Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans
Abstract SEP-363856 is a trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT1A) agonist, currently in Phase 3 clinical trials for the treatment of schizophrenia. Although SEP-363856 activates TAAR1 and 5-HT1A receptors in vitro, an accessible marker of time- and concentra...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-04-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-021-01331-9 |
| _version_ | 1818607457257127936 |
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| author | Seth C. Hopkins Nina Dedic Kenneth S. Koblan |
| author_facet | Seth C. Hopkins Nina Dedic Kenneth S. Koblan |
| author_sort | Seth C. Hopkins |
| collection | DOAJ |
| description | Abstract SEP-363856 is a trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT1A) agonist, currently in Phase 3 clinical trials for the treatment of schizophrenia. Although SEP-363856 activates TAAR1 and 5-HT1A receptors in vitro, an accessible marker of time- and concentration-dependent effects of SEP-363856 in humans is lacking. In rodents, SEP-363856 has been shown to suppress rapid eye movement (REM) sleep. The aim of the current study was to translate the REM sleep effects to humans and determine pharmacokinetic/pharmacodynamic (PK/PD) relationships of SEP-363856 on a measure of brain activity. The effects of SEP-363856 were evaluated in a randomized, double-blind, placebo-controlled, 2-way crossover study of single oral doses (50 and 10 mg) on REM sleep in healthy male subjects (N = 12 at each dose level). Drug concentrations were sampled during sleep to interpolate individual subject’s pharmacokinetic trajectories. SEP-363856 suppressed REM sleep parameters with very large effect sizes (>3) following single doses of 50 mg and plasma concentrations ≥100 ng/mL. Below that effective concentration, the 10 mg dose elicited much smaller effects, increasing only the latency to REM sleep (effect size = 1). The PK/PD relationships demonstrated that REM sleep probability increased as drug concentrations declined below 100 ng/mL over the course of the night. SEP-363856 was generally safe and well tolerated at both doses. The REM sleep-suppressing effects of SEP-363856 provide an accessible marker of brain activity, which can aid in dose selection and help elucidate its therapeutic potential in further clinical trials. |
| first_indexed | 2024-12-16T14:27:03Z |
| format | Article |
| id | doaj.art-dd0a23c2a1284660abbf9f68fe67166d |
| institution | Directory Open Access Journal |
| issn | 2158-3188 |
| language | English |
| last_indexed | 2024-12-16T14:27:03Z |
| publishDate | 2021-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj.art-dd0a23c2a1284660abbf9f68fe67166d2022-12-21T22:28:21ZengNature Publishing GroupTranslational Psychiatry2158-31882021-04-0111111010.1038/s41398-021-01331-9Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humansSeth C. Hopkins0Nina Dedic1Kenneth S. Koblan2Sunovion Pharmaceuticals IncSunovion Pharmaceuticals IncSunovion Pharmaceuticals IncAbstract SEP-363856 is a trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT1A) agonist, currently in Phase 3 clinical trials for the treatment of schizophrenia. Although SEP-363856 activates TAAR1 and 5-HT1A receptors in vitro, an accessible marker of time- and concentration-dependent effects of SEP-363856 in humans is lacking. In rodents, SEP-363856 has been shown to suppress rapid eye movement (REM) sleep. The aim of the current study was to translate the REM sleep effects to humans and determine pharmacokinetic/pharmacodynamic (PK/PD) relationships of SEP-363856 on a measure of brain activity. The effects of SEP-363856 were evaluated in a randomized, double-blind, placebo-controlled, 2-way crossover study of single oral doses (50 and 10 mg) on REM sleep in healthy male subjects (N = 12 at each dose level). Drug concentrations were sampled during sleep to interpolate individual subject’s pharmacokinetic trajectories. SEP-363856 suppressed REM sleep parameters with very large effect sizes (>3) following single doses of 50 mg and plasma concentrations ≥100 ng/mL. Below that effective concentration, the 10 mg dose elicited much smaller effects, increasing only the latency to REM sleep (effect size = 1). The PK/PD relationships demonstrated that REM sleep probability increased as drug concentrations declined below 100 ng/mL over the course of the night. SEP-363856 was generally safe and well tolerated at both doses. The REM sleep-suppressing effects of SEP-363856 provide an accessible marker of brain activity, which can aid in dose selection and help elucidate its therapeutic potential in further clinical trials.https://doi.org/10.1038/s41398-021-01331-9 |
| spellingShingle | Seth C. Hopkins Nina Dedic Kenneth S. Koblan Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans Translational Psychiatry |
| title | Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans |
| title_full | Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans |
| title_fullStr | Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans |
| title_full_unstemmed | Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans |
| title_short | Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans |
| title_sort | effect of taar1 5 ht1a agonist sep 363856 on rem sleep in humans |
| url | https://doi.org/10.1038/s41398-021-01331-9 |
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