Ramelteon A Melatonin Receptor Agonist in the Treatment of Insomnia
Ramelteon A Melatonin Receptor Agonist in the Treatment of Insomnia
Insomnia is a common condition characterized by difficulty falling asleep, increased night-time wakefulness or inadequate sleep duration. Insomnia can result in daytime consequences, including tiredness, difficulty concentrating, and irritability, as well as increased healthcare utilization and reduced work productivity, lower quality of life or quality of social relationships, and decrements in memory, mood, or cognitive function.1,2 Acute insomnia refers to periods of difficulty sleeping lasting one day to a few weeks, while chronic insomnia refers to sleep difficulty lasting at least three nights per week for one month or more.2
Up to 75% of adults report symptoms of a sleep problem occurring a few nights per week or more, while approximately 10–15% have chronic insomnia.2,3,4
Management of insomnia includes sleep hygiene education, cognitive behavioral therapy, and pharmacological therapy.2 Pharmacological agents include benzodiazepines, non-benzodiazepine benzodiazepine receptor agonists, antihistamines, antidepressants, melatonin, herbal products, and nutritional supplements.2,5 Although highly effective at reducing sleep latency, benzodiazepine and the nonbenzodiazepine benzodiazepine receptor agonists are associated with varying degrees of residual daytime sedation, abuse liability, and toxicity.6 Antidepressants and antihistamines are also effective in some patients, but have troublesome adverse effects.1,2 Limited data also suggest that melatonin is effective in the treatment of chronic insomnia.1 In the 2005 Sleep in America Poll, 7% of respondents reported using prescription sleep medication at least a few nights each month, 9% reported using over-the-counter sleep aids, 11% reported using alcohol, beer or wine specifically to help them sleep, and 2% reported using melatonin for sleep.
Melatonin is a neurohormone released from the pineal gland in association with the light–dark cycle that regulates sleep.The sleep-promoting and circadian effects of melatonin are attributed to interactions with two subtypes of human melatonin receptors:MT1 and MT2.7 A third subtype,MT3, is a peripheral receptor.8The MT1 receptor, localized in the hypothalamic suprachiasmatic nucleus, is believed to mediate circadian and reproductive effects of melatonin. The MT2 receptor, found in the hypothalamic suprachiasmatic nucleus and the neural retina, is thought to mediate the effects of melatonin on circadian rhythms and regulate visual function.The role of the MT3 receptor has not been defined.9 Endogenous melatonin secretion occurs approximately two hours before an individual’s habitual bedtime and is correlated with the onset of evening sleepiness. Suppression of melatonin production correlates with insomnia. Increasing plasma melatonin concentrations are associated with increased sleepiness.7
Ramelteon
Ramelteon (Rozerem™, Takeda) is a melatonin receptor agonist that was approved by the US Food and Drug Administration (FDA) in July 2005 for the treatment of insomnia characterized by difficulty with sleep onset.10 It is also under evaluation for use in the treatment of circadian rhythm disorders.9
Pharmacology
Ramelteon is a tricyclic indan derivative that is a potent and selective human melatonin MT1 and MT2 receptor agonist.9,11 Ramelteon has very low affinity for the MT3 receptor. In comparison with melatonin, ramelteon has six-fold higher affinity for the MT1 receptor and fourfold higher affinity for the MT2 receptor, but 94-fold lower affinity for the MT3 receptor.9 The selectivity of ramelteon for MT1 over MT2 is more than 1,000-fold greater than that of melatonin, as melatonin has greater affinity for MT2 receptors than MT1 receptors.12 Ramelteon has exhibited no measurable affinity for the gamma-aminobutyric acid (GABA) receptor complex, the benzodiazepine, cytokine, dopamine, noradrenaline, acetylcholine, neuropeptide, opiate, or serotonin receptors, or ion channels and transporters.10,13 It has exhibited low affinity for the serotonin 5-hydroxytryptamine (HT)2B receptor. Unlike melatonin, it did not exhibit activity at the serotonin 5-HT1A receptor or the dopamine D1 receptor.13 wakefulness and increased slow wave sleep and rapid eye movement (REM) sleep, with effects persisting for six hours. Melatonin produced similar effects; however, effects only persisted for two hours after administration.9 In monkeys, ramelteon reduced the latency to sleep onset in a dose-dependent manner. Unlike melatonin, ramelteon also increased the total duration of sleep.14,15 In other animal models, ramelteon did not exhibit impairment of performance on learning or memory assessments (water maze and delayed matching-to-position tasks in rats), unlike diazepam and triazolam. In the conditioned place-preference test in rats, neither ramelteon nor melatonin showed evidence of rewarding properties, in contrast to diazepam, triazolam, and morphine.16
2. National Center on Sleep Disorders Research, Insomnia: Assessment and Management in Primary Care, NIH Publication No. 98-4088, National Institutes of Health (1998 September).
