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Jasper Dingemanse - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacological Interactions between the Dual Orexin Receptor Antagonist Daridorexant and Ethanol in a Double-Blind, Randomized, Placebo-Controlled, Double-Dummy, Four-Way Crossover Phase I Study in Healthy Subjects
    CNS Drugs, 2020
    Co-Authors: Benjamin Berger, Clemens Muehlan, Sander Brooks, Rob Zuiker, Muriel Richard, Jasper Dingemanse
    Abstract:

    Background Daridorexant (ACT-541468) is a potent dual Orexin Receptor Antagonist under development for the treatment of sleep disorders. Concomitant intake of ethanol and hypnotics has been shown to result in additive/supra-additive depression of the central nervous system, resulting in pronounced sedation. Objective The aim of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between ethanol and daridorexant. Method This was a single-center, double-blind, placebo-controlled, randomized, four-way crossover study conducted in 19 healthy male/female subjects. Subjects received the following four treatments: ethanol with daridorexant, daridorexant alone, ethanol alone, and placebo. Daridorexant 50 mg and the matching placebo were administered as single oral tablets. Ethanol was infused intravenously and clamped at a level of 0.6 g/L for 5 h. The PK of ethanol and daridorexant were assessed and a battery of PD tests performed. Results Concomitant administration of ethanol prolonged the time to reach maximum plasma concentrations ( t _max) of daridorexant (median difference 1.25 h). No other relevant PK interactions were observed. Coadministration with ethanol produced a numerically greater impairment on saccadic peak velocity, body sway, visual analog scale (VAS) alertness, VAS alcohol intoxication, smooth pursuit, and adaptive tracking compared with daridorexant alone. All treatments were generally well tolerated without serious adverse events (AEs). The most commonly reported treatment-emergent AEs following coadministration of daridorexant and ethanol included somnolence, headache, fatigue, sudden onset of sleep, and dizziness. Conclusions Apart from a shift in t _max, no relevant changes in PK parameters were observed following coadministration of daridorexant and ethanol. The coadministration led to reinforced drug actions that were, at most, indicative of infra-additive effects on certain PD markers. Patients will be advised not to consume ethanol with daridorexant. Clinical Trials Registration number: NCT03609775 (ClinicalTrials.gov Identifier)

  • Clinical pharmacology, efficacy, and safety of Orexin Receptor Antagonists for the treatment of insomnia disorders.
    Expert Opinion on Drug Metabolism & Toxicology, 2020
    Co-Authors: Clemens Muehlan, Isabelle Zenklusen, Cedric Vaillant, Stephan Kraehenbuehl, Jasper Dingemanse
    Abstract:

    The last two decades have witnessed a rapid increase in the knowledge about the role of the Orexin system, particularly in the regulation of wakefulness and arousal. Dual Orexin Receptor Antagonist...

  • The dual Orexin Receptor Antagonist daridorexant does not affect the pharmacokinetics of the BCRP substrate rosuvastatin.
    Clinical and Experimental Pharmacology and Physiology, 2020
    Co-Authors: Isabelle Zenklusen, Clemens Muehlan, Ivan Ulc, Jiří Liška, Jasper Dingemanse
    Abstract:

    Daridorexant is a dual Orexin Receptor Antagonist in clinical development for the treatment of insomnia. Breast-cancer resistant protein (BCRP) is an efflux pump expressed in intestinal epithelium and hepatocytes, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds. In vitro, daridorexant inhibits BCRP with an IC50 of 3.0 μmol/L. The BCRP substrate rosuvastatin is a cholesterol-lowering drug, recommended for clinical drug-drug interaction (DDI) studies. In order to exclude an inhibitory effect of daridorexant on BCRP, this single-centre, open-label, two-treatment Phase 1 study investigated the effect of daridorexant at steady state on the pharmacokinetics (PK) of single-dose rosuvastatin in 20 healthy male subjects. In addition, safety and tolerability were assessed. A single oral dose of 10 mg rosuvastatin on Day 1 was followed by 96 hours observation. Thereafter, 25 mg daridorexant was administered once daily (o.d.) on Days 5-8 and in combination with 10 mg rosuvastatin on Day 8. On Days 9-12, subjects received 25 mg daridorexant alone. PK sampling was performed up to 120 hours after treatment administration. The results showed that concomitant administration of 25 mg daridorexant o.d. at steady state did not affect the exposure parameters of rosuvastatin in a relevant way, as indicated by the ratios of geometric means (GMRs) ([rosuvastatin + daridorexant]/[rosuvastatin alone]) of 0.93 for both Cmax and AUC0-∞ . Administration of a single dose of 10 mg rosuvastatin, multiple doses of 25 mg daridorexant alone or in combination were well tolerated. Taken together, daridorexant and BCRP substrates can be safely co-administered.

