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 or both of the orexin receptors, OX1 and OX2. Medical applications include treatment of sleep disorders such as insomnia.[1][2]

Examples[edit]

Marketed[edit]

  • Daridorexant (nemorexant; Quviviq) – dual OX1 and OX2 antagonist – approved for insomnia in January 2022, formerly under development for sleep apnea[3] – half-life 8 hours
  • Lemborexant (Dayvigo) – dual OX1 and OX2 antagonist – approved for insomnia in December 2019 and released June 1 2020, under development for circadian rhythm sleep disorders, chronic obstructive pulmonary disease, and sleep apnea – half-life 17–55 hours
  • Suvorexant (Belsomra) – dual OX1 and OX2 antagonist – approved for insomnia in August 2014, under development for delirium – half-life 12 hours

Under development[edit]

  • 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 [4]
  • Vornorexant (ORN-0829, TS-142) – dual OX1 and OX2 antagonist – under development for insomnia and sleep apnea, up to phase 2 – half-life 1.5–3 hours[5]

Not marketed[edit]

  • ACT-335827 – selective OX1 antagonist
  • Almorexant (ACT-078573) – dual OX1 and OX2 antagonist – development of the drug was abandoned in January 2011 [6]
  • EMPA – selective OX2 antagonist
  • Filorexant (MK-6096) – dual OX1 and OX2 antagonist – development was discontinued in 2015 [7]
  • 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[8]
  • SB-408124 – selective OX1 antagonist
  • TCS-OX2-29 – first non-peptide selective OX2 antagonist

Medical uses[edit]

Insomnia[edit]

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).[9][10][11][12][13]

Network meta-analyses have found that orexin receptor antagonists including suvorexant and lemborexant are more effective in the treatment of insomnia than other sleep aids including benzodiazepines (e.g., triazolam, temazepam), Z-drugs (e.g., zolpidem, zopiclone), antihistamines (e.g., doxepin, diphenhydramine, doxylamine), antidepressants (e.g., trazodone, mirtazapine, amitriptyline), anticonvulsants (e.g., gabapentin, pregabalin), and melatonin receptor agonists (e.g., melatonin, ramelteon).[14][13][9]

Orexin receptor antagonists are not currently used as first-line treatments for insomnia due to cost and concerns about possible misuse liability.[14]

Delirium[edit]

Suvorexant appears to be effective in the prevention of delirium.[15][16]

Side effects[edit]

Side effects of orexin receptor antagonists include somnolence, daytime sleepiness and sedation, headache, abnormal dreams, fatigue, and dry mouth.[9][10][11][13][12]

Rates of somnolence or fatigue with orexin receptor antagonists in clinical trials were 7% (vs. 3% with placebo) for suvorexant 15 to 20 mg,[17] 7 to 10% (vs. 1.3% for placebo) for lemborexant 5 to 10 mg,[18] and 5 to 6% (vs. 4% with placebo) for daridorexant 25 to 50 mg.[19]

Pharmacology[edit]

Pharmacokinetics[edit]

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.[20] 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.[20][21]

Research[edit]

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.[22][23][24] Seltorexant is under development for treatment of major depressive disorder however and is in phase 3 trials for this indication.[25] 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.[25][26][27]

References[edit]