3. Roth T,“Prevalence, associated risks, and treatment patterns of insomnia”, J Clin Psychiatry (2005);66(suppl. 9): pp. 10–13.
4. National Sleep Foundation, 2005 Sleep in America Poll – Summary of findings (March 2005), http://www. sleepfoundation.org/_content/hottopics/2005_summary_of_findings.pdf (accessed February 21, 2006).
5. Erman M K,“Therapeutic options in the treatment of insomnia”, J Clin Psychiatry (2005);66(Suppl. 9): pp. 18–23.
6. Griffiths R R, Johnson M W,“Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds”, J Clin Psychiatry (2005);66(suppl. 9): pp. 31–41.
7. Pandi-Perumal S R, Zisapel N, Srinivasan V, Cardinali D P, “Melatonin and sleep in aging population”, Exp Gerontology (2005);40: pp. 911–925.
8. Richardson G S, “The human circadian system in normal and disordered sleep”, J Clin Psychiatry (2005);66(suppl. 9): pp. 3–9.
9. Uchikawa O, Fukatsu K, Tokunoh R et al., “Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists”, J Med Chem (2002);45: pp. 4,222–4,239.
10. RozeremT M [package insert],Takeda Pharmaceuticals America, Inc., Lincolnshire, Illinois (August 2005).
11. Kato K, Hirai K, Nishiyama K et al., “Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist”, Neuropharmacology (2005);48: pp. 301–310.
12. Hirai K, Kato K, Nishiyama K et al.,“TAK-375 and its metabolites are selective agonists at MLs1s receptors” [abstract], Sleep (2003);26(suppl.): p.A79.
13. Miyamoto M, Kata K, Hirai K, Uchikawa O, Ohkawa S, “TAK-375 and its active metabolite: lack of binding to non-ML receptor binding sites” [abstract], Sleep (2003);26(suppl): p.A79.
14. Yukuhiro N, Kimura H, Nishikawa H et al., “Effects of ramelteon (TAK-375) on nocturnal sleep in freely moving monkeys”, Brain Res (2004);1,027: pp. 59–66.
15. Yukuhiro N, Nishikawa H, Kimura H, Ohkawa S, Miyamoto M, “Sleep in freely moving monkeys: comparison of TAK-375, melatonin, and zolpidem” [abstract], Sleep (2003);26(suppl.): p.A80.
16. Miyamoto M, Nishikawa H, Ota H, Uchikawa O, Ohkawa S, “Behavioral pharmacology of ramelteon (TAK-375) in small mammals” [abstract], Ann Neurol (2003);54(suppl. 7): p. S46. mammals” [abstract], Ann Neurol (2003);54(suppl. 7): p. S46.
17. Stevenson S, Bryson S,Amakye D, Hibberd M,“Study to investigate the absolute bioavailability of a single oral dose of ramelteon (TAK-375) in healthy male subjects” [abstract], Clin Pharmacol Ther (2004);75: p. P22.
