Suvorexant, FDA-approved to treat insomnia, has demonstrated efficacy in helping patients with insomnia improve their ability to fall asleep and remain asleep (Table 1).1 This first-in-class compound represents a novel mechanism of action to promoting sleep that may avoid some problems associated with other hypnotics.2
Clinical implications
Insomnia is among the most common clinical complaints in psychiatry and medicine. The FDA-approved insomnia medications include several benzodiazepine-receptor agonists (zolpidem, eszopiclone, zaleplon), a melatonin-receptor agonist (ramelteon), and a histamine-receptor antagonist (low-dose doxepin). Suvorexant joins these drugs and is an entirely novel compound that is the first orexin- (also called hypocretin) receptor antagonist approved by the FDA for any indication.
Through a highly targeted mechanism of action, suvorexant could enhance sleep for patients with insomnia, while maintaining an acceptable safety profile.3 The drug should help patients with chronic insomnia, particularly those who have difficulty maintaining sleep—the sleep disturbance pattern that is most challenging to treat pharmacotherapeutically.
Because orexin antagonists have not been used outside of clinical trials, it is too soon to tell whether suvorexant will have the ideal real-world efficacy and safety profile to make it a first-line treatment for insomnia patients, or if it will be reserved for those who have failed a trial of several other treatments.4
In theory, the orexin antagonist approach to treating insomnia could represent a major advance that modulates the fundamental pathology of the disorder.5 The syndrome of chronic insomnia encompasses not just the nighttime sleep disturbance but also an assortment of daytime symptoms that can include fatigue, poor concentration, irritability, and decreased school or work performance but usually not sleepiness. This constellation of nighttime and daytime symptoms could be conceptualized as a manifestation of persistent CNS hyperarousal. Because the orexin system promotes and reinforces arousal, perhaps an orexin antagonist that dampens the level of orexin activity will ameliorate the full spectrum of insomnia symptoms—not simply sedate patients.6
How suvorexant works
Suvorexant is a potent and reversible dual orexin-receptor antagonist. The orexin system, first described in 1998, has a key role in promoting and stabilizing wakefulness.7 Evidence suggests that people with chronic insomnia exhibit a central hyperarousal that perpetuates their sleep difficulty. Accordingly, a targeted pharmaceutical approach that reduces orexin activity should facilitate sleep onset and sleep maintenance for these patients. It is well known that the regulation of sleep and wakefulness depends on the interaction of multiple nuclei within the hypothalamus. Orexinergic neurons in the perifornical-lateral hypothalamic region project widely in the CNS and have especially dense connections with wake-promoting cholinergic, serotonergic, noradrenergic, and histaminergic neurons.6
A precursor prepro-orexin peptide is split into 2 orexin neurotransmitters (orexin A and orexin B). These 2 orexins bind with 2 G-protein-coupled receptors (OX1R and OX2R) that have both overlapping and distinct distributions.7 Suvorexant is highly selective and has similar affinity for OX1R and OX2R, functioning as an antagonist for both.8 Fundamentally, suvorexant enhances sleep by dampening the arousing wake drive.
Pharmacokinetics
Suvorexant is available as an immediate-release tablet with pharmacokinetic properties that offer benefits for sleep onset and maintenance.9 Ingestion under fasting conditions results in a median time to maximum concentration (Tmax) of approximately 2 hours, although the Tmax values vary widely from patient to patient (range 30 minutes to 6 hours). Although suvorexant can be taken with food, there is a modest absorption delay after a high-fat meal, resulting in a further Tmax delay of approximately 1.5 hours.
Suvorexant is primarily metabolized through the cytochrome P450 (CYP) 3A pathway, with limited contribution by CYP2C19. There are no active metabolites. The suvorexant blood level and risk of side effects will be higher with concomitant use of CYP3A inhibitors. The drug should not be administered with strong CYP3A inhibitors; the initial dosage should be reduced with moderate CYP3A inhibitors. Concomitant use of strong CYP3A inducers can result in a low suvorexant level and reduced efficacy.
Suvorexant has little effect on other medications, although a person taking digoxin might experience intestinal P-glycoprotein inhibition with a slight rise in the digoxin level. In a patient taking both medications, monitoring of the digoxin level is recommended.
The elimination half-life of suvorexant is approximately 12 hours, with a steady state in approximately 3 days. Because the half-life of suvorexant is moderately long for a sleep-promoting medication, use of the drug might be associated with residual sleepiness the morning after bedtime dosing. The risk for next-morning sleepiness or impairment should be minimized, however, when using the recommended dosages. Elimination is approximately two-thirds through feces and one-third in the urine.
Suvorexant metabolism can be affected by sex and body mass index. Females and obese people have a modestly elevated exposure to suvorexant, as reflected by the area under the curve and maximum concentration (Cmax). These patients might not require dosage adjustments unless they are obese and female, in which case they should take a lower dosage.
Age and race have not been shown to influence suvorexant metabolism to a significant degree. Patients with renal impairment and those with mild or moderate hepatic impairment do not need dosage adjustment. Suvorexant has not been evaluated in patients with severe hepatic impairment.