  • Pharmacokinetics and Pharmacodynamics of the Dual Orexin Receptor Antagonist Daridorexant in Japanese and Caucasian Subjects.
    Journal of Clinical Psychopharmacology, 2020
    Co-Authors: Clemens Muehlan, Rob Zuiker, Pierre Peeters, Racheal Rowles, Jasper Dingemanse
    Abstract:

    PURPOSE/BACKGROUND Daridorexant is a dual Orexin Receptor Antagonist in development for the treatment of sleep disorders. Thus far, it has not yet been studied in Japanese subjects. Study objectives were to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of single- and multiple-dose administration of daridorexant in healthy Caucasian and Japanese subjects. METHODS/PROCEDURES This was a double-blind, placebo-controlled, randomized study. Subjects received once-daily doses of daridorexant (25 or 50 mg) or placebo for 5 days. Pharmacokinetics and safety were investigated using standard assessments. To assess PD effects, a battery of tests (saccadic peak velocity, body sway, adaptive tracking performance, and visual analog scales for alertness, mood, and calmness), known to be sensitive to sleep-promoting drugs was used. FINDINGS/RESULTS On day 1, PK variables were similar between Caucasian and Japanese subjects. On day 5, slight accumulation occurred in Japanese but not in Caucasian subjects, resulting in a higher maximum concentration (1403 vs 1006 ng/mL) and area under the curve (8256 vs 6306 ng·h/mL) at a dose of 50 mg, whereas values for time to maximum concentration and half-life were similar. Daridorexant dose-dependently reduced vigilance, attention, visuomotor coordination, and postural stability. Pharmacokinetic effects were detectable within 1 hour after drug administration and returned to baseline 4 to 8 hours postdose. Overall, Japanese showed slightly larger PD effects and reported more adverse events than Caucasians. The most frequently reported were somnolence, fatigue, and headache. Changes in other safety assessments were unremarkable. IMPLICATIONS/CONCLUSIONS The PK, PD, and safety profile of daridorexant were similar in Japanese and Caucasian subjects.

  • Clinical pharmacology of the dual Orexin Receptor Antagonist ACT-541468 in elderly subjects: Exploration of pharmacokinetics, pharmacodynamics and tolerability following single-dose morning and repeated-dose evening administration:
    Journal of Psychopharmacology, 2019
    Co-Authors: Clemens Muehlan, Margaux Boehler, Sander Brooks, Rob Zuiker, Joop M. A. Van Gerven, Jasper Dingemanse
    Abstract:

    Background:The dual Orexin Receptor Antagonist ACT-541468 showed sedative pharmacodynamic effects during initial clinical testing in adult subjects. The present study explored pharmacokinetics, pha...

Matthew D. Troyer - One of the best experts on this subject based on the ideXlab platform.

  • Effects of Suvorexant, an Orexin Receptor Antagonist, on Respiration during Sleep In Patients with Obstructive Sleep Apnea.
    Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 2016
    Co-Authors: John Palcza, Adrianna Gipson, Russell Rosenberg, Meir H Kryger, John A Wagner, Deborah Card, Christopher Lines, Matthew D. Troyer
    Abstract:

    Study Objectives:To investigate the respiratory effects of suvorexant, an Orexin Receptor Antagonist for treating insomnia, in patients with obstructive sleep apnea (OSA).Methods:This was a randomi...

  • psychomotor effects pharmacokinetics and safety of the Orexin Receptor Antagonist suvorexant administered in combination with alcohol in healthy subjects
    Journal of Psychopharmacology, 2015
    Co-Authors: Hong Sun, Eric Mangin, John A Wagner, Ka Lai Yee, Sean Gill, Wen Liu, Deborah Panebianco, Dennis Morrison, Jacqueline B. Mccrea, Matthew D. Troyer
    Abstract:

