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 edit

Marketed edit

  • 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 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 [12]
  • 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[13]

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 [14]
  • EMPA – selective OX2 antagonist
  • Filorexant (MK-6096) – dual OX1 and OX2 antagonist – development was discontinued in 2015 [15]
  • 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[16]
  • 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).[17][18][19][20][21]

Orexin receptor antagonists are not currently used as first-line treatments for insomnia due to cost and concerns about possible misuse liability.[22]

Delirium edit

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

Side effects edit

Side effects of orexin receptor antagonists include somnolence, daytime sleepiness and sedation, headache, abnormal dreams, fatigue, and dry mouth.[17][18][19][21][20]

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

Contraindications edit

Narcolepsy, a neurological disorder caused by orexin deficiency, is a contraindication to the use of orexin antagonists.[26]

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.[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][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.[7] These factors do not significantly affect the pharmacokinetics of lemborexant[7] 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][28][30] In patients with moderate to severe hepatic impairment, dose adjustments of these medications may be necessary.[31]

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.[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.[35][36][37]

References edit

  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.
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  29. ^ 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.
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  31. ^ 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.
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  37. ^ 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

External links edit