A randomized, single‐dose, crossover study of the effects of ulotaront on electrocardiogram intervals in subjects with schizophrenia
Abstract This study (NCT04369391) evaluated the effects of ulotaront (SEP‐363856), a novel trace amine‐associated receptor 1 (TAAR1) agonist in development for schizophrenia, on electrocardiogram parameters. Study design was a randomized, single‐dose, three‐period crossover (ulotaront 150 mg, placeb...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-06-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13512 |
| _version_ | 1797804501451669504 |
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| author | Hironobu Tsukada Snezana M. Milanovic Borje Darpo Hongqi Xue Kuangnan Xiong Emily Tripp Lisa Lennek MaryAlice Worden Seth C. Hopkins Gerald R. Galluppi |
| author_facet | Hironobu Tsukada Snezana M. Milanovic Borje Darpo Hongqi Xue Kuangnan Xiong Emily Tripp Lisa Lennek MaryAlice Worden Seth C. Hopkins Gerald R. Galluppi |
| author_sort | Hironobu Tsukada |
| collection | DOAJ |
| description | Abstract This study (NCT04369391) evaluated the effects of ulotaront (SEP‐363856), a novel trace amine‐associated receptor 1 (TAAR1) agonist in development for schizophrenia, on electrocardiogram parameters. Study design was a randomized, single‐dose, three‐period crossover (ulotaront 150 mg, placebo, moxifloxacin 400 mg). Sixty subjects with schizophrenia completed all periods. Ulotaront had no clinically relevant effect on heart rate, PR interval, or QRS duration. In by‐time‐point analysis (secondary analysis), the upper bound of the two‐sided 90% confidence interval for ΔΔQTcF (QT interval corrected for heart rate using Fridericia's formula) was below 10 ms at all time points for ulotaront. In concentration‐QTc analysis (primary analysis), a linear mixed‐effects model with ulotaront and its major metabolite SEP‐383103 was selected as the primary model based on prespecified criteria. Effect on ∆∆QTcF exceeding 10 ms can be excluded within observed ranges of ulotaront and SEP‐383103 plasma concentrations up to ~574 and ~272 ng/mL, respectively. The upper bound of 90% CI for ΔΔQTcF can be predicted to be below 10 ms at the highest anticipated clinical exposure, currently defined as steady‐state mean Cmax at ulotaront 100 mg/day in CYP2D6 poor metabolizers, ~416 and ~211 ng/mL for ulotaront and SEP‐383103, respectively. Assay sensitivity was demonstrated by the QTc effect caused by moxifloxacin. In conclusion, ulotaront is unlikely to cause clinically relevant QTc prolongation in patients with schizophrenia at the anticipated maximum therapeutic dose. |
| first_indexed | 2024-03-13T05:38:08Z |
| format | Article |
| id | doaj.art-fb931202cdb44672bb881bd23a3cb680 |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-03-13T05:38:08Z |
| publishDate | 2023-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-fb931202cdb44672bb881bd23a3cb6802023-06-14T06:03:57ZengWileyClinical and Translational Science1752-80541752-80622023-06-011661063107410.1111/cts.13512A randomized, single‐dose, crossover study of the effects of ulotaront on electrocardiogram intervals in subjects with schizophreniaHironobu Tsukada0Snezana M. Milanovic1Borje Darpo2Hongqi Xue3Kuangnan Xiong4Emily Tripp5Lisa Lennek6MaryAlice Worden7Seth C. Hopkins8Gerald R. Galluppi9Sunovion Pharmaceuticals Inc. Marlborough Massachusetts USASunovion Pharmaceuticals Inc. Marlborough Massachusetts USAClario Rochester New York USAClario Rochester New York USASunovion Pharmaceuticals Inc. Marlborough Massachusetts USASunovion Pharmaceuticals Inc. Marlborough Massachusetts USASunovion Pharmaceuticals Inc. Marlborough Massachusetts USASunovion Pharmaceuticals Inc. Marlborough Massachusetts USASunovion Pharmaceuticals Inc. Marlborough Massachusetts USASunovion Pharmaceuticals Inc. Marlborough Massachusetts USAAbstract This study (NCT04369391) evaluated the effects of ulotaront (SEP‐363856), a novel trace amine‐associated receptor 1 (TAAR1) agonist in development for schizophrenia, on electrocardiogram parameters. Study design was a randomized, single‐dose, three‐period crossover (ulotaront 150 mg, placebo, moxifloxacin 400 mg). Sixty subjects with schizophrenia completed all periods. Ulotaront had no clinically relevant effect on heart rate, PR interval, or QRS duration. In by‐time‐point analysis (secondary analysis), the upper bound of the two‐sided 90% confidence interval for ΔΔQTcF (QT interval corrected for heart rate using Fridericia's formula) was below 10 ms at all time points for ulotaront. In concentration‐QTc analysis (primary analysis), a linear mixed‐effects model with ulotaront and its major metabolite SEP‐383103 was selected as the primary model based on prespecified criteria. Effect on ∆∆QTcF exceeding 10 ms can be excluded within observed ranges of ulotaront and SEP‐383103 plasma concentrations up to ~574 and ~272 ng/mL, respectively. The upper bound of 90% CI for ΔΔQTcF can be predicted to be below 10 ms at the highest anticipated clinical exposure, currently defined as steady‐state mean Cmax at ulotaront 100 mg/day in CYP2D6 poor metabolizers, ~416 and ~211 ng/mL for ulotaront and SEP‐383103, respectively. Assay sensitivity was demonstrated by the QTc effect caused by moxifloxacin. In conclusion, ulotaront is unlikely to cause clinically relevant QTc prolongation in patients with schizophrenia at the anticipated maximum therapeutic dose.https://doi.org/10.1111/cts.13512 |
| spellingShingle | Hironobu Tsukada Snezana M. Milanovic Borje Darpo Hongqi Xue Kuangnan Xiong Emily Tripp Lisa Lennek MaryAlice Worden Seth C. Hopkins Gerald R. Galluppi A randomized, single‐dose, crossover study of the effects of ulotaront on electrocardiogram intervals in subjects with schizophrenia Clinical and Translational Science |
| title | A randomized, single‐dose, crossover study of the effects of ulotaront on electrocardiogram intervals in subjects with schizophrenia |
| title_full | A randomized, single‐dose, crossover study of the effects of ulotaront on electrocardiogram intervals in subjects with schizophrenia |
| title_fullStr | A randomized, single‐dose, crossover study of the effects of ulotaront on electrocardiogram intervals in subjects with schizophrenia |
| title_full_unstemmed | A randomized, single‐dose, crossover study of the effects of ulotaront on electrocardiogram intervals in subjects with schizophrenia |
| title_short | A randomized, single‐dose, crossover study of the effects of ulotaront on electrocardiogram intervals in subjects with schizophrenia |
| title_sort | randomized single dose crossover study of the effects of ulotaront on electrocardiogram intervals in subjects with schizophrenia |
| url | https://doi.org/10.1111/cts.13512 |
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