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

• 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

• 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

• 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

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). ^{[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

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

Side effects

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

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

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. ^[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

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

External links

• Media related to Orexin receptor antagonists at Wikimedia Commons