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Absolute Bioavailability of Tasimelteon

Torres, Rosarelis PhD1,*; Dressman, Marlene A. PhD1; Kramer, William G. PhD2; Baroldi, Paolo MD, PhD1

doi: 10.1097/MJT.0000000000000195
Original Articles

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.

1Vanda Pharmaceuticals, Washington, DC; and

2Kramer Consulting LLC, North Potomac, MD.

Address for correspondence: Vanda Pharmaceuticals, Inc, 2200 Pennsylvania Avenue NW, Suite 300-E, Washington, DC 20037. E-mail:

This work was funded in its entirety by Vanda Pharmaceuticals, Inc, Washington, DC.

R. Torres, M. A. Dressman, and P. Baroldi are employees of Vanda Pharmaceuticals, Inc, W. G. Kramer is a paid consultant to Vanda Pharmaceuticals, Inc.

The authors declare that this study was performed in accordance with research ethical guidelines.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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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

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This study was conducted at a single center in Overland Park, KS ( 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.

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Study design

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.

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Study participants

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.

Table 1

Table 1

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.

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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.

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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).



Table 2

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).

Table 3

Table 3

Table 4

Table 4

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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.

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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.

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The authors acknowledge Synchrony Medical Communications, LLC, West Chester, PA, for providing technical editorial assistance.

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1. Vachharajani NN, Yeleswaram K, Boulton DW. Preclinical pharmacokinetics and metabolism of BMS-214778, a novel melatonin receptor agonist. J Pharm Sci. 2003;92:760–772.
2. Lavedan C, Forsberg M, Gentile AJ. Tasimelteon: a circadian regulator with a selective and unique binding profile. Neuropharmacology. [published online ahead of print December 19, 2014]. doi:10.1016/j.neuropharm.2014.12.004.
3. Lewy AJ, Newsome DA. Different types of melatonin circadian secretory rhythms in some blind subjects. J Clin Endocrinol Metab. 1983;56:1103–1107.
4. Sack RL, Lewy AJ, Blood ML, et al.. Circadian rhythm abnormalities in totally blind people: incidence and clinical significance. J Clin Endocrinol Metab. 1992;75:127–134.
5. Lockley SW, Skene DJ, Tabandeh H, et al.. Relationship between napping and melatonin in the blind. J Biol Rhythms. 1997;12:16–25.
6. Sack RL, Lewy AJ. Circadian rhythm sleep disorders: lessons from the blind. Sleep Med Rev. 2001;5:189–206.
7. Licamele L, Dressman M, Feeney J, et al.. Pleiomorphic expression of N24HSWD in the totally blind. Paper presented at: 26th Annual Meeting of the Associated Professional Sleep Societies, LLC; June 10, 2012; Boston, MA.
8. Czeisler CA, Gooley JJ. Sleep and circadian rhythms in humans. Cold Spring Harb Symp Quant Biol. 2007;72:579–597.
9. Küller R. The influence of light on circarhythms in humans. J Physiol Anthropol Appl Hum Sci. 2002;21:87–91.
10. Lockley SW. Circadian rhythms: influence of light in humans. In: Squire LR, ed. Encyclopedia of Neuroscience. Oxford, United Kingdom: Academic Press; 2009:971–988.
11. Skene DJ, Lockley SW, Thapan K, et al.. Effects of light on human circadian rhythms. Reprod Nutr Dev. 1999;39:295–304.
12. Lockley SW, Arendt J, Skene DJ. Visual impairment and circadian rhythm disorders. Dialogues Clin Neurosci. 2007;9:301–314.
13. Czeisler CA, Khalsa SBS. The human circadian timing system and sleep-wake regulation. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia, PA: W.B. Saunders Company; 2000:353–375.
14. Lockley SW, Arendt J, Skene D. Visual impairment and circadian rhythm sleep disorders. In: Kushida CA, ed. Encyclopedia of Sleep. Waltham, MA: Academic Press; 2013:428–437.
15. Lockley SW, Skene DJ, Arendt J, et al.. Relationship between melatonin rhythms and visual loss in the blind. J Clin Endocrinol Metab. 1997;82:3763–3770.
16. Lockley S, Tabandeh H, Skene D, et al.. Day-time naps and melatonin in blind people. Lancet. 1995;346:1491.
17. Uchiyama M, Lockley SW. Non-24-hour sleep-wake syndrome in sighted and blind patients. Sleep Med Clin. 2009;4:195–211.
18. Scheer FA, Hilton MF, Mantzoros CS, et al.. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A. 2009;106:4453–4458.
19. Reutrakul S, Hood MM, Crowley SJ, et al.. Chronotype is independently associated with glycemic control in type 2 diabetes. Diabetes Care. 2013;36:2523–2529.
20. Nguyen KD, Fentress SJ, Qiu Y, et al.. Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes. Science. 2013;341:1483–1488.
21. Lockley SW, Dressman MA, Xiao C, et al.. RESET study demonstrates that tasimelteon maintains entrainment of melatonin and cortisol in totally blind individuals with non-24-hour circadian rhythms. Paper presented at: The Endocrine Society's 95th Annual Meeting & Expo; June 16, 2013; San Francisco, CA.
22. Lockley SW, Dressman MA, Xiao C, et al.. Tasimelteon treatment entrains the circadian clock and demonstrates a clinically meaningful benefit in totally blind individuals with non-24-hour circadian rhythms. Paper presented at: The Endocrine Society's 95th Annual Meeting & Expo; June 13, 2013; San Francisco, CA.
23. Swick TJ, Sliman JA, Dressman MA, et al.. Tasimelteon, a dual melatonin receptor agonist for treatment of non-24 hour disorder: pooled safety analysis in placebo controlled randomized trials. Paper presented at: 167th Annual Meeting of the American Psychiatric Association; May 6, 2014, New York, NY.
24. Sliman JA, Dressman MA, Xiao C, et al.. Tasimelteon, a novel treatment for non-24 hour disorder: pooled safety analysis of two phase II and two phase III placebo controlled studies. Sleep. 2014;37:A167–A168.
25. Hetlioz™ (tasimelteon) capsules, for oral use [package insert]. Washington, DC: Vanda Pharmaceuticals, Inc.; 2014.
26. Torres R, Kramer WG, Baroldi P. Pharmacokinetics of the dual melatonin receptor agonist tasimelteon in subjects with hepatic or renal impairment. J Clin Pharmacol. [published online ahead of print November 24, 2014]. doi:10.1002/jcph.440.
27. Harter JG, Peck CC. Chronobiology. Suggestions for integrating it into drug development. Ann N Y Acad Sci. 1991;618:563–571.
28. DeMuro RL, Nafziger AN, Blask DE, et al.. The absolute bioavailability of oral melatonin. J Clin Pharmacol. 2000;40:781–784.
29. Stevenson S, Bryson S, Amakye D. Study to investigate the absolute bioavailability of a single oral dose of ramelteon (TAK-375) in healthy male subjects. Clin Pharmacol Ther. 2004;75:P22.

tasimelteon; Non-24-Hour Sleep-Wake Disorder; Non-24; pharmacokinetics; absolute bioavailability

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