The Experts below are selected from a list of 165 Experts worldwide ranked by ideXlab platform
Mihael H Polymeropoulos - One of the best experts on this subject based on the ideXlab platform.
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simulated driving performance in healthy adults after night time administration of 20 mg Tasimelteon
Journal of Sleep Research, 2021Co-Authors: Rosarelis Torres, Changfu Xiao, Gunther Birznieks, Michaela Fisher, Christos Polymeropoulos, Gary G Kay, Mihael H PolymeropoulosAbstract:An impairment in next day driving performance has been reported for almost every drug currently United States Food and Drug Administration (FDA) approved for improvement of sleep in chronic and transient insomnia. Tasimelteon, a melatonin receptor agonist, demonstrated significant improvements in night-time sleep, daytime naps, and sleep timing in non-24-hr sleep-wake disorder (Non-24) by entraining these patients to a 24-hr day as measured by melatonin and cortisol rhythms. Given this new mechanism of action of entraining the biological clock, we conducted a study to evaluate the potential effect Tasimelteon may have on the ability to operate a motor vehicle. The study was conducted in 48 healthy adult subjects using a randomised, double-blind, placebo and active (zopiclone 7.5 mg) controlled study with a 3-period cross-over design. Driving performance was assessed by measuring standard deviation of lateral position (SDLP) using the validated Cognitive Research Corporation Driving Simulator-MiniSim. The difference in least square mean SDLP for Tasimelteon was 1.22 cm reflecting a non-significant increase in SDLP change from placebo (p = .1119). In contrast, treatment with the active control, zopiclone 7.5 mg, was associated with a meaningful and significant increase in SDLP, change from placebo for zopiclone was 4.14 cm (p < .0001). The lack of clinically meaningful and statistically significant finding with Tasimelteon was further supported by the symmetry analysis, which showed the distribution of within-subject differences between Tasimelteon and placebo was symmetric about zero. At the FDA-approved 20 mg dose to treat Non-24, Tasimelteon did not impair next-day driving performance compared to placebo in adult healthy volunteers.
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efficacy of Tasimelteon hetlioz in the treatment of jet lag disorder evaluated in an 8 h phase advance model a multicenter randomized double blind placebo controlled trial
Frontiers in Neurology, 2020Co-Authors: Christos Polymeropoulos, Changfu Xiao, Gunther Birznieks, Michael A Mohrman, Madison S Keefe, Jennifer L Brzezynski, Jingyuan Wang, Lydia S Prokosch, Vasilios Polymeropoulos, Mihael H PolymeropoulosAbstract:Background: Most travelers experience Jet Lag Disorder (JLD) symptoms due to misalignment of their circadian rhythms with respect to the new time zone. We assessed the efficacy and safety of Tasimelteon (HETLIOZ®) in healthy participants using a laboratory model of JLD induced by an 8-h phase advance of the sleep-wake cycle (JET8 Study). We hypothesized that Tasimelteon treatment in participants experiencing JLD would cause increased sleep time, increased next-day alertness, and reduced next-day sleepiness. Methods: We undertook a randomized, double-blind, placebo-controlled trial in 12 US clinical research sleep centers. We screened healthy adults ages 18-73 years, who were eligible for the randomization phase of JET8 if they typically went to bed between 21:00 and 01:00, slept between 7 and 9 h each night, and slept at a consistent bedtime. We used block randomization stratified by site to assign participants (1:1) to receive a single oral dose of Tasimelteon (20 mg) or placebo 30 min before their 8-h phase-advanced bedtime. The primary endpoint was Total Sleep Time in the first 2/3 of the night (TST2/3), which was measured by polysomnography during the 8-h sleep episode, and assessed in the intent-to-treat population. The trial is completed and registered with ClinicalTrials.gov, NCT03373201. Results: Between October 16, 2017 and January 17, 2018, we screened 607 healthy participants for JET8, of whom 320 (53%) were assigned to receive Tasimelteon (n = 160) or placebo (n = 160). Tasimelteon treatment increased TST2/3 (primary endpoint) by 60.3 min (95%CI 44.0 to 76.7, P < 0.0001) and whole night TST by 85.5 min (95% CI 64.3 to 106.6, P < 0.0001), improved next day alertness, next day sleepiness, and shortened latency to persistent sleep by -15.1 min (95% CI -26.2 to -4.0, P = 0.0081). Conclusion: A single dose of Tasimelteon improves the primary symptoms of JLD, including nighttime insomnia and next day functioning among participants in a laboratory model of JLD simulating eastward trans-meridian travel by inducing an 8-h phase advance of the sleep-wake cycle.
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Tasimelteon hetlioz r effective in the treatment of jet lag disorder in an 8 hour phase advance a multicenter randomized double blind placebo controlled trial
medRxiv, 2020Co-Authors: Christos Polymeropoulos, Changfu Xiao, Gunther Birznieks, Michael A Mohrman, Madison S Keefe, Jennifer L Brzezynski, Jingyuan Wang, Lydia S Prokosch, Vasilios Polymeropoulos, Mihael H PolymeropoulosAbstract:Background: Travelers frequently experience Jet Lag Disorder (JLD) symptoms due to misalignment of the circadian rhythm with respect to the new time zone. In the JET8 Study, we assessed the efficacy and safety of Tasimelteon (HETLIOZ(R)) in healthy participants using a laboratory model of JLD induced by an 8-h phase advance of the sleep-wake cycle. We hypothesized that Tasimelteon treatment in participants experiencing JLD would cause increased sleep time, increased next-day alertness, and reduced next-day sleepiness. Methods: We undertook a randomized, double-blind, placebo-controlled trial in 12 US clinical research sleep centers. We screened healthy adults ages 18-73 years, who were eligible for the randomization phase of JET8 if they typically went to bed between 21:00 and 01:00, slept between 7-9 hours each night, and slept at a consistent bedtime. We used block randomization stratified by site to assign participants (1:1) to receive a single oral dose of Tasimelteon (20mg) or placebo 30 min before their 8-h phase-advanced bedtime. The primary endpoint was Total Sleep Time in the first 2/3 of the night (TST2/3), which was measured by polysomnography during the 8-h sleep episode, and assessed in the intent-to-treat population. The trial is completed and registered with ClinicalTrials.gov, NCT03373201. Results: Between October 16, 2017 and January 17, 2018, we screened 607 healthy participants for JET8, of whom 320 (53%) were assigned to receive Tasimelteon (n=160) or placebo (n=160). Tasimelteon treatment resulted in increased TST2/3 by 60.3 min (95%CI 44.0 to 76.7, P<0.0001) compared to placebo and had a highly significant benefit in secondary endpoints including TST of the whole night, next day alertness, next day sleepiness, and latency to persistent sleep. Conclusion: A single dose of Tasimelteon improves symptoms, including sleep and next day functioning in participants, following an 8-h phase advance of the sleep-wake cycle in a laboratory model of JLD simulating eastward trans-meridian travel.