    A double-blind crossover study investigated psychomotor effects, pharmacokinetics, and safety of the Orexin Receptor Antagonist suvorexant with and without alcohol. Healthy adults (n=31) were randomized to receive placebo or suvorexant (40 mg) plus placebo solution or alcohol (0.7 g/kg) in each of four treatments (single doses; morning administration). The US Food and Drug Administration approved suvorexant dose is 10 mg (up to 20 mg) daily. Pharmacodynamic effects were assessed using tests of digit vigilance (DVT; primary endpoint), choice reaction time, digit symbol substitution, numeric working memory, immediate/delayed word recall, body sway and subjective alertness. Suvorexant alone did not significantly affect DVT reaction time, but did impact some pharmacodynamic tests. Suvorexant with alcohol increased reaction time versus either alone (mean difference at 2 h: 44 ms versus suvorexant, p<0.001; 24 ms, versus alcohol, p<0.05) and had additive negative effects on tests of vigilance, working/episodic memory, postural stability and alertness. No effects of suvorexant alone or with alcohol were observed by 9 h. No important changes in pharmacokinetic parameters were observed upon co-administration. All treatments were generally well tolerated without serious adverse events. In conclusion, co-administration of 40 mg suvorexant and 0.7 g/kg alcohol had additive negative psychomotor effects. Patients are advised not to consume alcohol with suvorexant.

  • Effects of the Orexin Receptor Antagonist suvorexant on respiration during sleep in healthy subjects
    The Journal of Clinical Pharmacology, 2015
    Co-Authors: Naoto Uemura, Christopher Lines, Gary Zammit, Hong Sun, Jacqueline B. Mccrea, Mardik Donikyan, Rong Liu, Bonnie Louridas, Sabrina Marsilio, Matthew D. Troyer
    Abstract:

    Abstract Suvorexant is an Orexin Receptor Antagonist for treating insomnia. The maximum approved dose in the United States and Japan is 20 mg. We evaluated suvorexant effects on respiration during sleep in a randomized, double-blind, 3-period crossover study of healthy adult men (n = 8) and women (n = 4) ≤ 50 years old who received single-dose suvorexant 40 mg, 150 mg, and placebo. Respiration during sleep was measured by oxygen saturation (SpO2 , primary end point) and the Apnea Hypopnea Index (AHI). The study was powered to detect a reduction greater than 5% in SpO2 . There was no effect of suvorexant on mean SpO2 during sleep. The mean (90%CI) treatment differences versus placebo were -0.3 (-1.2-0.6) for 40 mg and 0.0 (-0.9-0.9) for 150 mg. There were no dose-related trends in individual SpO2 values. Mean SpO2 was >96% for all treatments during total sleep time and during both non-REM and REM sleep. There was no effect of either suvorexant dose on AHI. The mean (90%CI) treatment differences versus placebo were 0.8 (-0.7-2.3) for 40 mg and -0.2 (-1.7-1.3) for 150 mg. Suvorexant was generally well tolerated; there were no serious adverse experiences or discontinuations. These data from healthy subjects suggest that suvorexant lacks clinically important respiratory effects during sleep at doses greater than the maximum recommended dose for treating insomnia.

  • effects of suvorexant an Orexin Receptor Antagonist on breathing during sleep in patients with chronic obstructive pulmonary disease
    Respiratory Medicine, 2015
    Co-Authors: John Palcza, Russell Rosenberg, Tara Siringhaus, Janice Rowe, Meir H Kryger, John A Wagner, Christopher Lines, Matthew D. Troyer
    Abstract:

    Summary Objectives There is a general concern that hypnotic medications in patients with respiratory disorders have the potential to decrease respiratory effort and blunt the arousal response to hypoxemia which may lead to sleep breathing disorders. We investigated whether suvorexant, an Orexin Receptor Antagonist approved for treatment of insomnia at a maximum daily dose of 20 mg in the US, causes sleep breathing disorders in patients with chronic obstructive pulmonary disease (COPD). Design This was a randomized, double-blind, placebo-controlled, 2-period, cross-over, study performed in 9 sleep laboratories/clinical research units in the United States. The participants were 25 COPD patients aged 39–72 y with mild-to-moderate airflow limitation based on GOLD spirometry criteria. In each period, patients received suvorexant (40 mg in 2 , primary endpoint) and Apnea Hypopnea Index (AHI, secondary endpoint). The study was powered to rule out a difference between treatments of −2 percentage points in SpO 2 on Day 4. Results There was no treatment effect following single and multiple doses of suvorexant on mean SpO 2 during total sleep time (Day 1: suvorexant = 93.14%, placebo = 93.24%, difference = −0.10 [90% CI: −0.50, 0.31]; Day 4: suvorexant = 93.38%, placebo = 92.99%, difference = 0.39 [90% CI: −0.12, 0.91]). There was no clinically meaningful increase in mean AHI by suvorexant compared with placebo on Day 1 (difference = 0.72 [90% CI: −0.60, 2.04]) or Day 4 (difference = 2.05 [90% CI: 0.33, 3.77]). Conclusions These data do not suggest an overt respiratory depressant effect with 30–40 mg daily doses of suvorexant, up to twice the maximum recommended dose for treating insomnia in the US, in patients with mild-to-moderate COPD. Trial registration Clinicaltrials.gov identifier: NCT01293006.

