The major metabolite of ramelteon, M-II, is pharmacologically active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively. However, M-II circulates at higher concentrations than the parent producing 20- to 100-fold greater mean systemic exposure when compared to ramelteon. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes.
The pharmacokinetic profile of Ramelteon Tablets has been evaluated in healthy subjects as well as in subjects with hepatic or renal impairment. When administered orally to humans in doses ranging from 4 to 64 mg, ramelteon undergoes rapid, high first-pass metabolism, and exhibits linear pharmacokinetics. Maximal serum concentration (Cmax) and area under the concentration-time curve (AUC) data show substantial intersubject variability, consistent with the high first-pass effect; the coefficient of variation for these values is approximately 100%. Several metabolites have been identified in human serum and urine.
Absorption
Ramelteon is absorbed rapidly, with median peak concentrations occurring at approximately 0.75 hour (range, 0.5 to 1.5 hours) after fasted oral administration. Although the total absorption of ramelteon is at least 84%, the absolute oral bioavailability is only 1.8% due to extensive first-pass metabolism.
Distribution
In vitro protein binding of ramelteon is approximately 82% in human serum, independent of concentration. Binding to albumin accounts for most of that binding, since 70% of the drug is bound in human serum albumin. Ramelteon is not distributed selectively to red blood cells.
Ramelteon has a mean volume of distribution after intravenous administration of 73.6 L, suggesting substantial tissue distribution.
Metabolism
Metabolism of ramelteon consists primarily of oxidation to hydroxyl and carbonyl derivatives, with secondary metabolism producing glucuronide conjugates. CYP1A2 is the major isozyme involved in the hepatic metabolism of ramelteon; the CYP2C subfamily and CYP3A4 isozymes are also involved to a minor degree.
The rank order of the principal metabolites by prevalence in human serum is M-II, M-IV, M-I, and M-III. These metabolites are formed rapidly and exhibit a monophasic decline and rapid elimination. The overall mean systemic exposure of M-II is approximately 20- to 100-fold higher than parent drug.
Elimination
Following oral administration of radiolabeled ramelteon, 84% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 88%. Less than 0.1% of the dose was excreted in urine and feces as the parent compound. Elimination was essentially complete by 96 hours postdose.
Repeated once daily dosing with Ramelteon Tablets does not result in significant accumulation owing to the short elimination half-life of ramelteon (on average, approximately one to 2.6 hours).
The half-life of M-II is two to five hours and independent of dose. Serum concentrations of the parent drug and its metabolites in humans are at or below the lower limits of quantitation within 24 hours.
Effect of Food
When administered with a high-fat meal, the AUC0-inf for a single 16 mg dose of Ramelteon Tablets was 31% higher and the Cmax was 22% lower than when given in a fasted state. Median Tmax was delayed by approximately 45 minutes when Ramelteon Tablets were administered with food. Effects of food on the AUC values for M-II were similar. It is therefore recommended that Ramelteon Tablets not be taken with or immediately after a high-fat meal [see Dosage and Administration (2.1)].