Pharmacodynamics<unk>  acts as a selective dual antagonist of the orexin (hypocretin) receptors OX1 and OX2. These receptors are the biological targets of the endogenous wakefulness-promoting orexin neuropeptides orexin-A and orexin-B. The binding affinities (Ki) of<unk>  at the human orexin receptors are 0.55nM for the OX1 receptor and 0.35nM for the OX2 receptor. The antagonistic potencies or functional inhibition (Kb) of<unk>  at the human orexin receptors are 65nM for the OX1 receptor and 41nM for the OX2 receptor. Hence,<unk>  shows similar affinities and antagonistic activities at the OX1 and OX2 receptors in vitro.<unk>  is highly selective for the orexin receptors over a large number of other targets (170 screened off-target receptors, enzymes, and transporters). In contrast to certain other sedatives and hypnotics,<unk>  is not a benzodiazepine or Z-drug and does not interact with GABA receptors. Mechanism of action<unk>  is thought to exert its therapeutic effects in the treatment of insomnia by blocking the orexin receptors and thereby blocking the effects of the endogenous wakefulness-promoting orexin neuropeptides orexin-A and orexin-B. The orexin neuropeptides are produced exclusively by a relatively small population of 20,000 to 80,000 neurons located in the lateral hypothalamus in the brain. These neurons project widely throughout the brain and mediate excitatory signaling to key centers involved in sleep–wake regulation, including the noradrenergic locus coeruleus, histaminergic tuberomammillary nucleus, serotonergic raphe nucleus, and dopaminergic ventral tegmental area. The orexin system shows circadian rhythmicity in its activity, with high activity during waking and low to no activity during sleep or at night. Orexin system activity during wakefulness is also higher with behavioral activation and with high-intensity emotions. Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations, as well as sleep attacks and fragmented sleep. Narcolepsy with cataplexy, also known as type 1 narcolepsy, is thought to be caused by loss of orexin-producing neurons in the lateral hypothalamus, possibly mediated by autoimmune mechanisms related to environmental triggers in genetically susceptible individuals. There is an 80 to 100% loss of orexin-producing neurons in the lateral hypothalamus and very low or undetectable levels of orexin-A in cerebrospinal fluid in people with narcolepsy. Similarly, narcolepsy with cataplexy in dogs is caused by a mutation in the gene encoding the OX2 receptor, and knockout mice for genes encoding orexin system proteins such as prepro-orexin or the OX2 receptor show a narcolepsy-like phenotype. Although there is hypersomnolence in narcolepsy, people with the condition do not sleep more overall than normal individuals but instead experience more sleepiness and sleep during daytime in tandem with disturbed sleep at night. They do not usually feel well-rested during the day. Besides narcolepsy, the orexin system may also be involved in the etiology of insomnia. In addition, orexin signaling appears to change with age, and this may be involved in age-related sleep disturbances. Orexin receptor antagonists may be expected to produce effects similar to those in narcolepsy. However, the effects of acute transient pharmacological antagonism of the orexin receptors are not necessarily the same as in the chronic and severe orexin deficiency in narcolepsy. Modulation of orexin signaling with orexin receptor antagonists produces effects that occur more at night when drug levels are high and less during the day when levels are low. In addition, long-term neural changes may develop in narcolepsy to compensate for the orexin deficiency in the condition. In animals and humans, orexin receptor agonists such as orexin-A and danavorexton dose-dependently produce wakefulness and locomotor activity while orexin receptor antagonists like<unk>  transiently reduce locomotor activity and dose-dependently promote sleep. Acute orexin receptor antagonists can promote sleep in animals to a greater extent than what occurs in narcolepsy-like orexin system loss. In addition, little to no cataplexy has been observed even with high doses of orexin receptor antagonists in animals and humans. It is unknown if long-term use of orexin receptor antagonists may produce compensatory neural changes or narcolepsy-like symptoms. Endogenous orexinergic tone is expected to play an important moderating influence in terms of the effects of orexin receptor modulators. As an example, rising orexin levels during the day may help to competitively offset the next-day residual effects of nightly-dosed orexin receptor antagonists. Pharmacokinetics<unk>  levels over a period of 48hours with single oral doses of 10, 50, and 100mg<unk>  in healthy young men. The half-lives with these doses in the study were 9.0hours, 10.8hours, and 13.1hours, respectively. Absorption The absolute bioavailability of<unk>  is 82% at a dose of 10mg.