  • respiratory safety of the Orexin Receptor Antagonist suvorexant during sleep in patients with compromised respiratory function and in healthy subjects p5 293
    Neurology, 2014
    Co-Authors: Matthew D. Troyer, John Palcza, Tara Siringhaus, Janice Rowe, Gary Zammit, Naoto Uemura, Mardik Donikyan, Rong Liu, Jackie Mccrea, Deborah Card
    Abstract:

    BACKGROUND: Suvorexant is an Orexin Receptor Antagonist being developed for insomnia. In clinical trials, doses of 10-40mg were generally well-tolerated and improved sleep in insomnia patients. There is a concern regarding use of current hypnotics in patients with respiratory disorders due to the potential to decrease respiratory effort. Therefore, the effects of suvorexant on respiration during sleep in Chronic Obstructive Pulmonary Disease(COPD) and Obstructive Sleep Apnea(OSA) patients, as well as in healthy subjects, were evaluated in 3 studies. DESIGN/METHODS: Study-1 and Study-2 were randomized, double-blind, placebo-controlled, 2-period crossover studies of suvorexant (40mg in patients 18-64 years-old, 30mg in patients 蠅65 years-old) following single-night and 4-consecutive-night administration. Study-1 enrolled patients 蠅18 years-old with mild-to-moderate COPD and Study-2 enrolled patients 18-64 years-old with mild-to-moderate OSA. Study-3 was a randomized, double-blind, single-dose, 3-period crossover study where healthy-subjects ≤50 years-old received suvorexant 150mg (supratherapetic-dose), 40mg, and placebo. Respiratory function during sleep was measured by oxygen-saturation (SaO 2 , primary endpoint in Study-1 and 3) and Apnea-Hypopnea-Index (AHI, primary endpoint in Study-2). RESULTS: In Study-1 in COPD patients, there was no effect of single and multiple-doses of suvorexant on mean SaO 2 during sleep, and no clinically-meaningful effect on AHI(difference from placebo 2 during sleep after single or multiple-doses. In Study-3 in healthy-subjects, there was no effect of suvorexant 150mg or 40mg on mean SaO 2 during sleep, or on AHI. Suvorexant was generally well-tolerated in all 3 studies. CONCLUSIONS: Overall, these data indicate a lack of important respiratory effects at suvorexant doses effective for treating insomnia. To date, there is no clinical experience with suvorexant in patients with severe COPD or OSA. Study Supported by: Merck Disclosure: Dr. Troyer has received personal compensation for activities with Merck & Co., Inc. as an employee. Dr. Troyer holds stock and/or stock options in Merck & Co. Inc., which sponsored research in which Dr. Troyer was involved as an investigator. Dr. Uemura has received personal compensation for activities with Merck & Co. Inc., as an employee. Dr. Uemera holds stock and/or stock options in Merck & Co. Inc. Dr. McCrea has received personal compensation for activities with Merck & Co., Inc. as an employee. Dr. McCrea holds stock and/or stock options in Merck & Co., Inc. Dr. Palcza has received personal compensation for activities with Merck & Co. Inc. as an employee. Dr. Palcza holds stock and/or stock options in Merck & Co. Inc. Dr. Donikyan has received research support from Merck & Co. Inc. Dr. Zammit has received research support from Merck. Dr. Liu has received personal compensation for activities with Merck & Co., Inc. as an employee. Dr. Liu holds stock and/or stock options in Merck & Co., Inc. Dr. Siringhaus has received personal compensation for activities with Merck & Co. Inc., as an employee. Dr. Siringhaus holds stock and/or stock options in Merck & Co., Inc. Dr. Rowe has received personal compensation for activities with Merck & Co. Inc. as an employee. Dr. Rowe holds stock and/or stock options in Merck & Co. Inc. Dr. Card has received personal compensation for activities with Merck & Co., Inc. Dr. Card holds stock and/or stock options in Merck & Co., Inc. Dr. Marsilio has received personal compensation for activities with Merck & Co. Inc. as an employee. Dr. Marsilio has received research support from Merck & Co., Inc. Dr. Grant has received research support from Merck & Co., Inc. Dr. Rosenberg has nothing to disclose. Dr. Wagner has received personal compensation for activities with Merck & Co. Inc. Dr. Wagner holds stock and/or stock options in Merck & Co. Inc. Dr. Sun has received personal compensation for activities with Merck & Co. Inc. Dr. Sun has received research support from Merck & Co. Inc.