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le Tasimelteon entraine l horloge circadienne et procure une amelioration significative aux personnes totalement aveugles souffrant du libre cours
Neurophysiologie Clinique-clinical Neurophysiology, 2015Co-Authors: Steven W Lockley, Rosarelis Torres, Christian Lavedan, Marlene Dressman, Xiao Changfu, Dennis M Fisher, Louis Licamele, Mihael H PolymeropoulosAbstract:Objectif Demontrer l’efficacite du Tasimelteon pour aider a synchroniser le rythme circadien de personnes totalement aveugles, souffrant du syndrome libre-cours. Methodes L’etude « Safety and Efficacy of Tasimelteon » (SET) est une recherche clinique multicentrique, a double insu, avec placebo pour traiter des patients totalement aveugles souffrant du syndrome libre-cours. Le rythme circadien etait determine a l’aide de la concentration urinaire du 6-sulfatoxymelatonine (aMT6s) et du cortisol. Les patients avec des plaintes de troubles du sommeil et un syndrome confirme de libre-cours ont ete inclus dans l’etude. Les patients prenaient tous les jours soit du Tasimelteon (20 mg), soit du placebo, pendant 6 mois, a heure fixe, 1 heure avant coucher. Le rythme circadien a ete reevalue 2 semaines apres le debut du traitement. Le sommeil subjectif de nuit et les siestes diurnes etaient notes chaque jour. Resultats Quatre-vingt-quatre patients (dont 35 femmes, âges de 21 a 84 ans) repartis aleatoirement et 79 etudies pour l’entrainement du rythme circadien. Plus de patients etaient entraines par le Tasimelteon que par le placebo, tel que mesure par l’aMT6s urinaire et l’heure de secretion du cortisol ( p = 0,0171 et p = 0,0313, respectivement). Le nombre de patients ayant une amelioration clinique etait plus grand pour le Tasimelteon et il y avait aussi une amelioration significative dans l’impression clinique globale de changement, ainsi que dans les mesures de 3 parametres du sommeil, en comparaison des patients sous placebo ( p Conclusion Le Tasimelteon entraine le rythme circadien chez des patients aveugles souffrant de libre-cours. Les patients traites avec le Tasimelteon ont aussi montre des ameliorations cliniques significatives dans les tests veille et sommeil, et dans leur fonctionnement global. Cette etude demontre que le Tasimelteon est un regulateur effectif du rythme circadien, capable d’entrainer l’horloge circadienne. Ces resultats amenent la preuve d’une amelioration directe et cliniquement significative pour les patients souffrant de libre-cours.
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Tasimelteon treatment entrains the circadian clock and demonstrates significant benefit on sleep and wake parameters in totally blind individuals with non 24 hour circadian rhythms
Sleep Medicine, 2013Co-Authors: Steven W Lockley, Louis Licamele, M Dressman, R Torres, C Lavedan, Mihael H PolymeropoulosAbstract:Introduction The majority of totally blind individuals exhibit non-24-h circadian rhythms due to light signals not reaching the suprachiasmatic nucleus, resulting in Non-24-h Sleep–Wake Disorder (Non-24), a serious circadian rhythm disorder with no approved treatment. Tasimelteon is a novel circadian regulator in development for Non-24 with selective agonist activity for melatonin MT1 and MT2 receptors. Materials and methods Two phase III placebo-controlled studies in blind Non-24 patients assessed safety, efficacy and maintenance of effect of Tasimelteon treatment (20 mg/day). Circadian period was assessed from urinary 6-sulfatoxymelatonin (aMT6s) and cortisol. Clinical assessments included a Non-24 Clinical Response Scale (N24CRS), nighttime sleep, daytime naps and Clinical Global Impression of Change (CGIC). Results Entrainment Study (SET) ( n = 84): Tasimelteon entrained the circadian clock (aMT6s: 20.0% vs. 2.6%; cortisol: 17.5% vs. 2.6%), had more clinical responders on the N24CRS (23.7 vs. 0%), improved CGIC (2.6% vs. 3.4), increased sleep in the worst quartile of nights (LQ-nTST) (57% vs. 17 min), and decreased nap duration in the worst quartile of days (UQ-dTSD) (46% vs. 18 min), compared to placebo ( p n = 20): Tasimelteon-entrained patients were randomized to continued treatment or placebo. Tasimelteon maintained entrainment compared to placebo (aMT6s: 90% vs. 20%; cortisol: 80% vs. 20%). In treated patients, nighttime sleep (LQ-nTST) increased, and daytime sleep (UQ-dTSD) decreased, by 67 and 59 min/day, respectively ( p Conclusion Tasimelteon entrained the circadian pacemaker in blind patients with Non-24, and caused significant clinical improvement in multiple measures of sleep, wake and global functioning. Discontinuation of Tasimelteon abolished circadian entrainment, resulting in an hour less sleep each night and an hour more sleep each day. These studies demonstrate that Tasimelteon is an effective circadian regulator, and that continued treatment is required to maintain entrainment and the resulting clinical benefits. Acknowledgements Support for the study was provided by Vanda Pharmaceuticals Inc. (ClinicalTrials.gov NCT01163032 and NCT01430754). Statistical and Analytical Support was provided by Dennis Fisher at ”P Less Than” company.
