Wikipedia

Orexin antagonist

Anorexin receptor antagonist,ororexin antagonist,is a drug that inhibits the effect oforexinby acting as areceptor antagonistof one (selective orexin receptor antagonist or SORA) or both (dual orexin receptor antagonis or DORA) of theorexin receptors,OX1andOX2.[1]Medical applications include treatment ofsleep disorderssuch asinsomnia.[2][3]

Examples

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Marketed

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  • Daridorexant(nemorexant; Quviviq) – dual OX1and OX2antagonist – approved for insomnia in January 2022,[4]formerly under development for sleep apnea[5]– half-life 8 hours[6]
  • Lemborexant(Dayvigo) – dual OX1and OX2antagonist – 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 OX1and OX2antagonist – 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 OX1and OX2antagonist – under development for insomnia, up to phase 3[12]
  • Nivasorexant(ACT-539313) – selective OX1antagonist – 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 OX2antagonist – 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 OX1antagonist – 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 OX1and OX2antagonist – under development for insomnia and sleep apnea, up to phase 2 – half-life 1.5–3 hours[16]

Not marketed

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  • ACT-335827– selective OX1antagonist
  • Almorexant(ACT-078573) – dual OX1and OX2antagonist – development of the drug was abandoned in January 2011[17]
  • EMPA– selective OX2antagonist
  • Filorexant(MK-6096) – dual OX1and OX2antagonist – development was discontinued in 2015[18]
  • GSK-649868(SB-649868) – dual OX1and OX2antagonist – was in development for potential use in sleep disorders
  • JNJ-10397049– selective OX2antagonist
  • RTIOX-276– selective OX1antagonist
  • SB-334867– first non-peptide selective OX1antagonist – has been shown to producesedativeandanorecticeffects in animals[19]
  • SB-408124– selective OX1antagonist
  • TCS-OX2-29– first non-peptide selective OX2antagonist

Medical uses

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Insomnia

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Orexin receptor antagonistsdose-dependentlyimprove sleep parameters includinglatency to persistent sleep(LPS),wake after sleep onset(WASO),sleep efficiency(SE),total sleep time(TST), andsleep quality(SQ).[20][21][22][23][24]

Orexin receptor antagonists are not currently used asfirst-line treatmentsfor insomnia due to cost and concerns about possiblemisuse liability.[25]

Delirium

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

Side effects

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Side effectsof orexin receptor antagonists includesomnolence,daytime sleepiness and sedation,headache,abnormal dreams,fatigue,anddry 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 20mg,[26]7 to 10% (vs. 1.3% for placebo) for lemborexant 5 to 10mg,[27]and 5 to 6% (vs. 4% with placebo) for daridorexant 25 to 50mg.[28]

Contraindications

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

Pharmacology

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Pharmacokinetics

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Theelimination half-livesof clinically used orexin receptor antagonists are 12 hours forsuvorexant,about 17 to 19 hours ( "effective" half-life) or 55 hours (terminal elimination half-life) forlemborexant,and 6 to 10 hours for daridorexant.[8]The elimination half-lives of investigational orexin receptor antagonists are 2 to 3 hours forseltorexantand about 1.5 to 3 hours forvornorexant.[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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Filorexantwas studied for but was not found to be effective in the treatment ofdiabetic neuropathy,migraine,andmajor depressive disorderinphase 2clinical trials.[35][36][37]Seltorexantis under development for treatment of major depressive disorder however and is inphase 3trials for this indication.[38]Also, suvorexant is in aphase 4trial for use as anadjuncttoantidepressanttherapy 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.PMC9879039.PMID36713640.
  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.PMID18673167.
  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.PMID21170610.S2CID42562238.
  4. ^abcPreskorn 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.PMID36649550.S2CID255944492.
  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.PMC9502995.PMID36144776.
  7. ^abcdKeks 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.PMID35491942.S2CID248494625.
  8. ^abcMuehlan 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.PMID32901578.S2CID221572078.
  9. ^abXu 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.PMC7386982.PMID32791676.
  10. ^abTian 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.PMID34881812.S2CID245076331.
  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.PMC4651361.PMID26648692.
  12. ^"YZJ 1139".AdisInsight.14 September 2022.Retrieved31 October2024.
  13. ^"Nivasorexant - Idorsia Pharmaceuticals".AdisInsight.5 November 2023.Retrieved31 October2024.
  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.PMID11298806.S2CID24935644.
  20. ^abXue 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.PMID34902823.S2CID244689706.
  21. ^abKuriyama 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.PMID28365447.
  22. ^abKishi 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.PMC4552781.PMID26317363.
  23. ^abKishi 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.PMID32531478.S2CID219620600.
  24. ^abMcElroy 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.PMC10394202.PMID34121443.
  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.PMID34560134.S2CID237589779.
  26. ^"Belsomra- suvorexant tablet, film coated".DailyMed.U.S. National Library of Medicine.Retrieved30 January2020.
  27. ^"Dayvigo- lemborexant tablet, film coated".DailyMed.U.S. National Library of Medicine.Retrieved17 June2021.
  28. ^"Quviviq (daridorexant) tablets, for oral use, [controlled substance schedule pending]"(PDF).U.S.Food and Drug Administration(FDA).Retrieved3 March2022.
  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.PMID32890017.S2CID221511561.
  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.eISSN1550-9109.ISSN0161-8105.
  31. ^abZiemichód 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.PMC9502995.PMID36144776.
  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.PMID36649550.S2CID255944492.
  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.PMC4651361.PMID26648692.
  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.PMID32901578.S2CID221572078.
  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.PMC6086961.PMID30092886.
  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.PMC6591110.PMID30590027.
  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.PMC7142186.PMID31782044.
  38. ^abJacobson 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.PMID35043499.S2CID248119793.
  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.PMID30576764.S2CID56482209.
  40. ^Clinical trial numberNCT02669030for "A Six Week, Randomized, Double-Blind Placebo-Controlled, Suvorexant Augmentation Study of Antidepressant Treatment of Major Depressive Disorder With Residual Insomnia" atClinicalTrials.gov
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