients. These factors do not significantly affect the pharmacokinetics of lemborexant or daridorexant.[28]

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.[29] [30] In patients with moderate to severe hepatic impairment, dose adjustments of these medications may be necessary.[31]

Research

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.[32] [33] [34] Seltorexant is under development for treatment of major depressive disorder however and is in phase 3 trials for this indication.[35] 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.[36]

Notes and References

  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 . . Review . English . 15 . 17–38 . 10.2147/NSS.S201994 . 9879039 . 36713640 . free.
  2. Roecker AJ, Coleman PJ . Orexin receptor antagonists: medicinal chemistry and therapeutic potential . Current Topics in Medicinal Chemistry . 8 . 11 . 977–987 . 2008 . 18673167 . 10.2174/156802608784936746 .
  3. Cao M, Guilleminault C . Hypocretin and its emerging role as a target for treatment of sleep disorders . Current Neurology and Neuroscience Reports . 11 . 2 . 227–234 . April 2011 . 21170610 . 10.1007/s11910-010-0172-9 . 42562238 .
  4. Preskorn SH . 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 . January 2023 . 36649550 . 10.1097/PRA.0000000000000690 . 255944492 .
  5. Web site: Daridorexant - Idorsia Pharmaceuticals . AdisInsight . Springer Nature Switzerland AG .
  6. Ziemichód W, Grabowska K, Kurowska A, Biała G . A Comprehensive Review of Daridorexant, a Dual-Orexin Receptor Antagonist as New Approach for the Treatment of Insomnia . Molecules . 27 . 18 . 6041 . September 2022 . 36144776 . 9502995 . 10.3390/molecules27186041 . free .
  7. Keks NA, Hope J . Lemborexant, an orexin receptor antagonist sedative-hypnotic: Is it useful for insomnia in psychiatric disorders? . Australasian Psychiatry . 30 . 4 . 530–532 . August 2022 . 35491942 . 10.1177/10398562221092310 . 248494625 .
  8. Sutton EL . Profile of suvorexant in the management of insomnia . English . Drug Design, Development and Therapy . 9 . 6035–6042 . 2015-11-11 . 26648692 . 4651361 . 10.2147/DDDT.S73224 . free .
  9. Web site: Seltorexant - Janssen Research & Development/Minerva Neurosciences . AdisInsight . Springer Nature Switzerland AG .
  10. Web site: Vornorexant - Taisho Pharmaceutical . AdisInsight . Springer Nature Switzerland AG .
  11. Web site: Almorexant . AdisInsight . Springer Nature Switzerland AG .
  12. Web site: Filorexant . AdisInsight . Springer Nature Switzerland AG .
  13. Rodgers RJ, Halford JC, Nunes de Souza RL, Canto de Souza AL, Piper DC, Arch JR, Upton N, Porter RA, Johns A, Blundell JE . 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 . April 2001 . 11298806 . 10.1046/j.0953-816x.2001.01518.x . 24935644 .
  14. Xue T, Wu X, Chen S, Yang Y, Yan Z, Song Z, Zhang W, Zhang J, Chen Z, Wang Z . The efficacy and safety of dual orexin receptor antagonists in primary insomnia: A systematic review and network meta-analysis . Sleep Medicine Reviews . 61 . 101573 . February 2022 . 34902823 . 10.1016/j.smrv.2021.101573 . 244689706 .
  15. Wang L, Pan Y, Ye C, Guo L, Luo S, Dai S, Chen N, Wang E . 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 . December 2021 . 34560134 . 10.1016/j.neubiorev.2021.09.035 . 237589779 . free .
  16. Xu S, Cui Y, Shen J, Wang P . Suvorexant for the prevention of delirium: A meta-analysis . Medicine . 99 . 30 . e21043 . July 2020 . 32791676 . 7386982 . 10.1097/MD.0000000000021043 .
  17. Tian Y, Qin Z, Han Y . Suvorexant with or without ramelteon to prevent delirium: a systematic review and meta-analysis . Psychogeriatrics . 22 . 2 . 259–268 . March 2022 . 34881812 . 10.1111/psyg.12792 . 245076331 .
  18. Kuriyama A, Tabata H . Suvorexant for the treatment of primary insomnia: A systematic review and meta-analysis . Sleep Medicine Reviews . 35 . 1–7 . October 2017 . 28365447 . 10.1016/j.smrv.2016.09.004 .
  19. Kishi T, Matsunaga S, Iwata N . Suvorexant for Primary Insomnia: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials . PLOS ONE . 10 . 8 . e0136910 . 2015 . 26317363 . 4552781 . 10.1371/journal.pone.0136910 . free . 2015PLoSO..1036910K .