Gunther Birznieks - One of the best experts on this subject based on the ideXlab platform.
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Tasimelteon safely and effectively improves sleep in smith magenis syndrome a double blind randomized trial followed by an open label extension
Genetics in Medicine, 2021Co-Authors: Christos Polymeropoulos, Changfu Xiao, Michaela Fisher, Justin Brooks, Emily Czeisler, Mary M Gibson, Kailey Kite, Sandra Smieszek, Sarah H Elsea, Gunther BirznieksAbstract:Purpose To assess the efficacy of Tasimelteon to improve sleep in Smith-Magenis syndrome (SMS). Methods A 9-week, double-blind, randomized, two-period crossover study was conducted at four US clinical centers. Genetically confirmed patients with SMS, aged 3 to 39, with sleep complaints participated in the study. Patients were assigned to treatment with Tasimelteon or placebo in a 4-week crossover study with a 1-week washout between treatments. Eligible patients participated in an open-label study and were followed for >3 months. Results Improvement of sleep quality (DDSQ50) and total sleep time (DDTST50) on the worst 50% of nights were primary endpoints. Secondary measures included actigraphy and behavioral parameters. Over three years, 52 patients were screened, and 25 patients completed the randomized portion of the study. DDSQ50 significantly improved over placebo (0.4, p = 0.0139), and DDTST50 also improved (18.5 minutes, p = 0.0556). Average sleep quality (0.3, p = 0.0155) and actigraphy-based total sleep time (21.1 minutes, p = 0.0134) improved significantly, consistent with the primary outcomes. Patients treated for ≥90 days in the open-label study showed persistent efficacy. Adverse events were similar between placebo and Tasimelteon. Conclusion Tasimelteon safely and effectively improved sleep in SMS.
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simulated driving performance in healthy adults after night time administration of 20 mg Tasimelteon
Journal of Sleep Research, 2021Co-Authors: Rosarelis Torres, Changfu Xiao, Gunther Birznieks, Michaela Fisher, Christos Polymeropoulos, Gary G Kay, Mihael H PolymeropoulosAbstract:An impairment in next day driving performance has been reported for almost every drug currently United States Food and Drug Administration (FDA) approved for improvement of sleep in chronic and transient insomnia. Tasimelteon, a melatonin receptor agonist, demonstrated significant improvements in night-time sleep, daytime naps, and sleep timing in non-24-hr sleep-wake disorder (Non-24) by entraining these patients to a 24-hr day as measured by melatonin and cortisol rhythms. Given this new mechanism of action of entraining the biological clock, we conducted a study to evaluate the potential effect Tasimelteon may have on the ability to operate a motor vehicle. The study was conducted in 48 healthy adult subjects using a randomised, double-blind, placebo and active (zopiclone 7.5 mg) controlled study with a 3-period cross-over design. Driving performance was assessed by measuring standard deviation of lateral position (SDLP) using the validated Cognitive Research Corporation Driving Simulator-MiniSim. The difference in least square mean SDLP for Tasimelteon was 1.22 cm reflecting a non-significant increase in SDLP change from placebo (p = .1119). In contrast, treatment with the active control, zopiclone 7.5 mg, was associated with a meaningful and significant increase in SDLP, change from placebo for zopiclone was 4.14 cm (p < .0001). The lack of clinically meaningful and statistically significant finding with Tasimelteon was further supported by the symmetry analysis, which showed the distribution of within-subject differences between Tasimelteon and placebo was symmetric about zero. At the FDA-approved 20 mg dose to treat Non-24, Tasimelteon did not impair next-day driving performance compared to placebo in adult healthy volunteers.
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efficacy of Tasimelteon hetlioz in the treatment of jet lag disorder evaluated in an 8 h phase advance model a multicenter randomized double blind placebo controlled trial
Frontiers in Neurology, 2020Co-Authors: Christos Polymeropoulos, Changfu Xiao, Gunther Birznieks, Michael A Mohrman, Madison S Keefe, Jennifer L Brzezynski, Jingyuan Wang, Lydia S Prokosch, Vasilios Polymeropoulos, Mihael H PolymeropoulosAbstract:Background: Most travelers experience Jet Lag Disorder (JLD) symptoms due to misalignment of their circadian rhythms with respect to the new time zone. We assessed the efficacy and safety of Tasimelteon (HETLIOZ®) in healthy participants using a laboratory model of JLD induced by an 8-h phase advance of the sleep-wake cycle (JET8 Study). We hypothesized that Tasimelteon treatment in participants experiencing JLD would cause increased sleep time, increased next-day alertness, and reduced next-day sleepiness. Methods: We undertook a randomized, double-blind, placebo-controlled trial in 12 US clinical research sleep centers. We screened healthy adults ages 18-73 years, who were eligible for the randomization phase of JET8 if they typically went to bed between 21:00 and 01:00, slept between 7 and 9 h each night, and slept at a consistent bedtime. We used block randomization stratified by site to assign participants (1:1) to receive a single oral dose of Tasimelteon (20 mg) or placebo 30 min before their 8-h phase-advanced bedtime. The primary endpoint was Total Sleep Time in the first 2/3 of the night (TST2/3), which was measured by polysomnography during the 8-h sleep episode, and assessed in the intent-to-treat population. The trial is completed and registered with ClinicalTrials.gov, NCT03373201. Results: Between October 16, 2017 and January 17, 2018, we screened 607 healthy participants for JET8, of whom 320 (53%) were assigned to receive Tasimelteon (n = 160) or placebo (n = 160). Tasimelteon treatment increased TST2/3 (primary endpoint) by 60.3 min (95%CI 44.0 to 76.7, P < 0.0001) and whole night TST by 85.5 min (95% CI 64.3 to 106.6, P < 0.0001), improved next day alertness, next day sleepiness, and shortened latency to persistent sleep by -15.1 min (95% CI -26.2 to -4.0, P = 0.0081). Conclusion: A single dose of Tasimelteon improves the primary symptoms of JLD, including nighttime insomnia and next day functioning among participants in a laboratory model of JLD simulating eastward trans-meridian travel by inducing an 8-h phase advance of the sleep-wake cycle.
