Pharmacodynamics<unk>  is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the non-human MT3 receptor.<unk>  demonstrates full agonist activity in vitro in cells expressing human MT1 or MT2 receptors, and high selectivity for human MT1 and MT2 receptors compared to the non-human MT3 receptor. The affinity of<unk>  for the MT1 and MT2 receptors is 3 to 16 times higher than that of melatonin.<unk>  has 8-fold higher affinity for the MT1 receptor over the MT2 receptor. The binding profile of<unk>  distinguishes it from melatonin, tasimelteon, and agomelatine. The major metabolite of<unk> , M-II, is active and has approximately one-tenth and one-fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively, and is 17- to 25-fold less potent than<unk>  in in vitro functional assays. Although the potency of M-II at MT1 and MT2 receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20- to 100-fold greater mean systemic exposure when compared to<unk> . M-II has weak affinity for the serotonin 5-HT2B receptor, but no appreciable affinity for other receptors or enzymes. Similar to<unk> , M-II does not interfere with the activity of a number of endogenous enzymes.<unk>  has no appreciable affinity for the GABA receptors or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, noradrenaline, acetylcholine, and opioids.<unk>  also does not interfere with the activity of a number of selected enzymes in a standard panel. Mechanism of action The activity of<unk>  at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep–wake cycle. Pharmacokinetics Absorption The total absorption of<unk>  is 84% while its oral bioavailability is 1.8%. The low bioavailability of<unk>  is due to extensive first-pass metabolism. The absorption of<unk>  is rapid, with peak levels being reached after approximately 0.75 hours (range 0.5–1.5 hours). Food increases peak concentrations of<unk>  by 22% and overall exposure by 31% and delays the time to peak levels by approximately 0.75 hours. The pharmacokinetics of<unk>  are linear across a dose range of 4 to 64 mg. There is substantial interindividual variability in the peak concentrations and area-under-the-curve levels of<unk>  which is consistent with high first-pass metabolism. Distribution The volume of distribution of<unk>  is 73.6 L, which suggests substantial tissue distribution. The plasma protein binding of<unk>  is 82% independently of concentration.<unk>  is primarily bound to albumin (70%). The medication is not selectively distributed to red blood cells. Metabolism<unk>  is metabolized in the liver primarily by oxidation via hydroxylation and carbonylation. It is also secondarily metabolized to produce glucuronide conjugates.<unk>  is metabolized mainly by CYP1A2 while CYP2C enzymes and CYP3A4 are involved to a minor extent. The metabolites of<unk>  include M-I, M-II, M-III, and M-IV. Exposure to M-II is approximately 20- to 100-fold higher than to<unk> . Elimination<unk>  is excreted 84% in urine and 4% in feces. Less than 0.1% of drug is excreted as unchanged<unk> . Elimination of<unk>  is essentially complete by 96 hours following a single dose. The elimination half-life of<unk>  is 1 to 2.6 hours while the half-life of M-II, the major active metabolite of<unk> , is 2 to 5 hours. The half-lives of<unk>  and M-II are substantially longer than that of melatonin, which has a half-life in the range of 20 to 45 minutes. Levels of<unk>  and its metabolites at or below the limit of detectability within 24 hours following a dose. Special populations Peak levels of<unk>  and overall exposure are about 86% and 97% higher, respectively, in elderly adults compared to younger adults. Conversely, peak levels of M-II are 13% and overall exposure 30% higher in elderly adults than in younger adults. The elimination half-life of<unk>  is 2.6 hours in elderly adults.
Ramelteon
Enarodustat
Elixir
Miglustat
Snoezelen
Ecallantide
Patisiran
Zileuton