Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach
Journal Paper/Review - Jul 23, 2020
Mueller-Schoell Anna, Schwab Matthias, Zgheib Nathalie K, Tfayli Arafat, Chowbay Balram, Chen Sylvia, Eccles Diana, Copson Ellen, Mathijssen Ron H J, Koolen Stijn L W, Neven Patrick, Jörger Markus, Huisinga Wilhelm, Brauch Hiltrud, Michelet Robin, Mürdter Thomas, Schroth Werner, Klopp-Schulze Lena, Kloft Charlotte
Endoxifen is one of the most important metabolites of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (C ) is observed under tamoxifen standard dosing and patients with breast cancer who do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at a 26% higher recurrence risk compared with patients with endoxifen concentrations exceeding this value. In this investigation, 10 clinical tamoxifen studies were pooled (1,388 patients) to investigate influential factors on C using nonlinear mixed-effects modeling. Age and body weight were found to significantly impact C in addition to CYP2D6 phenotype. Compared with postmenopausal patients, premenopausal patients had a 30% higher risk for subtarget C at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1-13.8-fold higher risk for subtarget C compared with elderly low-weight patients. Considering ever-rising obesity rates and the clinical importance of tamoxifen for premenopausal patients, this subpopulation may benefit most from individualized tamoxifen dosing.