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Tasimelteon hetlioz r effective in the treatment of jet lag disorder in an 8 hour phase advance a multicenter randomized double blind placebo controlled trial
medRxiv, 2020Co-Authors: Christos Polymeropoulos, Changfu Xiao, Gunther Birznieks, Michael A Mohrman, Madison S Keefe, Jennifer L Brzezynski, Jingyuan Wang, Lydia S Prokosch, Vasilios Polymeropoulos, Mihael H PolymeropoulosAbstract:Background: Travelers frequently experience Jet Lag Disorder (JLD) symptoms due to misalignment of the circadian rhythm with respect to the new time zone. In the JET8 Study, we assessed the efficacy and safety of Tasimelteon (HETLIOZ(R)) in healthy participants using a laboratory model of JLD induced by an 8-h phase advance of the sleep-wake cycle. We hypothesized that Tasimelteon treatment in participants experiencing JLD would cause increased sleep time, increased next-day alertness, and reduced next-day sleepiness. Methods: We undertook a randomized, double-blind, placebo-controlled trial in 12 US clinical research sleep centers. We screened healthy adults ages 18-73 years, who were eligible for the randomization phase of JET8 if they typically went to bed between 21:00 and 01:00, slept between 7-9 hours each night, and slept at a consistent bedtime. We used block randomization stratified by site to assign participants (1:1) to receive a single oral dose of Tasimelteon (20mg) or placebo 30 min before their 8-h phase-advanced bedtime. The primary endpoint was Total Sleep Time in the first 2/3 of the night (TST2/3), which was measured by polysomnography during the 8-h sleep episode, and assessed in the intent-to-treat population. The trial is completed and registered with ClinicalTrials.gov, NCT03373201. Results: Between October 16, 2017 and January 17, 2018, we screened 607 healthy participants for JET8, of whom 320 (53%) were assigned to receive Tasimelteon (n=160) or placebo (n=160). Tasimelteon treatment resulted in increased TST2/3 by 60.3 min (95%CI 44.0 to 76.7, P<0.0001) compared to placebo and had a highly significant benefit in secondary endpoints including TST of the whole night, next day alertness, next day sleepiness, and latency to persistent sleep. Conclusion: A single dose of Tasimelteon improves symptoms, including sleep and next day functioning in participants, following an 8-h phase advance of the sleep-wake cycle in a laboratory model of JLD simulating eastward trans-meridian travel.
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melatonin agonist Tasimelteon vec 162 for transient insomnia after sleep time shift two randomized controlled multicentre trials
Obstetrical & Gynecological Survey, 2009Co-Authors: Shantha M W Rajaratnam, Dennis M Fisher, Mihael H Polymeropoulos, Thomas Roth, Christin Scott, Gunther Birznieks, Elizabeth B KlermanAbstract:Substantial evidence suggests that exogenous melatonin and melatonin agonists promote sleep and entrain endogenous circadian rhythms. Two previous meta-analyses evaluated the efficacy of melatonin treatment in patients with secondary sleep disorders or circadian rhythm sleep disorders and reached opposite conclusions on efficacy. This study presents the results of 2 randomized, double-blind, placebo-controlled, parallel-group trials, which evaluated Tasimelteon (VEC-162), a novel melatonin agonist, in a model of transient insomnia induced by a 5-hour advance in the sleep-wake schedule. The investigators hypothesized that the melatonin agonist would reduce the sleep disruption produced by transient insomnia and readjust circadian rhythms. The study subjects in the phase II study were 39 healthy individuals who were randomized to receive either Tasimelteon (in doses of 10 [n = 9], 20 [n = 8], 50 [n = 7], or 100 mg [n = 7]) or placebo (n = 8) 30 minute before bedtime. The plasma melatonin concentration was measured for circadian phase assessment. The study subjects in the phase III study were 411 healthy individuals who were randomized to receive either Tasimelteon (20 [n = 100], 50 [n = 102], or 100 mg [n = 106]) or placebo (n = 103) 30 minute before bedtime. Changes in sleep patterns were assessed by polysomnography in the phase II and III studies with prespecified primary efficacy outcomes. Safety was assessed by daily queries about adverse events and physical examinations. In the phase II study, compared with placebo, Tasimelteon increased sleep efficiency and duration, and reduced sleep latency and latency to persistent sleep. There was a dose-dependent shift in plasma melatonin to an earlier hour associated with treatment. In addition to improvements in sleep latency, efficiency, duration, and latency to persistent sleep, treated-individuals in the phase III study had reduced wake after sleep onset (improved sleep maintenance). The frequency and severity of adverse events were low and similar among all treatment groups. These findings indicate that Tasimelteon improves sleep initiation and maintenance simultaneously with a shift in endogenous circadian rhythms and has therapeutic potential for transient insomnia associated with circadian rhythm sleep disorders.
Changfu Xiao - One of the best experts on this subject based on the ideXlab platform.
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Tasimelteon safely and effectively improves sleep in smith magenis syndrome a double blind randomized trial followed by an open label extension
Genetics in Medicine, 2021Co-Authors: Christos Polymeropoulos, Changfu Xiao, Michaela Fisher, Justin Brooks, Emily Czeisler, Mary M Gibson, Kailey Kite, Sandra Smieszek, Sarah H Elsea, Gunther BirznieksAbstract:Purpose To assess the efficacy of Tasimelteon to improve sleep in Smith-Magenis syndrome (SMS). Methods A 9-week, double-blind, randomized, two-period crossover study was conducted at four US clinical centers. Genetically confirmed patients with SMS, aged 3 to 39, with sleep complaints participated in the study. Patients were assigned to treatment with Tasimelteon or placebo in a 4-week crossover study with a 1-week washout between treatments. Eligible patients participated in an open-label study and were followed for >3 months. Results Improvement of sleep quality (DDSQ50) and total sleep time (DDTST50) on the worst 50% of nights were primary endpoints. Secondary measures included actigraphy and behavioral parameters. Over three years, 52 patients were screened, and 25 patients completed the randomized portion of the study. DDSQ50 significantly improved over placebo (0.4, p = 0.0139), and DDTST50 also improved (18.5 minutes, p = 0.0556). Average sleep quality (0.3, p = 0.0155) and actigraphy-based total sleep time (21.1 minutes, p = 0.0134) improved significantly, consistent with the primary outcomes. Patients treated for ≥90 days in the open-label study showed persistent efficacy. Adverse events were similar between placebo and Tasimelteon. Conclusion Tasimelteon safely and effectively improved sleep in SMS.
