Tasimelteon [(1R-trans)-N-[[2-(2,3-dihydro-4-benzofuranyl) cyclopropyl] methyl] propanamide] is a novel dual melatonin receptor agonist that was approved by the US Food and Drug Administration in January 2014 for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24). It is unknown exactly how tasimelteon exerts its therapeutic effect in patients with Non-24, but it is believed to be mediated by the specific and high-affinity binding of tasimelteon to the MT1 and MT2 receptors, which are thought to be involved in the control of circadian rhythms.1 The affinity of tasimelteon for the MT2 receptor is 4-fold higher than its affinity for the MT1 receptor.2
Non-24 is a serious chronic disorder that occurs primarily in blind patients with no conscious perception of light,3,4 with an estimated prevalence of 50%–70%.3–7 Light is the most powerful zeitgeber or environmental cue for the daily resetting of the circadian clock.8–13 Blind individuals who are unable to perceive light cannot synchronize their endogenous circadian clocks to the 24-hour light–dark cycle.14–17 As a result, the pacemaker, which resides in the suprachiasmatic nucleus of the hypothalamus, may revert to its endogenous non–24-hour period, which, in totally blind people, is on average 24.5 hours, although there is considerable interindividual variability. A period greater than 24 hours results in prolonged periods of misalignment of circadian rhythms with the 24-hour day. Downstream effects of this circadian misalignment with the 24-hour day include increased risk for cardiovascular disease, obesity, type II diabetes, and immune system dysregulation. The most common complaint of patients with Non-24 is the sleep–wake cycle disruption, including insomnia, excessive daytime sleepiness, or both.18–20
Two-phase 3 pivotal clinical studies demonstrated that tasimelteon entrains and maintains the entrainment of the circadian rhythms, including sleep–wake patterns in totally blind individuals with Non-24.21,22 Doses up to 300 mg were safe and well tolerated in clinical studies. The most common adverse events with an incidence >5% and at least twice as high for patients using tasimelteon compared with placebo included headache, transient increased alanine aminotransferase, nightmares/abnormal dreams, and urinary and upper respiratory tract infections.23–25 Tasimelteon is highly metabolized and mainly excreted in urine as metabolites. The major metabolites of tasimelteon are M9, M11, M12, M13, M14, and M3, a glucuronidated metabolite. Results of a mass balance study indicated that tasimelteon is highly metabolized after oral administration: less than 1% of the recovered administered dose was unchanged tasimelteon. The mean recovery of total radioactivity in the urine was 80%; approximately 4% of this radioactive dose was accounted for in feces.25
MATERIALS AND METHODS
This study was conducted at a single center in Overland Park, KS (ClinicalTrials.gov identifier: NCT02130999). Written informed consent was obtained from all healthy volunteers before undergoing any study-related procedures. The protocol was submitted to a properly constituted institutional review board, in agreement with local legal prescriptions (ICH 3.1–3.4), for formal approval of the study conduct. This study was conducted according to US and international standards of Good Clinical Practice, and the Declaration of Helsinki.
The study was an open-label, single-dose, randomized, 2-period, 2-treatment, 2-sequence, crossover study to determine the absolute bioavailability of oral tasimelteon (Hetlioz; Vanda Pharmaceuticals, Inc, Washington, DC) in healthy adult volunteers. Fourteen healthy volunteers were enrolled in the study. Each subject received 2 treatments: a 20-mg oral dose using the marketed capsule formulation and a 2-mg intravenous (IV) formulation infused over 30 minutes.
The study was divided into 2 phases: the screening phase and the inpatient evaluation phase. The screening phase comprised a screening visit and a baseline visit, during which the subject's eligibility was evaluated. Subjects who met all entry criteria for the study entered the inpatient evaluation phase. The evaluation phase consisted of 2 baseline periods (1 before each treatment period), 2 treatment periods with on-site observation and pharmacokinetic (PK) sampling for 24 hours, and an end-of-study visit. Each treatment period was separated by a washout period of 5 ± 2 days.
All 14 randomized subjects were male or female; between the ages of 18 and 55; and in good health based on medical history, physical examination, electrocardiography results, vital signs, and laboratory test results. Additionally, all subjects were able to provide written informed consent. Among the 14 subjects who participated in the study, 7 (50.0%) were males and 8 (57.1%) were white. The median age was 29.5 years, with a range of 19–53 years (Table 1). All subjects were nonsmokers and tested negative for cotinine at screening and baseline.
Subjects were randomly assigned to a treatment sequence. Eight subjects received the IV-oral treatment sequence and 6 subjects received the oral-IV treatment sequence.