Paolo Bettica - One of the best experts on this subject based on the ideXlab platform.

  • phase i studies on the safety tolerability pharmacokinetics and pharmacodynamics of sb 649868 a novel dual Orexin Receptor Antagonist
    Journal of Psychopharmacology, 2012
    Co-Authors: Paolo Bettica, Lisa Squassante, Gianluca Nucci, Caroline Pyke, Emiliangelo Ratti, Stefano Zamuner, Roberto Gomeni, Robert Alexander
    Abstract:

    The Orexin system plays a major role in the integration of metabolic and circadian influences that drive wakefulness. This paper describes initial Phase I trials of a novel dual Orexin Receptor Antagonist SB-649868 that has demonstrated preclinical potential for treatment of sleep disorders. The trial designs included a single ascending dose escalation study (dose range: 10–80 mg in the fed and fasted states) and a multiple repeat dose study (dose range: 5–30 mg in the fed state) enrolling a total of 103 male volunteer subjects. SB-649868 was well tolerated at all doses in this study population, with mechanism-related adverse events (e.g. somnolence and fatigue) observed in a majority of subjects after 60 and 80 mg single doses. Although total drug exposure was similar in the fed and fasted states, the rate, but not the extent, of absorption increased in the fed state, resulting in an increased Cmax. The typical estimated half-life of SB-649868 was 3–6 h – comparable with currently used hypnotic agents. R...

  • differential effects of a dual Orexin Receptor Antagonist sb 649868 and zolpidem on sleep initiation and consolidation sws rem sleep and eeg power spectra in a model of situational insomnia
    Neuropsychopharmacology, 2012
    Co-Authors: Paolo Bettica, Lisa Squassante, Brian Gennery, Raphaelle Winskysommerer, John A. Groeger, Derk-jan Dijk
    Abstract:

    Orexins have a role in sleep regulation, and Orexin Receptor Antagonists are under development for the treatment of insomnia. We conducted a randomised, double-blind, placebo-controlled, four-period crossover study to investigate the effect of single doses of the dual Orexin Receptor Antagonist SB-649868 (10 or 30 mg) and a positive control zolpidem (10 mg), an allosteric modulator of GABAA Receptors. Objective and subjective sleep parameters and next-day performance were assessed in 51 healthy male volunteers in a traffic noise model of situational insomnia. Compared with placebo, SB-649868 10 and 30 mg increased total sleep time (TST) by 17 and 31 min (p<0.001), whereas after zolpidem TST was increased by 11.0 min (p=0.012). Wake after sleep onset was reduced significantly by 14.7 min for the SB–6489698 30 mg dose (p<0.001). Latency to persistent sleep was significantly reduced after both doses of SB–6489698 (p=0.003), but not after zolpidem. Slow wave sleep (SWS) and electroencephalogram (EEG) power spectra in non-REM sleep were not affected by either dose of SB-640868, whereas SWS (p< 0.001) and low delta activity (<=1.0 Hz) were increased, and 2.25–11.0 Hz activity decreased after zolpidem. REM sleep duration was increased after SB-649868 30 mg (p=0.002) and reduced after zolpidem (p=0.049). Latency to REM sleep was reduced by 20.1 (p=0.034) and 34.0 min (p<0.001) after 10 and 30 mg of SB-649868. Sleep-onset REM episodes were observed. SB-649868 was well tolerated. This dual Orexin Receptor Antagonist exerts hypnotic activity, with effects on sleep structure and the EEG that are different from those of zolpidem.

