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

Journal Paper/Review - Jul 23, 2020

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Mueller-Schoell A, Klopp-Schulze L, Schroth W, Mürdter T, Michelet R, Brauch H, Huisinga W, Joerger M, Neven P, Koolen S, Mathijssen R, Copson E, Eccles D, Chen S, Chowbay B, Tfayli A, Zgheib N, 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.
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Journal Paper/Review (English)
Journal
Clin Pharmacol Ther 2020; 108
Publication Date
Jul 23, 2020
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Issn Electronic
1532-6535
Pages
661-670
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Brief description/objective

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.