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Tamoxifen population pharmacokinetics in breast cancer patients: metabolism, genetic polymorphism, hormonal status and age

Grant number: 16/20613-5
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): January 06, 2017
Effective date (End): August 05, 2017
Field of knowledge:Biological Sciences - Pharmacology - Clinical Pharmacology
Principal researcher:Vera Lúcia Lanchote
Grantee:João Paulo Bianchi Ximenez
Supervisor abroad: Oscar Della Pasqua
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: University College London (UCL), England  
Associated to the scholarship:14/16360-9 - Tamoxifen population pharmacokinetics in breast cancer patients: metabolism study, genetic polymorphism, hormonal status and age, BP.DR


The study aims to investigate the influence of age, hormonal status, CYP2D6, CYP3A and P-gp in vivo activities and genetic polimorphisms on tamoxifen kinetic disposition and metabolism in breast cancer patients. Thus, two groups of patients were defined according to age and hormonal status, pre-menopausal group (age < 50 years) and postmenopausal group (age > 60 years). Blood samples were collected from patients within 24 hours after tamoxifen daily dose to determine tamoxifen total and free plasma concentrations and total concentrations of its metabolites endoxifen and 4-OH-tamoxifen using LC-MS/MS. CYP2D6, CYP3A and P-gp in vivo activities using, respectively, the probes metoprolol, midazolam and fexofenadine were also evaluated. CYP2D6, CYP3A4/5, ABCC2 and ABCB1 genotypes were determined by Taqman allelic discrimination. Tamoxifen population pharmacokinetic model will be developed using the software NONMEM (Non-linear mixed effect level) in order to evaluate the main covariates. The results will express as means, 95% confidence intervals, medians and percentiles 25-75%. Mann-Whitney test (significance fixed at p <0.05) will be used to evaluate the influence of age and hormonal status on the pharmacokinetics of tamoxifen and its metabolites.

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