Disposition Kinetics and Tolerance of Escalating Single Doses of Ramelteon, a High‐Affinity MT₁ and MT₂ Melatonin Receptor Agonist Indicated for Treatment of Insomnia

Abstract

Ramelteon is a selective MT(1)/MT(2) receptor agonist, indicated for insomnia treatment. Safety, tolerance, pharmacokinetics, and cognitive performance were evaluated following increasing ramelteon doses. Healthy adults (35-65 years) were randomly assigned to receive 1 of 5 oral ramelteon doses (4, 8, 16, 32, or 64 mg; n = 8 per group) or placebo (n = 20). C(max) and AUC(infinity) (mean [%CV]) increased with each dose: C(max) = 1.15 (109), 5.73 (97), 6.92 (77), 17.4 (76), and 25.9 (77) ng/mL, respectively, and AUC(infinity) = 1.71 (114), 6.95 (108), 9.88 (78), 22.5 (80), and 36.1 (71 n x h/mL), respectively. Mean T(max) values of 0.75 to 0.94 hours and mean elimination half-life of 0.83 to 1.90 hours remained relatively constant. Ramelteon was extensively metabolized. Besides ramelteon, 4 metabolites, M-I, M-II, M-III, and M-IV, were measured in serum. Metabolite M-II, which has shown weak ramelteon-like activity in vitro, was the major metabolite in serum. Digit Symbol Substitution Test and visual analog scale alertness scores were similar across all dose groups and did not differ from placebo. All adverse events were mild or moderate and resolved before study completion.

Metabolism of Ramelteon in Human Liver Microsomes and Correlation with the Effect of Fluvoxamine on Ramelteon Pharmacokinetics

“…In this report, six metabolic pathways were shown for ramelteon in human liver microsomes. This is more than the three pathways previously reported, in which hydroxylation on the ethyl (corresponding to metabolite A), oxidation and ring opening of the furan (a downstream metabolite from metabolite B), and oxidation of the cyclopentyl ring (corresponding to metabolite H) were described previously (Karim et al, 2006). The biosynthesis and isolation of the eight metabolites and use of quantitative NMR to establish concentrations of stock solutions for these metabolites permitted determination of enzyme kinetic parameters for each ramelteon metabolic pathway.…”

“…To be able to successfully extrapolate in vitro inhibition data to the in vivo fluvoxamine-ramelteon DDI, as complete a picture of ramelteon clearance pathways as is possible must be obtained. Data on the clearance pathways of ramelteon in human are scant, and it has been stated that it is primarily cleared by P450-mediated metabolism with less than 0.1% of the drug excreted unchanged (Karim et al, 2006; Rozerem Product Label, http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ index.cfm?fuseactionϭsearch.label_approvalhistory). The objectives of the present study were to determine the in vitro metabolite profile of ramelteon, to quantitatively determine the enzymes involved in each metabolic pathway, and to attempt to extrapolate the in vivo DDI from in vitro data using various modeling approaches.…”

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

“…Blood melatonin levels after administration of an oral dose of 0.3 mg are similar to endogenous levels found in humans at night (Dollins et al, 1994). However, oral doses of melatonin or other ligands at Ն1 mg may increase blood levels several times above the concentration necessary to activate melatonin receptors and therefore may alter receptor sensitivity (Dollins et al, 1994;Vachharajani et al, 2003;Mulchahey et al, 2004;Karim et al, 2006). hMT 1 melatonin receptors expressed in heterologous mammalian cells show no observable changes in melatonin-receptor density, affinity, or functional sensitivity after exposure to physiological concentrations of melatonin for a period of time that mimics normal nocturnal exposure (i.e., 8 h) (Gerdin et al, 2004b).…”

A Review of Melatonin, Its Receptors and Drugs

“…In US, it received approval from FDA in 2005 for treatment of insomnia in individuals having difficulty in falling asleep [40]. Ramelteon is rapidly absorbed from gastrointestinal system with a rate of 84% and its half-life in blood circulation is 1-2 hours [41]. Among melatonergic agonist drugs, Ramelteon is the one having relatively higher affinity to both receptor subtypes [24].…”