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simulated driving performance in healthy adults after night time administration of 20 mg Tasimelteon
Journal of Sleep Research, 2021Co-Authors: Rosarelis Torres, Changfu Xiao, Gunther Birznieks, Michaela Fisher, Christos Polymeropoulos, Gary G Kay, Mihael H PolymeropoulosAbstract:An impairment in next day driving performance has been reported for almost every drug currently United States Food and Drug Administration (FDA) approved for improvement of sleep in chronic and transient insomnia. Tasimelteon, a melatonin receptor agonist, demonstrated significant improvements in night-time sleep, daytime naps, and sleep timing in non-24-hr sleep-wake disorder (Non-24) by entraining these patients to a 24-hr day as measured by melatonin and cortisol rhythms. Given this new mechanism of action of entraining the biological clock, we conducted a study to evaluate the potential effect Tasimelteon may have on the ability to operate a motor vehicle. The study was conducted in 48 healthy adult subjects using a randomised, double-blind, placebo and active (zopiclone 7.5 mg) controlled study with a 3-period cross-over design. Driving performance was assessed by measuring standard deviation of lateral position (SDLP) using the validated Cognitive Research Corporation Driving Simulator-MiniSim. The difference in least square mean SDLP for Tasimelteon was 1.22 cm reflecting a non-significant increase in SDLP change from placebo (p = .1119). In contrast, treatment with the active control, zopiclone 7.5 mg, was associated with a meaningful and significant increase in SDLP, change from placebo for zopiclone was 4.14 cm (p < .0001). The lack of clinically meaningful and statistically significant finding with Tasimelteon was further supported by the symmetry analysis, which showed the distribution of within-subject differences between Tasimelteon and placebo was symmetric about zero. At the FDA-approved 20 mg dose to treat Non-24, Tasimelteon did not impair next-day driving performance compared to placebo in adult healthy volunteers.
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efficacy of Tasimelteon hetlioz in the treatment of jet lag disorder evaluated in an 8 h phase advance model a multicenter randomized double blind placebo controlled trial
Frontiers in Neurology, 2020Co-Authors: Christos Polymeropoulos, Changfu Xiao, Gunther Birznieks, Michael A Mohrman, Madison S Keefe, Jennifer L Brzezynski, Jingyuan Wang, Lydia S Prokosch, Vasilios Polymeropoulos, Mihael H PolymeropoulosAbstract:Background: Most travelers experience Jet Lag Disorder (JLD) symptoms due to misalignment of their circadian rhythms with respect to the new time zone. We assessed the efficacy and safety of Tasimelteon (HETLIOZ®) in healthy participants using a laboratory model of JLD induced by an 8-h phase advance of the sleep-wake cycle (JET8 Study). We hypothesized that Tasimelteon treatment in participants experiencing JLD would cause increased sleep time, increased next-day alertness, and reduced next-day sleepiness. Methods: We undertook a randomized, double-blind, placebo-controlled trial in 12 US clinical research sleep centers. We screened healthy adults ages 18-73 years, who were eligible for the randomization phase of JET8 if they typically went to bed between 21:00 and 01:00, slept between 7 and 9 h each night, and slept at a consistent bedtime. We used block randomization stratified by site to assign participants (1:1) to receive a single oral dose of Tasimelteon (20 mg) or placebo 30 min before their 8-h phase-advanced bedtime. The primary endpoint was Total Sleep Time in the first 2/3 of the night (TST2/3), which was measured by polysomnography during the 8-h sleep episode, and assessed in the intent-to-treat population. The trial is completed and registered with ClinicalTrials.gov, NCT03373201. Results: Between October 16, 2017 and January 17, 2018, we screened 607 healthy participants for JET8, of whom 320 (53%) were assigned to receive Tasimelteon (n = 160) or placebo (n = 160). Tasimelteon treatment increased TST2/3 (primary endpoint) by 60.3 min (95%CI 44.0 to 76.7, P < 0.0001) and whole night TST by 85.5 min (95% CI 64.3 to 106.6, P < 0.0001), improved next day alertness, next day sleepiness, and shortened latency to persistent sleep by -15.1 min (95% CI -26.2 to -4.0, P = 0.0081). Conclusion: A single dose of Tasimelteon improves the primary symptoms of JLD, including nighttime insomnia and next day functioning among participants in a laboratory model of JLD simulating eastward trans-meridian travel by inducing an 8-h phase advance of the sleep-wake cycle.
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Tasimelteon hetlioz r effective in the treatment of jet lag disorder in an 8 hour phase advance a multicenter randomized double blind placebo controlled trial
medRxiv, 2020Co-Authors: Christos Polymeropoulos, Changfu Xiao, Gunther Birznieks, Michael A Mohrman, Madison S Keefe, Jennifer L Brzezynski, Jingyuan Wang, Lydia S Prokosch, Vasilios Polymeropoulos, Mihael H PolymeropoulosAbstract:Background: Travelers frequently experience Jet Lag Disorder (JLD) symptoms due to misalignment of the circadian rhythm with respect to the new time zone. In the JET8 Study, we assessed the efficacy and safety of Tasimelteon (HETLIOZ(R)) in healthy participants using a laboratory model of JLD induced by an 8-h phase advance of the sleep-wake cycle. We hypothesized that Tasimelteon treatment in participants experiencing JLD would cause increased sleep time, increased next-day alertness, and reduced next-day sleepiness. Methods: We undertook a randomized, double-blind, placebo-controlled trial in 12 US clinical research sleep centers. We screened healthy adults ages 18-73 years, who were eligible for the randomization phase of JET8 if they typically went to bed between 21:00 and 01:00, slept between 7-9 hours each night, and slept at a consistent bedtime. We used block randomization stratified by site to assign participants (1:1) to receive a single oral dose of Tasimelteon (20mg) or placebo 30 min before their 8-h phase-advanced bedtime. The primary endpoint was Total Sleep Time in the first 2/3 of the night (TST2/3), which was measured by polysomnography during the 8-h sleep episode, and assessed in the intent-to-treat population. The trial is completed and registered with ClinicalTrials.gov, NCT03373201. Results: Between October 16, 2017 and January 17, 2018, we screened 607 healthy participants for JET8, of whom 320 (53%) were assigned to receive Tasimelteon (n=160) or placebo (n=160). Tasimelteon treatment resulted in increased TST2/3 by 60.3 min (95%CI 44.0 to 76.7, P<0.0001) compared to placebo and had a highly significant benefit in secondary endpoints including TST of the whole night, next day alertness, next day sleepiness, and latency to persistent sleep. Conclusion: A single dose of Tasimelteon improves symptoms, including sleep and next day functioning in participants, following an 8-h phase advance of the sleep-wake cycle in a laboratory model of JLD simulating eastward trans-meridian travel.