<unk>  exposure does not increase dose-proportionalally over a dose range of 10 to 100mg, which is likely due to decreased absorption at higher doses. Exposure to<unk>  increases by about 75% with a doubling of dose from 20mg to 40mg. The time to peak levels of<unk>  is 2 to 3hours regardless of dose but with wide variation (range 30minutes to 8hours). Taking<unk>  with food does not modify<unk>  peak levels or area-under-the-curve levels (overall exposure) but does delay the time to peak concentrations by about 1.5hours. Steady-state levels of<unk>  with once-daily continuous administration are reached within 3days. Levels of<unk>  accumulate minimally, by about 1.2- to 1.6-fold, with repeated once-daily administration. Distribution The volume of distribution of<unk>  is approximately 49L. It crosses the blood–brain barrier and distributes into the central nervous system.<unk>  has high plasma protein binding (99.5%). It is bound to albumin and α1-acid glycoprotein (orosomucoid). Metabolism<unk>  is metabolized primarily by hydroxylation via CYP3A enzymes. CYP2C19 also contributes to<unk>  metabolism to a minor extent. The major circulating forms are<unk>  and its metabolite hydroxysuvorexant. The hydroxysuvorexant (M9) metabolite is not expected to be pharmacologically active. It showed 10-fold lower affinity for the orexin receptors than<unk>  in vitro, was a substrate for P-glycoprotein and was deemed unlike to blood–brain barrier, and did not show sedative effects in animal studies.<unk>  also has several other minor metabolites. Elimination<unk>  is eliminated mainly via metabolism. It is excreted primarily in feces (66%) predominantly as metabolites and to a lesser extent in urine (23%). The elimination half-life of<unk>  at a dose of 40mg is 12.2hours, with a range of 8 to 19hours. In another study, the half-life of<unk>  was 15hours with a range of 10 to 22hours. In one study, the half-lives of<unk>  (mean ± SD) were 9.0 ± 7.2hours at 10mg, 10.8 ± 3.6hours at 50mg, and 13.1 ± 5.8hours at 100mg. With doses of 120 to 240mg, the half-lives of<unk>  were 12.1 to 14.5hours in healthy young males and 14.4 to 15.8hours in healthy young females. The half-life of<unk> 's inactive metabolite hydroxysuvorexant is similar to that of<unk> . Specific populations Age and race do not influence the pharmacokinetics of<unk>  in a clinically meaningfully way. Exposure to<unk>  is slightly higher in women compared to men (Cmax 9% higher, AUC 17% higher), however dose adjustments based on gender are generally unnecessary.<unk>  exposure is greater in people with higher body mass index, such as obese people (Cmax 17% higher, AUC 31% higher). This is particularly the case in obese women relative to non-obese women (Cmax 25% higher, AUC 46% higher).<unk>  exposure with a single dose is not greater in people with moderate hepatic insufficiency compared to healthy individuals. However, the half-life of<unk>  at a dose of 20mg was prolonged from 14.7hours (range 10–22hours) to 19.1hours (range 11–49hours) in these individuals.<unk>  exposure is unchanged in people with severe renal impairment and no dosage adjustment is necessary in these individuals. Similarly to hepatic impairment, the half-life of<unk>  was increased to 19.4hours when used in combination with the strong CYP3A4 inhibitor ketoconazole and to 16.1hours with the moderate CYP3A4 inhibitor diltiazem while it was decreased to 7.7hours with the strong CYP3A4 inducer rifampin. Miscellaneous semi-log concentrations (% of Cmax) of the orexin receptor antagonists<unk> , lemborexant, daridorexant, and seltorexant with administration in humans. The terminal elimination half-lives in these studies were 12hours, 55hours, 6hours, and 2.5hours, respectively. The delayed time to peak levels (2–3hours) and long elimination half-life (12hours) of<unk>  are less than ideal for an insomnia medication as they result in a delayed onset of effect and significant next-day side effects such as daytime sedation. Orexin receptor antagonists with shorter half-lives and faster onsets of action are theoretically more optimal for therapeutic use as sleep aids. The ideal insomnia medication would not have a duration of action extending beyond about 8hours. Relative to<unk> , daridorexant has a shorter half-life (8hours) while lemborexant has a longer half-life (17–55hours). The investigational agents seltorexant and vornorexant, which are still in clinical trials, have comparatively very short half-lives in the range of 1.5 to 3hours.<unk>  dissociates from the orexin receptors slowly. As a result, its duration may be longer than that suggested by its circulating concentrations and half-life.
Suvorexant
Icatibant
Veristrat
Seltorexant
Daridorexant
Rimegepant
Atogepant
Ubrogepant