1 RAMELTEON: a MELATONIN RECEPTOR AGONIST 2 Richard Wurtman, MD 3 Massachusetts Institute of Technology, Cambridge, MA, 02139

1 RAMELTEON: A MELATONIN RECEPTOR AGONIST 2 Richard Wurtman, M.D. 3 Massachusetts Institute of Technology, Cambridge, MA, 02139, USA 4 5 6 7 8 9 10 11 12 13 14 Keywords: (Ramelteon), melatonin, pineal, MTI receptors, MT2 receptors, sleep, 15 GABA receptors, aging, desensitization 16 17 18 19 Address for correspondence: 77 Mass Ave. 46-5023 20 Cambridge, MA, 02139, USA 21 Telephone: 617-253-6731 22 FAX: 617-253-6882 23 e-mail: [email protected] ---------- 1 A. Summary: Ramelteon, the first melatonin receptor agonist to win FDA approval, 2 is presently marketed in the United States; its use is authorized to be marketed in the 3 United States for "..the treatment of insomnia associated with sleep onset". In laboratory 4 tests ramelteon has not exhibited potential for being abused or causing dependency, nor 5 has it been shown to interact with the neurotransmitter receptors that tend to be most 6 associated with these phenomena. Hence unlike other hypnotic agents ramelteon is a non- 7 scheduled drug. Few data have been published in peer-reviewedjournals describing 8 ramelteon's efficacy or side-effects in patients who actually suffer from insomnia, and no 9 comparison study has been performed to determine whether, when used at its 10 recommended 8 mg dose, ramelteon has any advantage over physiologic doses of 11 melatonin (0.2 - 0.5 mg), particularly for long-term use in older patients. 2 - - 1 2 B. Introduction 3 Ramelteon is the first FDA-approved agent believed to act by mimicking the 4 effects of the hormone melatonin. It does so, as described below, by combining with and 5 activating melatonin's MT1 and MT2 receptors in the brain, which may mediate 6 melatonin's sleep-promoting effects following its secretion from the pineal 7 gland 1,2,3,4,5,6,7,8.When melatonin is administered to young adults during the daytime or 8 early evening (for example, to those initiating eastbound travel, or undertaking shift 9 work) it promotes sleep onset 4,9;when given at bedtime to older adults who suffer from 10 prolonged nocturnal awakenings, it improves sleep efficiency and increases sleep 11 time 6,10. The fully-effective oral dose of melatonin (0.2-0.5 mg, usually 0.3 mg4,6)is the 12 same for both uses, and is equal to the amount needed to elevate plasma melatonin levels 13 to what they would normally be, during the night, in young adults (about 100-200 14 pcg/ml, up from 2-10 pcg/ml around noon). Among older people whose substantially- 15 calcified pineals secrete less of the hormone, nocturnal plasma melatonin levels may only 16 rise to 25-50 pcg/mlll-14; this deficiency apparently underlies their impairment in sleep 17 efficiencl and their hypnotic response to physiologic doses of melatonin.. 18 Melatonin for human consumption is unavailable in most of the world because, to 19 date, few companies have obtained the necessary data and solicited regulatory approval 20 to market it as a drug. The hormone is sold in the United States as an unregulated dietary 21 supplemene of indeterminate purity, usually in doses substantially higher than the 22 submilligram amounts needed to promote sleep. These supraphysiologic doses elevate 23 plasma melatonin levels well beyond their normal range (e.g., to 960-2440 pcg/ml after a 3 1 3 mg dose6,\3), and can cause hypothermia and hyperprolactinemia, among other side 2 effects. Moreover by desensitizing the MT115and MTi6 receptors they lose their ability 3 to promote sleep. 4 Hence, the actual contribution of exogenous melatonin to the treatment of sleep 5 disorders has remained a disappointment. But since it is widely accepted that melatonin 6 does, in fact, promote sleep, this situation has generated a commercial opportunity for 7 synthetic analogs of melatonin - like ramelteon - which, because they would be regulated 8 as a drug, would be of affirmed purity and would be used at a specific recommended 9 dose17. And since ramelteon, like melatonin itself, neither interacts with receptors for 10 GABA or other neurotransmitters, nor predisposes to substance abuse or dependenceI7-2o, 11 it has the great advantage, compared with most other sleep-promoting drugs, of not being 12 a scheduled compound 21-22.Thus, if future clinical experience affirms ramelteon's 13 efficacy and benign side-effect profile use of this drug may expand rapidly. 14 Unfortunately, very little published information is presently available to help 15 physicians decide whether to recommend ramelteon to patients with insomnia - only three 16 peer-reviewed publications. In one ofthese23 healthy, non-insomniac subjects received 17 single doses of the drug; in another 24insomniacs received the ramelteon for just two 18 consecutive days; and in a third25only subjective effects of the drug were described. 