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

Clin Pharmacokinet. 2016 Feb;55(2):249-55. doi: 10.1007/s40262-015-0315-x.

Abstract

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.

Publication types

  • Clinical Trial

MeSH terms

  • 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
  • Middle Aged
  • Paroxetine / pharmacology
  • Paroxetine / therapeutic use
  • Serotonin Uptake Inhibitors / pharmacology*
  • Serotonin Uptake Inhibitors / therapeutic use
  • Tamoxifen / analogs & derivatives*
  • Tamoxifen / blood
  • Tamoxifen / pharmacokinetics*
  • Venlafaxine Hydrochloride / pharmacology
  • Venlafaxine Hydrochloride / therapeutic use

Substances

  • Antidepressive Agents
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Tamoxifen
  • Citalopram
  • Paroxetine
  • Venlafaxine Hydrochloride
  • Cytochrome P-450 CYP2D6