  • Differential Effects of a Dual Orexin Receptor Antagonist (SB-649868) and Zolpidem on Sleep Initiation and Consolidation, SWS, REM Sleep, and EEG Power Spectra in a Model of Situational Insomnia
    Neuropsychopharmacology, 2012
    Co-Authors: Paolo Bettica, Lisa Squassante, Brian Gennery, John A. Groeger, Raphaelle Winsky-sommerer, Derk-jan Dijk
    Abstract:

    Orexins have a role in sleep regulation, and Orexin Receptor Antagonists are under development for the treatment of insomnia. We conducted a randomised, double-blind, placebo-controlled, four-period crossover study to investigate the effect of single doses of the dual Orexin Receptor Antagonist SB-649868 (10 or 30 mg) and a positive control zolpidem (10 mg), an allosteric modulator of GABAA Receptors. Objective and subjective sleep parameters and next-day performance were assessed in 51 healthy male volunteers in a traffic noise model of situational insomnia. Compared with placebo, SB-649868 10 and 30 mg increased total sleep time (TST) by 17 and 31 min (p

Derk-jan Dijk - One of the best experts on this subject based on the ideXlab platform.

  • differential effects of a dual Orexin Receptor Antagonist sb 649868 and zolpidem on sleep initiation and consolidation sws rem sleep and eeg power spectra in a model of situational insomnia
    Neuropsychopharmacology, 2012
    Co-Authors: Paolo Bettica, Lisa Squassante, Brian Gennery, Raphaelle Winskysommerer, John A. Groeger, Derk-jan Dijk
    Abstract:

    Orexins have a role in sleep regulation, and Orexin Receptor Antagonists are under development for the treatment of insomnia. We conducted a randomised, double-blind, placebo-controlled, four-period crossover study to investigate the effect of single doses of the dual Orexin Receptor Antagonist SB-649868 (10 or 30 mg) and a positive control zolpidem (10 mg), an allosteric modulator of GABAA Receptors. Objective and subjective sleep parameters and next-day performance were assessed in 51 healthy male volunteers in a traffic noise model of situational insomnia. Compared with placebo, SB-649868 10 and 30 mg increased total sleep time (TST) by 17 and 31 min (p<0.001), whereas after zolpidem TST was increased by 11.0 min (p=0.012). Wake after sleep onset was reduced significantly by 14.7 min for the SB–6489698 30 mg dose (p<0.001). Latency to persistent sleep was significantly reduced after both doses of SB–6489698 (p=0.003), but not after zolpidem. Slow wave sleep (SWS) and electroencephalogram (EEG) power spectra in non-REM sleep were not affected by either dose of SB-640868, whereas SWS (p< 0.001) and low delta activity (<=1.0 Hz) were increased, and 2.25–11.0 Hz activity decreased after zolpidem. REM sleep duration was increased after SB-649868 30 mg (p=0.002) and reduced after zolpidem (p=0.049). Latency to REM sleep was reduced by 20.1 (p=0.034) and 34.0 min (p<0.001) after 10 and 30 mg of SB-649868. Sleep-onset REM episodes were observed. SB-649868 was well tolerated. This dual Orexin Receptor Antagonist exerts hypnotic activity, with effects on sleep structure and the EEG that are different from those of zolpidem.

  • Differential Effects of a Dual Orexin Receptor Antagonist (SB-649868) and Zolpidem on Sleep Initiation and Consolidation, SWS, REM Sleep, and EEG Power Spectra in a Model of Situational Insomnia
    Neuropsychopharmacology, 2012
    Co-Authors: Paolo Bettica, Lisa Squassante, Brian Gennery, John A. Groeger, Raphaelle Winsky-sommerer, Derk-jan Dijk
    Abstract:

    Orexins have a role in sleep regulation, and Orexin Receptor Antagonists are under development for the treatment of insomnia. We conducted a randomised, double-blind, placebo-controlled, four-period crossover study to investigate the effect of single doses of the dual Orexin Receptor Antagonist SB-649868 (10 or 30 mg) and a positive control zolpidem (10 mg), an allosteric modulator of GABAA Receptors. Objective and subjective sleep parameters and next-day performance were assessed in 51 healthy male volunteers in a traffic noise model of situational insomnia. Compared with placebo, SB-649868 10 and 30 mg increased total sleep time (TST) by 17 and 31 min (p

Lisa Squassante - One of the best experts on this subject based on the ideXlab platform.