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Tasimelteon for non 24 hour sleep wake disorder in totally blind people set and reset two multicentre randomised double masked placebo controlled phase 3 trials
The Lancet, 2015Co-Authors: Marlene Dressman, Steven W Lockley, Dennis M Fisher, Louis Licamele, Changfu Xiao, Erin E Flynnevans, Joseph T HullAbstract:Summary Background Most totally blind people have non-24-hour sleep–wake disorder (non-24), a rare circadian rhythm disorder caused by an inability of light to reset their circadian pacemaker. In two consecutive placebo-controlled trials (SET and RESET), we assessed safety and efficacy (in terms of circadian entrainment and maintenance) of once-daily Tasimelteon, a novel dual-melatonin receptor agonist. Methods We undertook the placebo-controlled, randomised, double-masked trials in 27 US and six German clinical research centres and sleep centres. We screened totally blind adults (18–75 years of age), who were eligible for the randomisation phase of SET if they had a non-24-hour circadian period (τ) of 24·25 h or longer (95% CI greater than 24·0 and up to 24·9 h), as calculated from measurements of urinary 6-sulphatoxymelatonin rhythms. For SET, we used block randomisation to assign patients (1:1) to receive Tasimelteon (20 mg) or placebo every 24 h at a fixed clock time 1 h before target bedtime for 26 weeks. Patients who entered the open-label group receiving Tasimelteon in SET or who did not meet the SET inclusion criteria but did meet the RESET inclusion criteria were screened for RESET. A subset of the patients who entered the open-label group before the RESET study and who had eligible τ values were screened for RESET after completing the open-label treatment. In RESET, we withdrew Tasimelteon in a randomised manner (1:1) in patients who responded (ie, entrained) after a Tasimelteon run-in period. Entrainment was defined as having τ of 24·1 h or less and a 95% CI that included 24·0 h. In SET, the primary endpoint was the proportion of entrained patients, assessed in the intention-to-treat population. The planned step-down primary endpoint assessed the proportion of patients who had a clinical response (entrainment at month 1 or month 7 plus clinical improvement, measured by the Non-24 Clinical Response Scale). In RESET, the primary endpoint was the proportion of non-entrained patients, assessed in the intention-to-treat population. Safety assessments included adverse events and clinical laboratory measures, assessed in all treated patients. These trials are registered with ClinicalTrials.gov, numbers NCT01163032 and NCT01430754. Findings Between Aug 25, 2010, and July 5, 2012, we screened 391 totally blind patients for SET, of whom 84 (22%) were assigned to receive Tasimelteon (n=42) or placebo (n=42). Two patients in the Tasimelteon group and four in the placebo group discontinued the study before τ was measured, due to adverse events, withdrawal of consent, and a protocol deviation. Circadian entrainment occurred in eight (20%) of 40 patients in the Tasimelteon group compared with one (3%) of 38 patients in the placebo group at month 1 (difference 17%, 95% CI 3·2–31·6; p=0·0171). Nine (24%) of 38 patients showed a clinical response, compared with none of 34 in the placebo group (difference 24%, 95% CI 8·4–39·0; p=0·0028). Between Sept 15, 2011, and Oct 4, 2012, we screened 58 patients for eligibility in RESET, 48 (83%) of whom had τ assessed and entered the open-label Tasimelteon run-in phase. 24 (50%) patients entrained, and 20 (34%) were enrolled in the randomisation phase. Two (20%) of ten patients who were withdrawn to placebo remained entrained compared with nine (90%) of ten who continued to receive Tasimelteon (difference 70%, 95% CI 26·4–100·0; p=0·0026). No deaths were reported in either study, and discontinuation rates due to adverse events were comparable between the Tasimelteon (3 [6%] of 52 patients) and placebo (2 [4%] of 52 patients) treatment courses. The most common side-effects associated with Tasimelteon in SET were headache (7 [17%] of 42 patients given Tasimelteon vs 3 [7%] of 42 patients given placebo), elevated liver enzymes (4 [10%] vs 2 [5%]), nightmares or abnormal dreams (4 [10%] vs none), upper respiratory tract infection (3 [7%] vs none], and urinary tract infections (3 [7%] vs 1 [2%]). Interpretation Once-daily Tasimelteon can entrain totally blind people with non-24; however, continued Tasimelteon treatment is necessary to maintain these improvements. Funding Vanda Pharmaceuticals.
Christos Polymeropoulos - One of the best experts on this subject based on the ideXlab platform.
