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
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abstract
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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.
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citation
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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 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.
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type
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journal paper/review (English)
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date of publishing
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23-07-2020
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journal title
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Clin Pharmacol Ther (108/3)
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ISSN electronic
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1532-6535
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pages
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661-670
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PubMed
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32578187
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DOI
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10.1002/cpt.1960
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