  • phase i studies on the safety tolerability pharmacokinetics and pharmacodynamics of sb 649868 a novel dual Orexin Receptor Antagonist
    Journal of Psychopharmacology, 2012
    Co-Authors: Paolo Bettica, Lisa Squassante, Gianluca Nucci, Caroline Pyke, Emiliangelo Ratti, Stefano Zamuner, Roberto Gomeni, Robert Alexander
    Abstract:

    The Orexin system plays a major role in the integration of metabolic and circadian influences that drive wakefulness. This paper describes initial Phase I trials of a novel dual Orexin Receptor Antagonist SB-649868 that has demonstrated preclinical potential for treatment of sleep disorders. The trial designs included a single ascending dose escalation study (dose range: 10–80 mg in the fed and fasted states) and a multiple repeat dose study (dose range: 5–30 mg in the fed state) enrolling a total of 103 male volunteer subjects. SB-649868 was well tolerated at all doses in this study population, with mechanism-related adverse events (e.g. somnolence and fatigue) observed in a majority of subjects after 60 and 80 mg single doses. Although total drug exposure was similar in the fed and fasted states, the rate, but not the extent, of absorption increased in the fed state, resulting in an increased Cmax. The typical estimated half-life of SB-649868 was 3–6 h – comparable with currently used hypnotic agents. R...

  • differential effects of a dual Orexin Receptor Antagonist sb 649868 and zolpidem on sleep initiation and consolidation sws rem sleep and eeg power spectra in a model of situational insomnia
    Neuropsychopharmacology, 2012
    Co-Authors: Paolo Bettica, Lisa Squassante, Brian Gennery, Raphaelle Winskysommerer, John A. Groeger, Derk-jan Dijk
    Abstract:

    Orexins have a role in sleep regulation, and Orexin Receptor Antagonists are under development for the treatment of insomnia. We conducted a randomised, double-blind, placebo-controlled, four-period crossover study to investigate the effect of single doses of the dual Orexin Receptor Antagonist SB-649868 (10 or 30 mg) and a positive control zolpidem (10 mg), an allosteric modulator of GABAA Receptors. Objective and subjective sleep parameters and next-day performance were assessed in 51 healthy male volunteers in a traffic noise model of situational insomnia. Compared with placebo, SB-649868 10 and 30 mg increased total sleep time (TST) by 17 and 31 min (p<0.001), whereas after zolpidem TST was increased by 11.0 min (p=0.012). Wake after sleep onset was reduced significantly by 14.7 min for the SB–6489698 30 mg dose (p<0.001). Latency to persistent sleep was significantly reduced after both doses of SB–6489698 (p=0.003), but not after zolpidem. Slow wave sleep (SWS) and electroencephalogram (EEG) power spectra in non-REM sleep were not affected by either dose of SB-640868, whereas SWS (p< 0.001) and low delta activity (<=1.0 Hz) were increased, and 2.25–11.0 Hz activity decreased after zolpidem. REM sleep duration was increased after SB-649868 30 mg (p=0.002) and reduced after zolpidem (p=0.049). Latency to REM sleep was reduced by 20.1 (p=0.034) and 34.0 min (p<0.001) after 10 and 30 mg of SB-649868. Sleep-onset REM episodes were observed. SB-649868 was well tolerated. This dual Orexin Receptor Antagonist exerts hypnotic activity, with effects on sleep structure and the EEG that are different from those of zolpidem.

  • Differential Effects of a Dual Orexin Receptor Antagonist (SB-649868) and Zolpidem on Sleep Initiation and Consolidation, SWS, REM Sleep, and EEG Power Spectra in a Model of Situational Insomnia
    Neuropsychopharmacology, 2012
    Co-Authors: Paolo Bettica, Lisa Squassante, Brian Gennery, John A. Groeger, Raphaelle Winsky-sommerer, Derk-jan Dijk
    Abstract:

    Orexins have a role in sleep regulation, and Orexin Receptor Antagonists are under development for the treatment of insomnia. We conducted a randomised, double-blind, placebo-controlled, four-period crossover study to investigate the effect of single doses of the dual Orexin Receptor Antagonist SB-649868 (10 or 30 mg) and a positive control zolpidem (10 mg), an allosteric modulator of GABAA Receptors. Objective and subjective sleep parameters and next-day performance were assessed in 51 healthy male volunteers in a traffic noise model of situational insomnia. Compared with placebo, SB-649868 10 and 30 mg increased total sleep time (TST) by 17 and 31 min (p