18. Amakye D D, Hibberd M, Stevenson S J, “A phase I study to investigate the absolute bioavailability of a single oral dose of ramelteon (TAK-375) in healthy male subjects” [abstract], Sleep (2004);27(suppl.): p.A54.
19. Stubbs C, Karim A,“A safety, tolerance, and pharmacokinetic study of five single doses of TAK-375 in healthy adults” [abstract], Sleep (2003);26(suppl.): pp.A76–A77.
20. Stevenson S, Cornelissen K, Clarke E, Hibberd M, “Study of the absorption, metabolism, and excretion of (14C)-ramelteon (TAK-375)” [abstract], Clin Pharmacol Ther (2004);75(2): p. P22.
21. Hibberd M, Stevenson S J, “A phase-I open-label study of the absorption, metabolism, and excretion of (14C)-ramelteon (TAK- 375) following a single oral dose in healthy male subjects” [abstract], Sleep (2004);27(suppl.): p.A54.
22. Karim A,Tolbert D, Cao C, Zhao Z,“Effect of food on the systemic exposure of ramelteon (TAK-375) following a single dose” [abstract], J Clin Pharmacol (2004);44: p. 1,210.
23. Greenblatt D J, Harmatz J S,“Age and gender effects on the pharmacokinetics of TAK-375” [abstract], Sleep (2003);26(suppl.): p.A81.
24. Greenblatt D J, Harmatz J S, Karim A, “Effect of age and gender on the pharmacokinetics of ramelteon (TAK-375), a novel selective ML-1 receptor agonist” [abstract], J Am Geriatr Soc (2004);52(suppl. 4): p. S125.
25. Karim A,Tolbert D, Zhao Z, “Single and multiple dose pharmacokinetic evaluation of ramelteon (TAK-375) in subjects with and without hepatic impairment” [abstract], J Clin Pharmacol (2004);44: p. 1,210.
26. Tolbert D, Karim A, Zhao Z,“Evaluation of the single and multiple dose pharmacokinetics of ramelteon (TAK-375) in subjects with and without renal impairment” [abstract], J Clin. Pharmacol. (2004);44: p. 1,210.
27. Erman M, Seiden D, Zammit G, Sainati S, Zhang J, “An efficacy, safety, and dose-response study of ramelteon in patients with chronic primary insomnia”, Sleep Med (2006);7: pp. 17–24.
28. Zammit G, Roth T, Erman M et al., “Double-blind, placebo-controlled polysomnography and outpatient trial to evaluate the efficacy and safety of ramelteon in adult patients with chronic insomnia” [abstract], Associated Professional Sleep Societies 19th Annual Meeting, June 18–23, 2005, Denver, Colorado, abstract 0680.
29. Roth T, Seiden D, Zee P et al., “Phase III outpatient trial of ramelteon for the treatment of chronic insomnia in elderly patients” [abstract], J Am Geriatr Soc (2005);53(suppl. 4): p. S25.
30. Seiden D, Zee P,Weigand S et al., “Double-blind, placebo-controlled outpatient clinical trial of ramelteon for the treatment of chronic insomnia in an elderly population” [abstract], Associated Professional Sleep Societies 19th Annual Meeting, June 18–23, 2005, Denver, Colorado, abstract 0679.
31. Roth T, Stubbs C,Walsh J K,“Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment”, Sleep (2005);28: pp. 303–307.
32. Karim A, Tolbert D, Cao C, “Disposition kinetics and tolerance of escalating single doses of ramelteon, a high-affinity MT1 and MT2 melatonin receptor agonist indicated for treatment of insomnia”, J Clin Pharmacol (2006);46: pp. 140–148.
33. Greenblatt D J, Harmatz J S, “Effect of age and gender on the pharmacodynamics of TAK-375: tests of sedation, psychomotor function, and memory” [abstract], Sleep (2003);26(suppl.): p.A80.