  1. ^ Roecker AJ, Coleman PJ (2008). "Orexin receptor antagonists: medicinal chemistry and therapeutic potential". Curr Top Med Chem. 8 (11): 977–87. doi:10.2174/156802608784936746. PMID 18673167.
  2. ^ Cao M, Guilleminault C (April 2011). "Hypocretin and its emerging role as a target for treatment of sleep disorders". Curr Neurol Neurosci Rep. 11 (2): 227–34. doi:10.1007/s11910-010-0172-9. PMID 21170610. S2CID 42562238.
  3. ^ "Daridorexant - Idorsia Pharmaceuticals - AdisInsight".
  4. ^ "Seltorexant - Janssen Research & Development/Minerva Neurosciences - AdisInsight".
  5. ^ "Vornorexant - Taisho Pharmaceutical - AdisInsight".
  6. ^ "Almorexant - AdisInsight".
  7. ^ "Filorexant - AdisInsight".
  8. ^ Rodgers RJ, Halford JC, Nunes de Souza RL, Canto de Souza AL, Piper DC, Arch JR, Upton N, Porter RA, Johns A, Blundell JE (April 2001). "SB-334867, a selective orexin-1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats". Eur. J. Neurosci. 13 (7): 1444–52. doi:10.1046/j.0953-816x.2001.01518.x. PMID 11298806. S2CID 24935644.
  9. ^ a b c Xue T, Wu X, Chen S, Yang Y, Yan Z, Song Z, Zhang W, Zhang J, Chen Z, Wang Z (February 2022). "The efficacy and safety of dual orexin receptor antagonists in primary insomnia: A systematic review and network meta-analysis". Sleep Med Rev. 61: 101573. doi:10.1016/j.smrv.2021.101573. PMID 34902823. S2CID 244689706.
  10. ^ a b Kuriyama A, Tabata H (October 2017). "Suvorexant for the treatment of primary insomnia: A systematic review and meta-analysis". Sleep Med Rev. 35: 1–7. doi:10.1016/j.smrv.2016.09.004. PMID 28365447.
  11. ^ 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.
  12. ^ a b Kishi T, Nomura I, Matsuda Y, Sakuma K, Okuya M, Ikuta T, Iwata N (September 2020). "Lemborexant vs suvorexant for insomnia: A systematic review and network meta-analysis". J Psychiatr Res. 128: 68–74. doi:10.1016/j.jpsychires.2020.05.025. PMID 32531478. S2CID 219620600.
  13. ^ a b c 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". J Manag Care Spec Pharm. 27 (9): 1296–1308. doi:10.18553/jmcp.2021.21011. PMID 34121443.
  14. ^ a b Wang L, Pan Y, Ye C, Guo L, Luo S, Dai S, Chen N, Wang E (December 2021). "A network meta-analysis of the long- and short-term efficacy of sleep medicines in adults and older adults". Neurosci Biobehav Rev. 131: 489–496. doi:10.1016/j.neubiorev.2021.09.035. PMID 34560134. S2CID 237589779.
  15. ^ Xu S, Cui Y, Shen J, Wang P (July 2020). "Suvorexant for the prevention of delirium: A meta-analysis". Medicine (Baltimore). 99 (30): e21043. doi:10.1097/MD.0000000000021043. PMC 7386982. PMID 32791676.
  16. ^ 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.
  17. ^ "Belsomra- suvorexant tablet, film coated". DailyMed. Retrieved 30 January 2020.
  18. ^ "Dayvigo- lemborexant tablet, film coated". DailyMed. Retrieved 17 June 2021.
  19. ^ "Quviviq (daridorexant) tablets, for oral use, [controlled substance schedule pending]" (PDF). U.S. Food and Drug Administration (FDA). Retrieved 3 March 2022.
  20. ^ a b 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.
  21. ^ Uchiyama, M; Kambe, D; Imadera, Y; Sunaga, H; Hasegawa, S; Nogi, T; Kajiyama, Y; Yoshida, S; Ogo, H; Uchimura, N (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.
  22. ^ Janto K, Prichard JR, Pusalavidyasagar S (August 2018). "An Update on Dual Orexin Receptor Antagonists and Their Potential Role in Insomnia Therapeutics". J Clin Sleep Med. 14 (8): 1399–1408. doi:10.5664/jcsm.7282. PMC 6086961. PMID 30092886.
  23. ^ 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 Res. 1731: 146085. doi:10.1016/j.brainres.2018.12.036. PMC 6591110. PMID 30590027.
  24. ^ Han Y, Yuan K, Zheng Y, Lu L (April 2020). "Orexin Receptor Antagonists as Emerging Treatments for Psychiatric Disorders". Neurosci Bull. 36 (4): 432–448. doi:10.1007/s12264-019-00447-9. PMC 7142186. PMID 31782044.
  25. ^ a b 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.
  26. ^ Shariq AS, Rosenblat JD, Alageel A, Mansur RB, Rong C, Ho RC, Ragguett RM, Pan Z, Brietzke E, McIntyre RS (June 2019). "Evaluating the role of orexins in the pathophysiology and treatment of depression: A comprehensive review". Prog Neuropsychopharmacol Biol Psychiatry. 92: 1–7. doi:10.1016/j.pnpbp.2018.12.008. PMID 30576764. S2CID 56482209.
  27. ^ "A Six Week, Randomized, Double-Blind Placebo-Controlled, Suvorexant Augmentation Study of Antidepressant Treatment of Major Depressive Disorder With Residual Insomnia - Full Text View". ClinicalTrials.gov. 25 February 2019. Retrieved 2022-04-24.

External links[edit]