title: 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.
authors.affiliation: Takeda Global Research & Development Center, Inc, 475 Half Day Road, Lincolnshire, IL 60069, USA.
authors.forename: Aziz
authors.initials: A
authors.lastname: Karim
authors.forename: Dwain
authors.initials: D
authors.lastname: Tolbert
authors.forename: Charlie
authors.initials: C
authors.lastname: Cao
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001288:Attention / Q000187:drug effects; D001711:Biotransformation; D003071:Cognition / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007192:Indenes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D011597:Psychomotor Performance / Q000187:drug effects; D044094:Receptors, Melatonin / Q000819:agonists*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*
chemical_list: D007192:Indenes; D044094:Receptors, Melatonin; C495910:ramelteon