34. Sainati S,Tsymbalov S, Demissie S, Roth T,“Double-blind, placebo-controlled, two-way crossover study of ramelteon in subjects with mild to moderate chronic obstructive pulmonary disease (COPD)” [abstract], Associated Professional Sleep Societies 19th Annual Meeting, June 18–23, 2005, Denver, Colorado, abstract 0479.
35. Sainati S,Tsymbalov S, Demissie S, Roth T, “Double-blind, single-dose, two-way crossover study of ramelteon in subjects with mild to moderate obstructive sleep apnea” [abstract], Associated Professional Sleep Societies 19th Annual Meeting, June 18–23, 2005, Denver, Colorado, abstract 0480.
36. Johnson M, Griffiths R, Suess P, “Ramelteon and triazolam in humans: behavioral effects and abuse potential” [abstract], Associated Professional Sleep Societies 19th Annual Meeting, June 18–23, 2005, Denver, Colorado, abstract 0132.
37. France C,Weltman R, Cruz C, McMahon L, “Ramelteon does not have benzodiazepine agonist-like discriminative stimulus effects in normal or diazepam-dependent rhesus monkeys” [abstract],Associated Professional Sleep Societies 19th Annual Meeting, June 18–23, 2005, Denver, Colorado, abstract 0133.
38. France C,Weltman R, Cruz C,“Lack of primary physical dependence effects of ramelteon in rhesus monkeys” [abstract],Associated Professional Sleep Societies 19th Annual Meeting, June 18–23, 2005, Denver, Colorado, abstract 0134.
39. Nishida N, Sasaki M,Wakasa Y et al.,“Reinforcing effect of ramelteon assessed by intravenous self-administration experiments in rhesus monkeys” [abstract], Associated Professional Sleep Societies 19th Annual Meeting, June 18–23, 2005, Denver, Colorado, abstract 0135.
40. Tolbert D, Karim A, Demissie S,“A phase I study to evaluate the short-term effects of ramelteon (TAK-375) on endocrine function in healthy adult subjects” [abstract], J Clin Pharmacol (2004);44: p. 1,210.
41. Karim A,Tolbert D, Cao C, Zhao Z, Sainati S M, “The effect of multiple doses of ramelteon (TAK-375) on the single-dose pharmacokinetic profile of midazolam in healthy adult subjects” [abstract], Sleep (2004);27(suppl.): p.A47.
42. Tolbert D, Karim A, Johnson J et al.,“Two-period crossover study to assess the drug interaction between ramelteon (TAK-375) and theophylline in healthy adults” [abstract], Sleep (2004);27(suppl.): p.A48.
43. Tolbert D, Karim A, Cao C et al., “Study to assess drug interactions between ramelteon (TAK-375) and dextromethorphan in healthy adults” [abstract], Sleep (2004);27(suppl.): p.A50.
44. Karim A, Tolbert D, Cao C, Zhao Z, Harris S, “Open-label assessment of the pharmacokinetics and pharmacodynamics of warfarin in the presence of multiple doses of ramelteon in healthy adults” [abstract], Associated Professional Sleep Societies 19th Annual Meeting, June 18–23, 2005, Denver, Colorado, abstract 0136.
45. Karim A, Tolbert D, Cao C, Zhao Z, Sainati S M, “Effects of fluconazole and ketoconazole on the pharmacokinetics of ramelteon (TAK-375) in normal healthy male and female subjects” [abstract], Sleep (2004);27(suppl.): pp. A53–A54.
46. Sainati S M, Karim A,Tolbert D, Cao C, “Effects of multiple doses of fluoxetine on the systemic exposure of a single dose of ramelteon (TAK-375) in healthy adults” [abstract], Sleep (2004);27(suppl.): p.A48.
47. Karim A,Tolbert D, Cao C, Munsaka M, Copa A, “Study to assess the steady-state drug-drug interaction of omeprazole with ramelteon in healthy adults” [abstract],Associated Professional Sleep Societies 19th Annual Meeting, June 18–23, 2005, Denver, Colorado, abstract 0137.
