Factors Affecting Inter-individual Variability in Endoxifen Concentrations in Patients: Results From the Prospective TOTAM Trial

Abstract

Introduction: Endoxifen – the principal metabolite of tamoxifen – is subject to a high inter-individual variability in serum concentration. Numerous attempts have been made to explain this, but thus far only with limited success. By applying predictive modelling, we aimed to identify factors that determine the inter-individual variability. Aim is to develop a prediction model for endoxifen concentrations, as a strategy to individualize tamoxifen treatment by model-informed dosing in order to prevent subtherapeutic exposure and thus potential failure of therapy. Methods: Tamoxifen pharmacokinetics with demographic and pharmacogenetic data of 303 participants of the prospective TOTAM study were used. The inter-individual variability in endoxifen was analyzed according to multiple regression techniques in combination with multiple imputations to adjust for missing data and bootstrapping to adjust for the over-optimism of parameter estimates used for internal model validation. Results: Key predictors of endoxifen concentration were CYP2D6 genotype, age and weight, explaining altogether an average-based optimism corrected 57% (95% CI: 0.49-0.64) of the inter-individual variability. CYP2D6 genotype explained 54% of the variability. The remaining 3% could be explained by age and weight. Predictors of risk for subtherapeutic endoxifen were CYP2D6 genotype and age. The model showed an optimism-corrected discrimination of 90% (95% CI: 0.86-0.95) and sensitivity and specificity of 66% and 98%, respectively. Consecutively, there is a high probability of misclassifying patients with subtherapeutic endoxifen concentrations based on the prediction rule. Conclusion: The inter-individual variability of endoxifen concentration could largely be explained by CYP2D6 genotype and for a small proportion by age and weight. However, the remaining unexplained inter-individual variability is still high and therefore model-informed tamoxifen dosing should be accompanied by therapeutic drug monitoring.

Value of therapeutic drug monitoring of endoxifen in Egyptian premenopausal patients with breast cancer given tamoxifen adjuvant therapy: A pilot study

“…A previous study showed similar results where both age and weight were statistically significant predictors, but only explained a small percent (1.5-1.8%) of the total variability with small effect sizes after adjusting for CYP2D6 genotype, respectively. 42 Additionally, a prospective, multicenter study on 1977 patients with breast cancer taking adjuvant TAM, observed decreased END concentrations in older patients reflecting age effect on TAM metabolic ratio. 43 A suggested explanation is an expected reduction in older patients of the enzymatic activity causing the lower formation of END.…”