19 Unreviewed abstracts have also been published describing 35-day studies in insomniacs 20 or shorter studies in healthy subjects required to sleep in a laboratorj6-27, and an FDA 21 report17,briefly summarized two unpublished 35-day polysomnographic studies 22 performed on insomniacs and described the drug as significantly reducing latency to 23 persistent sleep. Apparently no study has examined the effects on sleep of administering 4 1 ramelteon to insomniac patients for more than 35 days, even though nothing in the drug's 2 package insert precludes its likely off-label use by aged insomniacs for prolonged 3 periods. And no study has compared ramelteon's efficacy and safety with that of 4 melatonin, the hormone that the drug was designed to replace2o. Such comparative data 5 would almost certainly have been required before a novel analog of any other hormone 6 would have been granted regulatory approval. 7 Given the paucity of information currently available concerning ramelteon, plus 8 the fact that it and melatonin apparently interact with the same MTI and MT2 receptors, 9 our ability to anticipate ramelteon's clinical effects may be enhanced if we also consider 10 those of melatonin itself. Melatonin does differ from ramelteon in that it also binds to a 11 third protein, sometimes termed the "MT3 receptor" but actually a detoxifying enzyme. 12 However this binding has not been shown to produce functional or behavioral 13 consequences. Hence it seems unlikely that ramelteon's failure to bind to MT3 14 differentiates its clinical effects from those of melatonin. 15 C. Effects ofRamelteon 16 a. Pharmacokinetics and Metabolism 17 When ramelteon [(S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8- 18 yl)ethyl] propionamide; MW 259.34] is administered at its recommended 8 mg oral 19 dosage it is rapidly absorbed, serum concentrations peaking after 0.5 - 1.5 hrs. at 5,700 20 pg!mI17-19or about 20-40 times nocturnal plasma melatonin levels3,4.Although at least 21 84% of the drug is actually absorbed its oral bioavailability is substantially lower (only 22 1.8%), because of extensive first-pass metabolism17.About 82% ofthe drug in human 23 serum is protein-bound, 70% of this to albumin17. Intravenous ramelteon exhibits a high 5 1 mean volume of distribution in humans (74 liters)17,suggesting that it readily enters most 2 tissues. 3 Ramelteon is metabolized by oxidation to hydroxyl and carbonyl derivatives, and 4 rapidly eliminated, principally as urinary metabolites, within 96 hours of oral 5 administration. Its elimination half-life is short, i.e. 1.0- 2.6 hrsI9,28,suggesting that the 6 drug does not accumulate in the brain after repeated daily dosings, however no data are 7 available on its actual brain levels in animals dosed repeatedly. If the brain does 8 accumulate ramelteon this would increase the likelihood that it - like pharmacologic 9 concentrations of melatonin itself - can desensitize the receptors on which it acts 15,16,29, 10 30,31,32,33.One ramelteon metabolite designated M-II, does exhibit biological activity, 11 binding both to melatonin MTI and MT2 receptors and to serotonin-2B receptorsl7. Its 12 affinities for human MTI and MT2 receptors are approximately one-tenth and one-fifth 13 those ofunmetabolized ramelteon. Although this metabolite is 17-25-fold less potent 14 than ramelteon in in vitro functional assays, it also circulates at much higher 15 concentrations, producing 20-100-fold greater mean systemic exposures. Thus it may 16 contribute to ramelteon' s biological effects. The consequences, if any, of M-II's binding 17 to serotonin receptors await characterization, but could also be important given 18 serotonin's known involvement in sleep. 19 Elderly subjects metabolize ramelteon significantly more slowly than younger 20 subjects, hence their total exposure to any dose (AVC) is almost twice as great17. Total 21 exposure is also increased 4-10-fold among patients with mild or moderate hepatic 22 impairment but not in those with renal disease.17 The metabolic fate of ramelteon is 23 markedly affected by other drugs which happen to interact with CPY-IA2 enzymes, - for 6 1 example, the antidepressant fluvoxamine can cause a 190-fo1dincrease in ramelteon's 2 AUC. Many other drugs (and even a food: grapefruit juice) inhibit or induce CYP1A2, 3 and might thus be expected to affect blood levels oframelteon28. 4 b. Neurochemical Effects 5 The ability of ramelteon to bind to brain receptors for melatonin or to 6 numerous other brain proteins (e.g., neurotransmitter receptors; ion channels; 7 neurotransmitter transporters) was examined using, for melatonin receptors, cultured 8 Chinese ovary (CHO) cells cloned to contain MT1 or MT2 receptors or brain 9 homogenates containing "MT3 receptors,,18. Ramelteon binding to other proteins was 10 assessed using commercial assay protocols.

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