Population pharmacokinetic modeling of tamoxifen and its active metabolite endoxifen in healthy volunteers of African ancestry genotyped for CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5.

Abstract

<title>Abstract</title> Purpose Wide inter-individual variability is seen in the clinical outcomes of tamoxifen treatment, which may be attributable to cytochrome P450 genetic polymorphisms. To investigate this, we analysed data from an open-label three parallel arm trial with 36 healthy volunteers of African ancestry to whom a dose of 20 mg of tamoxifen had been administered and drug concentrations of tamoxifen and its three metabolites measured over 34 time points after administration. Methods The data was best described by a pharmacokinetic model, which focused on tamoxifen and its active metabolite endoxifen only. The model was described by a two-compartment model for the parent linked to a one-compartment model for the metabolite. Results Data exploration and estimated pharmacokinetic parameters for both compounds indicated wide variability between participants. The findings demonstrated high inter individual variability (99.3%) in the formation of endoxifen with no evidence to suggest that the <italic>CYP2D6</italic> gene could explain this variation. Model diagnostic plots such as goodness of fit plots and visual predictive checks showed a good predictive performance of the model. Conclusion Age, BMI, <italic>CYP2D6</italic>, <italic>CYP3A4</italic>, <italic>CYP3A5</italic>, <italic>CYP2B6</italic>, <italic>CYP2C9</italic> and <italic>CYP2C19</italic> genotypes had no significant impact in explaining the variability in pharmacokinetic parameters for tamoxifen and endoxifen.