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Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach

Anna Mueller-Schoell, Lena Klopp-Schulze, Werner Schroth, Thomas Mürdter, Robin Michelet, Hiltrud Brauch, Wilhelm Huisinga, Markus Joerger, Patrick Neven, Stijn L W Koolen, Ron H J Mathijssen, Ellen Copson, Diana Eccles, Sylvia Chen, Balram Chowbay, Arafat Tfayli, Nathalie K Zgheib, Matthias Schwab & Charlotte Kloft

abstract 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.
   
citation Mueller-Schoell A, Klopp-Schulze L, Schroth W, Mürdter T, Michelet R, Brauch H, Huisinga W, Joerger M, Neven P, Koolen S L W, Mathijssen R H J, Copson E, Eccles D, Chen S, Chowbay B, Tfayli A, Zgheib N K, Schwab M, Kloft C. Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach. Clin Pharmacol Ther 2020; 108:661-670.
   
type journal paper/review (English)
date of publishing 23-07-2020
journal title Clin Pharmacol Ther (108/3)
ISSN electronic 1532-6535
pages 661-670
PubMed 32578187
DOI 10.1002/cpt.1960