Blood samples for determining the concentration of tasimelteon and its major metabolites, as well as the absolute bioavailability of tasimelteon, were obtained for each subject during a 24-hour span after administration by both routes. The concentrations of tasimelteon and its major metabolites in plasma were determined by using a validated specific liquid chromatography–mass spectrometry method that was described previously.26 Noncompartmental analysis was used to estimate the following PK parameters: maximum plasma concentration (Cmax), time to Cmax, elimination rate constant, half-life (t½), and area under the curve to infinity [AUC(inf)]. For tasimelteon, clearance (CL) and volume of distribution (Vz; IV) or CL and Vz uncorrected for bioavailability (CL/F and Vz/F; oral) also were calculated.
Comparison of dose-corrected AUC(inf) for tasimelteon and metabolites between the oral and IV treatments was performed using an analysis of variance model with treatment, period, and sequence as fixed effect, and subject within sequence as the classification variables, using the natural logarithms of the data. The absolute bioavailability (F) for tasimelteon was estimated as the least-squares geometric mean ratio, oral-to-IV, and the associated 90% confidence interval (CI) was calculated using the two 1-sided t tests procedure. The geometric mean ratio and CI were exponentiated back to the original scale.
All 14 subjects who were enrolled in the study completed the study.
The arithmetic mean ± standard error plasma concentrations of tasimelteon after oral and IV administration are illustrated in Figure 1, and the associated PK parameters are summarized in Table 2. The CL and Vz of tasimelteon, based on IV treatment, were 505 ± 135 mL per minute and 42.7 ± 7.02 L, respectively (Table 2). Based on the statistical comparison of dose-corrected AUC(inf), the absolute bioavailability was 38.33%, with a 90% CI of 26.94%–54.33%. The mean t½ was the same for the oral and IV routes, 1.06 ± 0.23 and 1.02 ± 0.23 hours, respectively (Table 2).
The mean ± SD for Cmax and AUC(inf) of tasimelteon's metabolites after oral and IV administration are summarized in Table 3. The metabolite-to-parent AUC(inf) ratios for the oral and IV routes are compared in Table 4. For the 4 metabolites that could be characterized after IV administration—M9, M11, M12, and M13—the ratios are lower than those observed after oral administration, suggesting presystemic or first-pass metabolism of tasimelteon (Table 4).
Three (21.4%) subjects experienced a treatment-emergent adverse event (TEAE) during the study. Two subjects (14.3%) experienced a TEAE while taking oral tasimelteon. One subject had mild drowsiness that resolved the same day, and 1 subject had mild headache that resolved the next day.
One subject experienced 2 TEAEs while taking IV tasimelteon. These were mild vomiting beginning on day 1 that resolved the next day and mild headache beginning on day 6 that resolved on the same day. None of the events were severe. There were no deaths, serious adverse events, or discontinuations due to TEAEs during the study period.
It is well known since the publication of the classic paper of Harter and Peck in 199127 that the PK of a drug can explain up to 50% of its therapeutic variability. Of all its PK parameters, the absolute bioavailability of a given drug represents the ultimate result of all the complex interplay between the absorption and elimination processes and, as such, is a critical piece of information for drug developers and prescribers. Many factors could affect the absolute bioavailability of a drug, including poor absorption into the enterocytes as the drug passes down the gastrointestinal tract, and high first-pass metabolism, which is considered to be because of metabolism in the intestine and liver before the drug reaches systemic circulation.
Low and variable absolute bioavailability because of extensive first-pass metabolism has been a problem with many orally administered drugs including exogenous melatonin and ramelteon, a melatonin agonist developed by Takeda Pharmaceutical Co, Ltd, Osaka, Japan, for the treatment of insomnia. After single oral administration, the absolute bioavailability of melatonin and ramelteon is about 15% and <2%, respectively.28,29 Low bioavailability leads to a high degree of intersubject variability in the systemic exposure to the drug, which, in turn, could lead to variable therapeutic and/or adverse responses.
Tasimelteon, in contrast, had an absolute bioavailability of 38%. Based on the recovery of total radioactivity in the urine, the absorption of tasimelteon as unchanged drug plus metabolites is 80%, although the parent accounts for <1%. Taken together, these data indicate that, although tasimelteon is subject to first-pass metabolism, a substantial fraction of its metabolism occurs post- rather than presystemically. This is supported by the metabolite-to-parent AUC ratios (Table 4)—those observed after IV administration are 20%–30% of those measured after oral administration.
In conclusion, the mean absolute bioavailability of tasimelteon after oral administration is 38%. The higher oral-to-IV exposure ratios and decrease in the metabolite-to-parent ratios after IV administration for tasimelteon's metabolites indicate that although tasimelteon is subject to first-pass metabolism, a substantial fraction of its metabolism occurs post- rather than presystemically. Both oral and IV tasimelteon were well tolerated during the study.
The authors acknowledge Synchrony Medical Communications, LLC, West Chester, PA, for providing technical editorial assistance.
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Keywords:Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
tasimelteon; Non-24-Hour Sleep-Wake Disorder; Non-24; pharmacokinetics; absolute bioavailability