  20. McElroy H, O'Leary B, Adena M, Campbell R, Monfared AA, Meier G . Comparative efficacy of lemborexant and other insomnia treatments: a network meta-analysis . Journal of Managed Care & Specialty Pharmacy . 27 . 9 . 1296–1308 . September 2021 . 34121443 . 10.18553/jmcp.2021.21011 . free . 10394202 .
  21. Kishi T, Nomura I, Matsuda Y, Sakuma K, Okuya M, Ikuta T, Iwata N . Lemborexant vs suvorexant for insomnia: A systematic review and network meta-analysis . Journal of Psychiatric Research . 128 . 68–74 . September 2020 . 32531478 . 10.1016/j.jpsychires.2020.05.025 . 219620600 .
  22. Web site: Belsomra- suvorexant tablet, film coated . DailyMed . U.S. National Library of Medicine . 30 January 2020.
  23. Web site: Dayvigo- lemborexant tablet, film coated . DailyMed . U.S. National Library of Medicine . 17 June 2021.
  24. Web site: Quviviq (daridorexant) tablets, for oral use, [controlled substance schedule pending]]. U.S. Food and Drug Administration (FDA). 3 March 2022.
  25. Earl DC, Van Tyle KM . New pharmacologic agents for insomnia and hypersomnia . Current Opinion in Pulmonary Medicine . 26 . 6 . 629–633 . November 2020 . 32890017 . 10.1097/MCP.0000000000000722 . 221511561 .
  26. Muehlan C, Vaillant C, Zenklusen I, Kraehenbuehl S, Dingemanse J . 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 . November 2020 . 32901578 . 10.1080/17425255.2020.1817380 . 221572078 .
  27. Uchiyama M, Kambe D, Imadera Y, Sunaga H, Hasegawa S, Nogi T, Kajiyama Y, Yoshida S, Ogo H, Uchimura N . 0146 Efficacy and Safety of Single Dose of TS-142, a Novel and Potent Dual Orexin Receptor Antagonist, in Insomnia Patients . Sleep . April 2020 . 43 . Supplement 1 . A58 . 0161-8105 . 1550-9109 . 10.1093/sleep/zsaa056.144 . free .
  28. Ziemichód W, Grabowska K, Kurowska A, Biała G . A Comprehensive Review of Daridorexant, a Dual-Orexin Receptor Antagonist as New Approach for the Treatment of Insomnia . Molecules . 27 . 18 . 6041 . September 2022 . 36144776 . 9502995 . 10.3390/molecules27186041 . free .
  29. Preskorn SH . 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 . January 2023 . 36649550 . 10.1097/PRA.0000000000000690 . 255944492 .
  30. Sutton EL . Profile of suvorexant in the management of insomnia . English . Drug Design, Development and Therapy . 9 . 6035–6042 . 2015-11-11 . 26648692 . 4651361 . 10.2147/DDDT.S73224 . free .
  31. Muehlan C, Vaillant C, Zenklusen I, Kraehenbuehl S, Dingemanse J . 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 . November 2020 . 32901578 . 10.1080/17425255.2020.1817380 . 221572078 .
  32. Janto K, Prichard JR, Pusalavidyasagar S . An Update on Dual Orexin Receptor Antagonists and Their Potential Role in Insomnia Therapeutics . Journal of Clinical Sleep Medicine . 14 . 8 . 1399–1408 . August 2018 . 30092886 . 6086961 . 10.5664/jcsm.7282 .
  33. Summers CH, Yaeger JD, Staton CD, Arendt DH, Summers TR . Orexin/hypocretin receptor modulation of anxiolytic and antidepressive responses during social stress and decision-making: Potential for therapy . Brain Research . 1731 . 146085 . March 2020 . 30590027 . 6591110 . 10.1016/j.brainres.2018.12.036 .
  34. Han Y, Yuan K, Zheng Y, Lu L . Orexin Receptor Antagonists as Emerging Treatments for Psychiatric Disorders . Neuroscience Bulletin . 36 . 4 . 432–448 . April 2020 . 31782044 . 7142186 . 10.1007/s12264-019-00447-9 .
  35. Jacobson LH, Hoyer D, de Lecea L . Hypocretins (orexins): The ultimate translational neuropeptides . Journal of Internal Medicine . 291 . 5 . 533–556 . May 2022 . 35043499 . 10.1111/joim.13406 . 248119793 .
  36. Shariq AS, Rosenblat JD, Alageel A, Mansur RB, Rong C, Ho RC, Ragguett RM, Pan Z, Brietzke E, McIntyre RS . Evaluating the role of orexins in the pathophysiology and treatment of depression: A comprehensive review . Progress in Neuro-Psychopharmacology & Biological Psychiatry . 92 . 1–7 . June 2019 . 30576764 . 10.1016/j.pnpbp.2018.12.008 . 56482209 .

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