Orexin antagonist
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.
Examples
Marketed
- Daridorexant – dual OX1 and OX2 antagonist – approved for insomnia in January 2022, formerly under development for sleep apnea – half-life 8 hours
- Lemborexant – 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 – dual OX1 and OX2 antagonist – approved for insomnia in August 2014, under development for delirium – half-life 12 hours
Under development
- Fazamorexant – dual OX1 and OX2 antagonist – under development for insomnia, up to phase 3 – half-life 2–4 hours
- Nivasorexant – selective OX1 antagonist – under development for binge eating disorder and previously for anxiety disorders, up to phase 2 – half-life 3–7 hours
- Seltorexant – selective OX2 antagonist – under development for major depressive disorder, insomnia, and sleep apnea, up to phase 3 – half-life 2–3 hours
- Tebideutorexant – selective OX1 antagonist – under development for major depressive disorder, no development reported for anxiety disorders and panic disorder, up to phase 2 – half-life 14–25 hours
- Vornorexant – dual OX1 and OX2 antagonist – under development for insomnia and sleep apnea, up to phase 3 in Japan – half-life 1.5–3 hours
Not marketed
- ACT-335827 – selective OX1 antagonist
- Almorexant – dual OX1 and OX2 antagonist – half-life 13–19 hours – development of the drug was abandoned in January 2011
- EMPA – selective OX2 antagonist
- Filorexant – dual OX1 and OX2 antagonist – half-life 3–6 hours – development was discontinued in 2015
- GSK-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
- 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, wake after sleep onset, sleep efficiency, total sleep time, and sleep quality.Orexin receptor antagonists are not currently used as first-line treatments for insomnia due to cost and concerns about possible misuse liability.
Delirium
Suvorexant appears to be effective in the prevention of delirium.Side effects
s of orexin receptor antagonists include somnolence, daytime sleepiness and sedation, headache, abnormal dreams, fatigue, and dry mouth.Rates of somnolence or fatigue with orexin receptor antagonists in clinical trials were 7% for suvorexant 15 to 20mg, 7 to 10% for lemborexant 5 to 10mg, and 5 to 6% for daridorexant 25 to 50mg.
Contraindications
, a neurological disorder caused by orexin deficiency, is a contraindication to the use of orexin antagonists.Pharmacology
Pharmacokinetics
The elimination half-lives of clinically used orexin receptor antagonists are 12 hours for suvorexant, about 17 to 19 hours or 55 hours for lemborexant, and 6 to 10 hours for daridorexant. 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.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.
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. In patients with moderate to severe hepatic impairment, dose adjustments of these medications may be necessary.