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Tasimelteon safely and effectively improves sleep in smith magenis syndrome a double blind randomized trial followed by an open label extension
Genetics in Medicine, 2021Co-Authors: Christos Polymeropoulos, Changfu Xiao, Michaela Fisher, Justin Brooks, Emily Czeisler, Mary M Gibson, Kailey Kite, Sandra Smieszek, Sarah H Elsea, Gunther BirznieksAbstract:Purpose To assess the efficacy of Tasimelteon to improve sleep in Smith-Magenis syndrome (SMS). Methods A 9-week, double-blind, randomized, two-period crossover study was conducted at four US clinical centers. Genetically confirmed patients with SMS, aged 3 to 39, with sleep complaints participated in the study. Patients were assigned to treatment with Tasimelteon or placebo in a 4-week crossover study with a 1-week washout between treatments. Eligible patients participated in an open-label study and were followed for >3 months. Results Improvement of sleep quality (DDSQ50) and total sleep time (DDTST50) on the worst 50% of nights were primary endpoints. Secondary measures included actigraphy and behavioral parameters. Over three years, 52 patients were screened, and 25 patients completed the randomized portion of the study. DDSQ50 significantly improved over placebo (0.4, p = 0.0139), and DDTST50 also improved (18.5 minutes, p = 0.0556). Average sleep quality (0.3, p = 0.0155) and actigraphy-based total sleep time (21.1 minutes, p = 0.0134) improved significantly, consistent with the primary outcomes. Patients treated for ≥90 days in the open-label study showed persistent efficacy. Adverse events were similar between placebo and Tasimelteon. Conclusion Tasimelteon safely and effectively improved sleep in SMS.
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simulated driving performance in healthy adults after night time administration of 20 mg Tasimelteon
Journal of Sleep Research, 2021Co-Authors: Rosarelis Torres, Changfu Xiao, Gunther Birznieks, Michaela Fisher, Christos Polymeropoulos, Gary G Kay, Mihael H PolymeropoulosAbstract:An impairment in next day driving performance has been reported for almost every drug currently United States Food and Drug Administration (FDA) approved for improvement of sleep in chronic and transient insomnia. Tasimelteon, a melatonin receptor agonist, demonstrated significant improvements in night-time sleep, daytime naps, and sleep timing in non-24-hr sleep-wake disorder (Non-24) by entraining these patients to a 24-hr day as measured by melatonin and cortisol rhythms. Given this new mechanism of action of entraining the biological clock, we conducted a study to evaluate the potential effect Tasimelteon may have on the ability to operate a motor vehicle. The study was conducted in 48 healthy adult subjects using a randomised, double-blind, placebo and active (zopiclone 7.5 mg) controlled study with a 3-period cross-over design. Driving performance was assessed by measuring standard deviation of lateral position (SDLP) using the validated Cognitive Research Corporation Driving Simulator-MiniSim. The difference in least square mean SDLP for Tasimelteon was 1.22 cm reflecting a non-significant increase in SDLP change from placebo (p = .1119). In contrast, treatment with the active control, zopiclone 7.5 mg, was associated with a meaningful and significant increase in SDLP, change from placebo for zopiclone was 4.14 cm (p < .0001). The lack of clinically meaningful and statistically significant finding with Tasimelteon was further supported by the symmetry analysis, which showed the distribution of within-subject differences between Tasimelteon and placebo was symmetric about zero. At the FDA-approved 20 mg dose to treat Non-24, Tasimelteon did not impair next-day driving performance compared to placebo in adult healthy volunteers.
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efficacy of Tasimelteon hetlioz in the treatment of jet lag disorder evaluated in an 8 h phase advance model a multicenter randomized double blind placebo controlled trial
Frontiers in Neurology, 2020Co-Authors: Christos Polymeropoulos, Changfu Xiao, Gunther Birznieks, Michael A Mohrman, Madison S Keefe, Jennifer L Brzezynski, Jingyuan Wang, Lydia S Prokosch, Vasilios Polymeropoulos, Mihael H PolymeropoulosAbstract:Background: Most travelers experience Jet Lag Disorder (JLD) symptoms due to misalignment of their circadian rhythms with respect to the new time zone. We assessed the efficacy and safety of Tasimelteon (HETLIOZ®) in healthy participants using a laboratory model of JLD induced by an 8-h phase advance of the sleep-wake cycle (JET8 Study). We hypothesized that Tasimelteon treatment in participants experiencing JLD would cause increased sleep time, increased next-day alertness, and reduced next-day sleepiness. Methods: We undertook a randomized, double-blind, placebo-controlled trial in 12 US clinical research sleep centers. We screened healthy adults ages 18-73 years, who were eligible for the randomization phase of JET8 if they typically went to bed between 21:00 and 01:00, slept between 7 and 9 h each night, and slept at a consistent bedtime. We used block randomization stratified by site to assign participants (1:1) to receive a single oral dose of Tasimelteon (20 mg) or placebo 30 min before their 8-h phase-advanced bedtime. The primary endpoint was Total Sleep Time in the first 2/3 of the night (TST2/3), which was measured by polysomnography during the 8-h sleep episode, and assessed in the intent-to-treat population. The trial is completed and registered with ClinicalTrials.gov, NCT03373201. Results: Between October 16, 2017 and January 17, 2018, we screened 607 healthy participants for JET8, of whom 320 (53%) were assigned to receive Tasimelteon (n = 160) or placebo (n = 160). Tasimelteon treatment increased TST2/3 (primary endpoint) by 60.3 min (95%CI 44.0 to 76.7, P < 0.0001) and whole night TST by 85.5 min (95% CI 64.3 to 106.6, P < 0.0001), improved next day alertness, next day sleepiness, and shortened latency to persistent sleep by -15.1 min (95% CI -26.2 to -4.0, P = 0.0081). Conclusion: A single dose of Tasimelteon improves the primary symptoms of JLD, including nighttime insomnia and next day functioning among participants in a laboratory model of JLD simulating eastward trans-meridian travel by inducing an 8-h phase advance of the sleep-wake cycle.
