Absolute Bioavailability of Tasimelteon.

Abstract

Tasimelteon is a novel dual melatonin receptor agonist and is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. This study was conducted to assess the absolute bioavailability of tasimelteon and to further assess the single-dose pharmacokinetics, safety, and tolerability of oral and intravenous (IV) routes of administration of the drug. This study was an open-label, single-dose, randomized, 2-period, 2-treatment, 2-sequence, crossover study in which 14 healthy volunteers were randomly administered tasimelteon as either a 20-mg capsule or IV administration of 2 mg infused over 30 minutes. Each subject received both treatments in a random order, separated by a washout period of 5 ± 2 days. The total clearance and volume of distribution of tasimelteon, from the IV treatment, were 505 mL per minute and 42.7 L, respectively. Based on the statistical comparison of dose-corrected area under the curve to infinity, the absolute bioavailability was 38%, with a 90% confidence interval of 27%-54%. The mean elimination half-life was the same for the oral and IV routes. The exposure ratios, oral-to-IV, for metabolites M9, M11, M12, and M13, were 133.27%, 118.28%, 138.76%, and 112.36%, respectively, suggesting presystemic or first-pass metabolism. Three (21.4%) subjects experienced a treatment-emergent adverse event (TEAE) during the study. All TEAEs were mild, considered related to study medication, and consistent with what has been seen in other studies. There were no deaths, serious adverse events, or discontinuations due to TEAEs. Both tasimelteon treatments were well tolerated during the study.