Model-based Quantification of Impact of Genetic Polymorphisms and Co-Medications on Pharmacokinetics of Tamoxifen and Six Metabolites in Breast Cancer.

Variations in clinical response to tamoxifen (TAM) may be related to polymorphic cytochromes P450 (CYPs) involved in forming its active metabolite endoxifen (ENDO). We developed a population pharmacokinetic (popPK) model for tamoxifen and six metabolites to determine clinically relevant factors of ENDO exposure. Concentration-time data for TAM and six metabolites come from a prospective, multicenter, 3-year follow-up study of adjuvant TAM (20 mg/day) in breast cancer patients, with plasma samples drawn every 6 months, and genotypes for 63 genetic polymorphisms (PHACS study, NCT01127295). Concentration data for TAM and six metabolites from 928 patients (n = 27,433 concentrations) were analysed simultaneously with a seven-compartment popPK model. CYP2D6 phenotype (poor [PM], intermediate [IM], normal [NM] and ultra-rapid [UM]), CYP3A4*22, CYP2C19*2 and CYP2B6*6 genotypes, concomitant CYP2D6 inhibitors, age and body weight had a significant impact on TAM metabolism. Formation of ENDO from N-desmethyltamoxifen was decreased by 84% (relative standard error [RSE] = 14%) in PM and by 47% (RSE = 9%) in IM patients and increased in UM patients by 27% (RSE = 12%) compared to NM. Dose-adjustment simulations support an increase from 20 mg/day to 40 and 80 mg/day in IM and PM, respectively, to reach ENDO levels similar to those in NM patients. However, when considering Antiestrogenic Activity Score (AAS), a dose increase to 60 mg/day in PM patients seems sufficient. This popPK model can be used as a tool to predict ENDO levels or AAS according to patient's CYP2D6 phenotype for TAM dose adaptation.