Lemborexant, FDA-approved for the treatment of insomnia, has demonstrated efficacy in improving both sleep onset and sleep maintenance.1 This novel compound is now the second approved insomnia medication classed as a dual orexin receptor antagonist (Table 1). This targeted mechanism of action aims to enhance sleep while limiting the adverse effects associated with traditional hypnotics.
Clinical implications
Insomnia symptoms affect approximately one-third of the general population at least occasionally. Approximately 10% of individuals meet DSM-5 criteria for insomnia disorder, which require nighttime sleep difficulty and daytime consequences persisting for a minimum of 3 months.2 The prevalence is considerably higher in patients with chronic medical disorders and comorbid psychiatric conditions, especially mood, anxiety, substance use, and stress- and trauma-related disorders. Clinical guidelines for treating insomnia disorder typically recommend cognitive-behavioral therapy for insomnia as a first choice and FDA-approved insomnia medications as secondary options.3
Currently approved insomnia medications fall into 4 distinct pharmacodynamics categories.4 Benzodiazepine receptor agonist hypnotics include 5 medications with classic benzodiazepine structures (estazolam, flurazepam, quazepam, temazepam, and triazolam) and 3 compounds (eszopiclone, zaleplon, and zolpidem) with alternate structures but similar mechanisms of action. There is 1 melatonin receptor agonist (ramelteon) and 1 histamine receptor antagonist (low-dose doxepin). Joining suvorexant (approved in 2014), lemborexant is the second dual orexin receptor antagonist.
The orexin (also called hypocretin) system was first described in 1998 and its fundamental role in promoting and coordinating wakefulness was quickly established.5 A relatively small number of hypothalamic neurons located in the lateral and perifornical regions produce 2 similar orexin neuropeptides (orexin A and orexin B) with widespread distributions, notably reinforcing the wake-promoting activity of histamine, acetylcholine, dopamine, serotonin, and norepinephrine. Consistent with the typical sleep-wake cycle, orexin release is limited during the nighttime. The orexin neuropeptides interact with 2 G-protein-coupled orexin receptors (OX1R, OX2R).
Animal studies showed that impairment in orexin system activity was associated with symptoms characteristic of narcolepsy, including cataplexy and excessive sleep episodes. Soon after, it was found that humans diagnosed with narcolepsy with cataplexy had markedly low CSF orexin levels.6 This recognition that excessively sleepy people with narcolepsy had a profound decrease in orexin production led to the hypothesis that pharmacologically decreasing orexin activity might be sleep-enhancing for insomnia patients, who presumably are excessively aroused. Numerous compounds soon were evaluated for their potential as orexin receptor antagonists. The efficacy of treating insomnia with a dual orexin receptor antagonist in humans was first reported in 2007 with almorexant, a compound that remains investigational.7 Research continues to investigate both single and dual orexin antagonist molecules for insomnia and other potential indications.
How it works
Unlike most hypnotics, which have widespread CNS depressant effects, lemborexant has a more targeted action in promoting sleep by suppressing the wake drive supported by the orexin system.8 Lemborexant is highly selective for the OX1R and OX2R orexin receptors, where it functions as a competitive antagonist. It is hypothesized that by modulating orexin activity with a receptor antagonist, excessive arousal associated with insomnia can be reduced, thus improving nighttime sleep. The pharmacokinetic properties allow benefits for both sleep onset and maintenance.
Pharmacokinetics
Lemborexant is available in immediate-release tablets with a peak concentration time (Tmax) of approximately 1 to 3 hours after ingestion. When taken after a high-fat and high-calorie meal, there is a delay in the Tmax, a decrease in the maximum plasma concentration (Cmax), and an increase in the concentration area under the curve (AUC0-inf).1
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