Augmentation of Endoxifen Exposure in Tamoxifen-Treated Women Following SSRI Switch

• Published in: Clinical pharmacokinetics Vol. 55; no. 2; pp. 249 - 255
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-02-2016; Springer Nature B.V
• Subjects: Adult; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Citalopram - pharmacology; Citalopram - therapeutic use; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 Inhibitors - pharmacology; Cytochrome P-450 CYP2D6 Inhibitors - therapeutic use; Female; Fluoxetine - pharmacology; Fluoxetine - therapeutic use; Genotype; Humans; Internal Medicine; Medicine; Medicine & Public Health; Middle Aged; Original; Original Research Article; Paroxetine - pharmacology; Paroxetine - therapeutic use; Pharmacology/Toxicology; Pharmacotherapy; Serotonin Uptake Inhibitors - pharmacology; Serotonin Uptake Inhibitors - therapeutic use; Tamoxifen - analogs & derivatives; Tamoxifen - blood; Tamoxifen - pharmacokinetics; Venlafaxine Hydrochloride - pharmacology; Venlafaxine Hydrochloride - therapeutic use; Paroxetine; Venlafaxine; Tamoxifen; Fluoxetine; Escitalopram
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-015-0315-x

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.