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

From Takeda Global Research & Development Center, Inc, Lincolnshire, Illinois.

Ramelteon is a selective MT₁/MT₂ 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 (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 = 1.71 (114), 6.95 (108), 9.88 (78), 22.5 (80), and 36.1 (71 ng·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.

Key Words: High-affinity melatonin MT₁/MT₂ receptor • insomnia • pharmacokinetics • single rising doses • tolerance

Address for reprints: Aziz Karim, PhD, ABCP, FCP, Takeda Global Research & Development Center, Inc, 475 Half Day Road, Lincolnshire, IL 60069.

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