Study to investigate the absolute bioavailability of a single oral dose of ramelteon (TAK-375) in healthy male subjects

Abstract

The aim of the study was to determine the absolute bioavailability of orally administered ramelteon (TAK-375), a novel selective ML1 receptor agonist currently under investigation for the treatment of insomnia and circadian rhythm sleep disorders. Eighteen healthy male subjects received a tablet formulation (16 mg) and a 5-minute IV infusion (2 mg) of ramelteon during this two-period crossover study. Blood samples were collected for the analysis of serum ramelteon and metabolites (M-I, M-II, M-III, and M-IV). The absolute bioavailability of ramelteon, based on the ratio for AUC (0-ω) (norm) between the tablet and IV formulation, following a single oral dose was very low (<2%). For individual subjects, the absolute bioavailability was variable, ranging from 0.5% to 12%. A previous study with radiolabeled ramelteon has shown that as much as 84% of the orally administered radioactivity was recovered in the urine, mostly as several metabolites, with unmetabolized ramelteon accounting for <0.1 % of the administered dose. These findings indicate that the oral absorption of ramelteon is excellent, but the drug undergoes extensive first-pass metabolism. Clinical Pharmacology & Therapeutics (2004) 75, P22–P22; doi: 10.1016/j.clpt.2003.11.085