Non-compartmental and population pharmacokinetics of tamoxifen in patients undergoing treatment for breast cancer: metabolism, hormonal status and genetic polymorphism

Author(s)

João Paulo Bianchi Ximenez

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC)
• Defense date: 2018-09-10

Examining board members

Vera Lucia Lanchote; Fernando Barbosa Junior; Riccardo Lacchini; Francisco José Cândido dos Reis

• Advisor: Vera Lucia Lanchote

Abstract

Tamoxifen (TAM) is the reference treatment for estrogen-sensitive breast cancer. TAM is metabolized in approximately 40 metabolites, with endoxifen (END) 100 times more potent than the unchanged drug as anti-estrogen in breast cancer cells. The present study evaluates the influence of hormonal status (Chapter 2) and genetic polymorphism (Chapter 3) on the pharmacokinetics of TAM and its metabolites END, 4-hydroxytamoxifen (4-HTAM) and Ndesmethyltamoxifen (NDTAM) in adjuvant treatment for breast cancer patients (n=40) with TAM (20 mg/day) for more than 80 days and phenotyped for CYP2D6, CYP3A4/5 and P-gp. Serial blood samples were collected at the 24 h TAM dosing interval. TAM and its metabolites were analyzed in plasma by LC-MS / MS (Chapter 1). The method had no matrix effect and showed linearities for TAM and END in the range of 1-1250 ng/mL, for 4-HTAM of 0.4-500 ng/mL and for NDTAM of 2-2500 ng/mL of plasma. The coefficients of variation and the relative standard errors of the accuracy and precision studies were less than 15%. In Chapter 2, patients were divided into premenopausal (n = 20) and postmenopausal (n = 20) groups in order to evaluate the influence of hormonal status on the non-compartmental pharmacokinetics of TAM. Premenopausal patients had lower CSS values (Student\'s t-test, p <0.05) for the active metabolite END (135% reduction), TAM, 4-HTAM and NDTAM metabolites (reduction of 70- 80%) when compared to postmenopausal patients. In addition to the hormonal status, the white or non-white race was also defined as a variable for the CSS values of the END, while body weight was defined as a variable for the NDTAM CSS values. In Chapter 3, an accurate and predictive population pharmacokinetic model was developed and validated for TAM and its metabolites END, 4-HTAM, and NDTAM, using the non-linear model of mixed effects for the 40 patients investigated, with the objective to simulate patients for the evaluation of the influence of genetic polymorphisms. The CSS ratios for TAM and its major metabolites for the simulated patients (n=100) with PM and NM phenotypes for CYP2D6 and CYP3A4/5 show that the CYP2D6 PM phenotype does not change the TAM CSS values, 4- HTAM and NDTAM but reduces by approximately 80% the CSS values of the active metabolite END, while the PM phenotype for CYP3A4/5 increases by five times the TAM CSS values and reduces by 50% the CSS values of the END , 4-HTAM and NDTAM metabolites. The variability in plasma concentrations of the END active metabolite can be inferred as multifactorial considering that concentrations lower than the 6 ng/mL threshold were observed for all patients simulated with phenotype PM for CYP2D6 and for 5 of the 40 investigated patients phenotyped as NMs or IMs for CYP2D6. Therefore, the monitoring of plasma concentrations of END, not the CYP2D6 phenotype, can be inferred as a good candidate to guide the strategy of optimizing the dosage regimen of TAM in the treatment of breast cancer. (AU)

• FAPESP's process: 14/16360-9 - Tamoxifen population pharmacokinetics in breast cancer patients: metabolism study, genetic polymorphism, hormonal status and age
• Grantee: João Paulo Bianchi Ximenez
• Support Opportunities: Scholarships in Brazil - Doctorate