Estimation of brain receptor occupancy for trazodone immediate release and once a day formulations
Abstract Trazodone is approved for the treatment of major depressive disorders, marketed as immediate release (IR), prolonged release, and once a day (OAD) formulation. The different formulations allow different administration schedules and may be useful to facilitate patients’ compliance to the ant...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-06-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13253 |
| _version_ | 1828793197546962944 |
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| author | Laura Oggianu Giorgio Di Dato Giorgina Mangano Maria Teresa Rosignoli Savannah McFeely Alice Ban Ke Hannah M. Jones Alessandro Comandini |
| author_facet | Laura Oggianu Giorgio Di Dato Giorgina Mangano Maria Teresa Rosignoli Savannah McFeely Alice Ban Ke Hannah M. Jones Alessandro Comandini |
| author_sort | Laura Oggianu |
| collection | DOAJ |
| description | Abstract Trazodone is approved for the treatment of major depressive disorders, marketed as immediate release (IR), prolonged release, and once a day (OAD) formulation. The different formulations allow different administration schedules and may be useful to facilitate patients’ compliance to the antidepressant treatment. A previously verified physiologically‐based pharmacokinetic model based on in vitro and in vivo information on trazodone pharmacokinetics was applied, aiming at predicting brain receptor occupancy (RO) after single and repeated dosing of the IR formulation and repeated dosing of the OAD formulation in healthy subjects. Receptors included in the simulations were selected using static calculations of RO based on the maximum unbound brain concentration (Cmax,brain,u) of trazodone for each formulation and dosing scheme, resulting in 16 receptors being simulated. Seven receptors were simulated for the IR low dose formulation (30 mg), with similar tonset and duration of coverage (range: 0.09–0.25 h and 2.1–>24 h, respectively) as well as RO (range: 0.64–0.92) predicted between day 1 and day 7 of dosing. The 16 receptors evaluated for the OAD formulation (300 mg) showed high RO (range: 0.97–0.84 for the receptors also covered by the IR formulation and 0.73–0.48 for the remaining) correlating with affinity and similar duration of time above the target threshold to the IR formulation (range: 2–>24 h). The dose‐dependent receptor coverage supports the multimodal activity of trazodone, which may further contribute to its fast antidepressant action and effectiveness in controlling different symptoms in depressed patients. |
| first_indexed | 2024-12-12T03:22:03Z |
| format | Article |
| id | doaj.art-d9d926ebb4ce4587b933ee559be1a693 |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-12-12T03:22:03Z |
| publishDate | 2022-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-d9d926ebb4ce4587b933ee559be1a6932022-12-22T00:40:08ZengWileyClinical and Translational Science1752-80541752-80622022-06-011561417142910.1111/cts.13253Estimation of brain receptor occupancy for trazodone immediate release and once a day formulationsLaura Oggianu0Giorgio Di Dato1Giorgina Mangano2Maria Teresa Rosignoli3Savannah McFeely4Alice Ban Ke5Hannah M. Jones6Alessandro Comandini7Angelini Pharma S.p.A. Rome ItalyAngelini Pharma S.p.A. Rome ItalyAngelini Pharma S.p.A. Rome ItalyAngelini Pharma S.p.A. Rome ItalyCertara UK Simcyp Division Sheffield UKCertara UK Simcyp Division Sheffield UKCertara UK Simcyp Division Sheffield UKAngelini Pharma S.p.A. Rome ItalyAbstract Trazodone is approved for the treatment of major depressive disorders, marketed as immediate release (IR), prolonged release, and once a day (OAD) formulation. The different formulations allow different administration schedules and may be useful to facilitate patients’ compliance to the antidepressant treatment. A previously verified physiologically‐based pharmacokinetic model based on in vitro and in vivo information on trazodone pharmacokinetics was applied, aiming at predicting brain receptor occupancy (RO) after single and repeated dosing of the IR formulation and repeated dosing of the OAD formulation in healthy subjects. Receptors included in the simulations were selected using static calculations of RO based on the maximum unbound brain concentration (Cmax,brain,u) of trazodone for each formulation and dosing scheme, resulting in 16 receptors being simulated. Seven receptors were simulated for the IR low dose formulation (30 mg), with similar tonset and duration of coverage (range: 0.09–0.25 h and 2.1–>24 h, respectively) as well as RO (range: 0.64–0.92) predicted between day 1 and day 7 of dosing. The 16 receptors evaluated for the OAD formulation (300 mg) showed high RO (range: 0.97–0.84 for the receptors also covered by the IR formulation and 0.73–0.48 for the remaining) correlating with affinity and similar duration of time above the target threshold to the IR formulation (range: 2–>24 h). The dose‐dependent receptor coverage supports the multimodal activity of trazodone, which may further contribute to its fast antidepressant action and effectiveness in controlling different symptoms in depressed patients.https://doi.org/10.1111/cts.13253 |
| spellingShingle | Laura Oggianu Giorgio Di Dato Giorgina Mangano Maria Teresa Rosignoli Savannah McFeely Alice Ban Ke Hannah M. Jones Alessandro Comandini Estimation of brain receptor occupancy for trazodone immediate release and once a day formulations Clinical and Translational Science |
| title | Estimation of brain receptor occupancy for trazodone immediate release and once a day formulations |
| title_full | Estimation of brain receptor occupancy for trazodone immediate release and once a day formulations |
| title_fullStr | Estimation of brain receptor occupancy for trazodone immediate release and once a day formulations |
| title_full_unstemmed | Estimation of brain receptor occupancy for trazodone immediate release and once a day formulations |
| title_short | Estimation of brain receptor occupancy for trazodone immediate release and once a day formulations |
| title_sort | estimation of brain receptor occupancy for trazodone immediate release and once a day formulations |
| url | https://doi.org/10.1111/cts.13253 |
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