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Tasimelteon hetlioz r effective in the treatment of jet lag disorder in an 8 hour phase advance a multicenter randomized double blind placebo controlled trial
medRxiv, 2020Co-Authors: Christos Polymeropoulos, Changfu Xiao, Gunther Birznieks, Michael A Mohrman, Madison S Keefe, Jennifer L Brzezynski, Jingyuan Wang, Lydia S Prokosch, Vasilios Polymeropoulos, Mihael H PolymeropoulosAbstract:Background: Travelers frequently experience Jet Lag Disorder (JLD) symptoms due to misalignment of the circadian rhythm with respect to the new time zone. In the JET8 Study, we assessed the efficacy and safety of Tasimelteon (HETLIOZ(R)) in healthy participants using a laboratory model of JLD induced by an 8-h phase advance of the sleep-wake cycle. We hypothesized that Tasimelteon treatment in participants experiencing JLD would cause increased sleep time, increased next-day alertness, and reduced next-day sleepiness. Methods: We undertook a randomized, double-blind, placebo-controlled trial in 12 US clinical research sleep centers. We screened healthy adults ages 18-73 years, who were eligible for the randomization phase of JET8 if they typically went to bed between 21:00 and 01:00, slept between 7-9 hours each night, and slept at a consistent bedtime. We used block randomization stratified by site to assign participants (1:1) to receive a single oral dose of Tasimelteon (20mg) or placebo 30 min before their 8-h phase-advanced bedtime. The primary endpoint was Total Sleep Time in the first 2/3 of the night (TST2/3), which was measured by polysomnography during the 8-h sleep episode, and assessed in the intent-to-treat population. The trial is completed and registered with ClinicalTrials.gov, NCT03373201. Results: Between October 16, 2017 and January 17, 2018, we screened 607 healthy participants for JET8, of whom 320 (53%) were assigned to receive Tasimelteon (n=160) or placebo (n=160). Tasimelteon treatment resulted in increased TST2/3 by 60.3 min (95%CI 44.0 to 76.7, P<0.0001) compared to placebo and had a highly significant benefit in secondary endpoints including TST of the whole night, next day alertness, next day sleepiness, and latency to persistent sleep. Conclusion: A single dose of Tasimelteon improves symptoms, including sleep and next day functioning in participants, following an 8-h phase advance of the sleep-wake cycle in a laboratory model of JLD simulating eastward trans-meridian travel.
Paolo Baroldi - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of the Dual Melatonin Receptor Agonist Tasimelteon in Subjects With Hepatic or Renal Impairment
2016Co-Authors: Rosarelis Torres, William G. Kramer, Paolo BaroldiAbstract:Tasimelteon is a circadian regulator that resets themaster clock in the suprachiasmatic nuclei of the hypothalamus by binding to bothmelatonin MT1 and MT2 receptors making it a dual melatonin receptor agonist. Tasimelteon has been approved by the United States Food and Drug Administration for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24). Two prospective, single-center, open-label studies evaluated the pharmacokinetics of Tasimelteon and its main metabolites after a single 20mg dose administered to subjects with mild or moderate hepatic impairment or severe renal impairment, including subjects on dialysis compared to healthy controls. In subjects with mild or moderate hepatic impairment, exposure to Tasimelteon after a single 20mg dose, as measured by area under the plasma concentration-time curve to infinity, was increased by approximately 2-fold. There was no apparent relationship between Tasimelteon clearance and renal function. No safety concerns were apparent in either study. Based on these results, the changes in the pharmacokinetics of Tasimelteon due to mild or moderate hepatic or severe renal impairment are not considered clinically relevant, and no dose adjustment is necessary in these patients. Keywords Tasimelteon, dual melatonin receptor agonists, pharmacokinetics, renal function impairment, hepatic function impairment The endogenous circadian pacemaker resides in the suprachiasmatic nucleus (SCN) of the hypothalamus, and its function is to regulate biological functions in a
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clinical assessment of drug drug interactions of Tasimelteon a novel dual melatonin receptor agonist
The Journal of Clinical Pharmacology, 2015Co-Authors: Brian W Ogilvie, Rosarelis Torres, William G. Kramer, Marlene Dressman, Paolo BaroldiAbstract:Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual melatonin receptor agonist that demonstrates specificity and high affinity for melatonin receptor types 1 and 2 (MT1 and MT2 receptors), is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. Tasimelteon is rapidly absorbed, with a mean absolute bioavailability of approximately 38%, and is extensively metabolized primarily by oxidation at multiple sites, mainly by cytochrome P450 (CYP) 1A2 and CYP3A4/5, as initially demonstrated by in vitro studies and confirmed by the results of clinical drug–drug interactions presented here. The effects of strong inhibitors and moderate or strong inducers of CYP1A2 and CYP3A4/5 on the pharmacokinetics of Tasimelteon were evaluated in humans. Coadministration with fluvoxamine resulted in an approximately 6.5-fold increase in Tasimelteon's area under the curve (AUC), whereas cigarette smoking decreased Tasimelteon's exposure by approximately 40%. Coadministration with ketoconazole resulted in an approximately 54% increase in Tasimelteon's AUC, whereas rifampin pretreatment resulted in a decrease in Tasimelteon's exposure of approximately 89%.
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Pharmacokinetics of the dual melatonin receptor agonist Tasimelteon in subjects with hepatic or renal impairment.
The Journal of Clinical Pharmacology, 2015Co-Authors: Rosarelis Torres, William G. Kramer, Paolo BaroldiAbstract:Tasimelteon is a circadian regulator that resets the master clock in the suprachiasmatic nuclei of the hypothalamus by binding to both melatonin MT1 and MT2 receptors making it a dual melatonin receptor agonist. Tasimelteon has been approved by the United States Food and Drug Administration for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24). Two prospective, single-center, open-label studies evaluated the pharmacokinetics of Tasimelteon and its main metabolites after a single 20 mg dose administered to subjects with mild or moderate hepatic impairment or severe renal impairment, including subjects on dialysis compared to healthy controls. In subjects with mild or moderate hepatic impairment, exposure to Tasimelteon after a single 20 mg dose, as measured by area under the plasma concentration-time curve to infinity, was increased by approximately 2-fold. There was no apparent relationship between Tasimelteon clearance and renal function. No safety concerns were apparent in either study. Based on these results, the changes in the pharmacokinetics of Tasimelteon due to mild or moderate hepatic or severe renal impairment are not considered clinically relevant, and no dose adjustment is necessary in these patients.
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Absolute Bioavailability of Tasimelteon.
American journal of therapeutics, 2015Co-Authors: Rosarelis Torres, William G. Kramer, Paolo BaroldiAbstract: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.
