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.

Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep‐Wake Disorders

“…In both preclinical and human studies, timed pulsatile melatonin administration was more efficacious than prolonged administration for phase‐shifting the circadian clock . Because the response of the endogenous clock is time dependent, the timing of administration as well as the pharmacokinetic parameters (Table ) of a given melatonin agonist will likely play a key role in its overall effects on the circadian system.…”

“…One of the primary drawbacks of dietary supplement melatonin is its documented poor and highly variable bioavailability from person to person due to high first‐pass metabolism in the liver, poor gut absorption, or possibly a combination of both factors . The four approved melatonin receptor agonists exhibit a wide range of absolute bioavailability parameters, with an average of 3.3% for agomelatine, 15% for prolonged‐release melatonin, 1.8% for ramelteon, and 38.3% for tasimelteon . It is notable that, in the absence of bioavailability data for the approved prolonged‐release melatonin formulation, the estimate provided for the approved product is based on immediate‐release formulations .…”

“…Whereas all of these compounds bind to both melatonin receptors, their differential binding affinities to MT 1 versus MT 2 are distinctive. Table summarizes the pharmacodynamic characteristics of these agonists …”

“…54,55 The four approved melatonin receptor agonists exhibit a wide range of absolute bioavailability parameters, with an average of 3.3% for agomelatine, 51 15% for prolonged-release melatonin, 52, 55, 56 1.8% for ramelteon, 49 and 38.3% for tasimelteon. 48 It is notable that, in the absence of bioavailability data for the approved prolonged-release melatonin formulation, the estimate provided for the approved product is based on immediate-release formulations. 39 The applicability of immediaterelease melatonin data to prolonged-release melatonin is unclear, given the slower absorption rate of the prolonged-release formulation.…”

Safety profile of tasimelteon, a melatonin MT1and MT2receptor agonist: pooled safety analyses from six clinical studies

“…Tasimelteon is rapidly and consistently absorbed, with a mean absolute bioavailability of 38% [2]. Tasimelteon is extensively metabolized with CYP1A2 and CYP3A4 being the major isozymes involved in the metabolism of tasimelteon [3].…”