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Augmentation of Endoxifen Exposure in Tamoxifen-Treated Women Following SSRI Switch
BACKGROUND AND OBJECTIVE: The anti-oestrogen tamoxifen requires metabolic activation to endoxifen by cytochrome P450 (CYP) enzymes, predominantly CYP2D6. Potent CYP2D6-inhibiting antidepressants can seriously disrupt tamoxifen metabolism, probably influencing the efficacy of tamoxifen. For this reas...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756062/ https://www.ncbi.nlm.nih.gov/pubmed/26446141 http://dx.doi.org/10.1007/s40262-015-0315-x |
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author | Binkhorst, Lisette Bannink, Marjolein de Bruijn, Peter Ruit, Jan Droogendijk, Helga van Alphen, Robbert J. den Boer, Tilly D. Lam, Mei Ho Jager, Agnes van Gelder, Teun Mathijssen, Ron H. J. |
author_facet | Binkhorst, Lisette Bannink, Marjolein de Bruijn, Peter Ruit, Jan Droogendijk, Helga van Alphen, Robbert J. den Boer, Tilly D. Lam, Mei Ho Jager, Agnes van Gelder, Teun Mathijssen, Ron H. J. |
author_sort | Binkhorst, Lisette |
collection | PubMed |
description | BACKGROUND AND OBJECTIVE: The anti-oestrogen tamoxifen requires metabolic activation to endoxifen by cytochrome P450 (CYP) enzymes, predominantly CYP2D6. Potent CYP2D6-inhibiting antidepressants can seriously disrupt tamoxifen metabolism, probably influencing the efficacy of tamoxifen. For this reason, paroxetine and fluoxetine are recommended not to be used with tamoxifen in breast cancer patients. We investigated the effects of switching potent CYP2D6-inhibiting antidepressants to weak CYP2D6-inhibiting antidepressants on the plasma pharmacokinetics of tamoxifen. METHODS: Ten breast cancer patients who were treated with tamoxifen in combination with a potent CYP2D6-inhibiting antidepressant (paroxetine or fluoxetine) for at least 4 weeks were enrolled. Under close supervision by a psychiatrist, patients were switched to treatment with escitalopram or venlafaxine (weak CYP2D6-inhibiting antidepressants). Before and after the switch, pharmacokinetic blood sampling was performed over 24 h. Pharmacokinetic parameters were estimated using noncompartmental analysis. Adverse effects were recorded during the study. RESULTS: Endoxifen exposure was ~3-fold higher during escitalopram co-administration than during paroxetine or fluoxetine co-administration (median 387 nM·h [range 159–637 nM·h] versus 99.2 nM·h [range 70.0–210 nM·h]; P = 0.012; Wilcoxon signed-rank test). The ratio of endoxifen to N-desmethyltamoxifen and the ratio of 4-hydroxytamoxifen to tamoxifen increased by 3.3- and ~1.5-fold, reflecting increased CYP2D6 activity. Antidepressant switching did not result in psychiatric problems or antidepressant-related adverse effects. CONCLUSION: In this study, switching to the weak CYP2D6 inhibitor escitalopram was safe and feasible and resulted in clinically relevant rises in endoxifen concentrations. We therefore advise switching paroxetine and fluoxetine to escitalopram in patients using tamoxifen. However, switching should always be weighed in individual patients. |
format | Online Article Text |
id | pubmed-4756062 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-47560622016-02-26 Augmentation of Endoxifen Exposure in Tamoxifen-Treated Women Following SSRI Switch Binkhorst, Lisette Bannink, Marjolein de Bruijn, Peter Ruit, Jan Droogendijk, Helga van Alphen, Robbert J. den Boer, Tilly D. Lam, Mei Ho Jager, Agnes van Gelder, Teun Mathijssen, Ron H. J. Clin Pharmacokinet Original Research Article BACKGROUND AND OBJECTIVE: The anti-oestrogen tamoxifen requires metabolic activation to endoxifen by cytochrome P450 (CYP) enzymes, predominantly CYP2D6. Potent CYP2D6-inhibiting antidepressants can seriously disrupt tamoxifen metabolism, probably influencing the efficacy of tamoxifen. For this reason, paroxetine and fluoxetine are recommended not to be used with tamoxifen in breast cancer patients. We investigated the effects of switching potent CYP2D6-inhibiting antidepressants to weak CYP2D6-inhibiting antidepressants on the plasma pharmacokinetics of tamoxifen. METHODS: Ten breast cancer patients who were treated with tamoxifen in combination with a potent CYP2D6-inhibiting antidepressant (paroxetine or fluoxetine) for at least 4 weeks were enrolled. Under close supervision by a psychiatrist, patients were switched to treatment with escitalopram or venlafaxine (weak CYP2D6-inhibiting antidepressants). Before and after the switch, pharmacokinetic blood sampling was performed over 24 h. Pharmacokinetic parameters were estimated using noncompartmental analysis. Adverse effects were recorded during the study. RESULTS: Endoxifen exposure was ~3-fold higher during escitalopram co-administration than during paroxetine or fluoxetine co-administration (median 387 nM·h [range 159–637 nM·h] versus 99.2 nM·h [range 70.0–210 nM·h]; P = 0.012; Wilcoxon signed-rank test). The ratio of endoxifen to N-desmethyltamoxifen and the ratio of 4-hydroxytamoxifen to tamoxifen increased by 3.3- and ~1.5-fold, reflecting increased CYP2D6 activity. Antidepressant switching did not result in psychiatric problems or antidepressant-related adverse effects. CONCLUSION: In this study, switching to the weak CYP2D6 inhibitor escitalopram was safe and feasible and resulted in clinically relevant rises in endoxifen concentrations. We therefore advise switching paroxetine and fluoxetine to escitalopram in patients using tamoxifen. However, switching should always be weighed in individual patients. Springer International Publishing 2015-10-08 2016 /pmc/articles/PMC4756062/ /pubmed/26446141 http://dx.doi.org/10.1007/s40262-015-0315-x Text en © The Author(s) 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Original Research Article Binkhorst, Lisette Bannink, Marjolein de Bruijn, Peter Ruit, Jan Droogendijk, Helga van Alphen, Robbert J. den Boer, Tilly D. Lam, Mei Ho Jager, Agnes van Gelder, Teun Mathijssen, Ron H. J. Augmentation of Endoxifen Exposure in Tamoxifen-Treated Women Following SSRI Switch |
title | Augmentation of Endoxifen Exposure in Tamoxifen-Treated Women Following SSRI Switch |
title_full | Augmentation of Endoxifen Exposure in Tamoxifen-Treated Women Following SSRI Switch |
title_fullStr | Augmentation of Endoxifen Exposure in Tamoxifen-Treated Women Following SSRI Switch |
title_full_unstemmed | Augmentation of Endoxifen Exposure in Tamoxifen-Treated Women Following SSRI Switch |
title_short | Augmentation of Endoxifen Exposure in Tamoxifen-Treated Women Following SSRI Switch |
title_sort | augmentation of endoxifen exposure in tamoxifen-treated women following ssri switch |
topic | Original Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756062/ https://www.ncbi.nlm.nih.gov/pubmed/26446141 http://dx.doi.org/10.1007/s40262-015-0315-x |
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