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

doi:10.1002/cpt.1960

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^*

^*Corresponding author for this work

Medical Oncology

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Endoxifen is one of the most important metabolites of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (C_{SS,min ENDX}) 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_{SS,min ENDX} using nonlinear mixed-effects modeling. Age and body weight were found to significantly impact C_{SS,min ENDX} in addition to CYP2D6 phenotype. Compared with postmenopausal patients, premenopausal patients had a 30% higher risk for subtarget C_{SS,min ENDX} 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_{SS,min ENDX} 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.

Original language	English
Pages (from-to)	661-670
Number of pages	10
Journal	Clinical Pharmacology & Therapeutics
Volume	108
Issue number	3
DOIs	https://doi.org/10.1002/cpt.1960
Publication status	Published - Sept 2020

Bibliographical note

Funding Information:
This work was, in part, supported by the Robert Bosch Stiftung, the Bundesministerium für Bildung und Forschung (BMBF; 01EK1509A), and the Deutsche Forschungsgemeinschaft (DFG; MU 1727/2-1 and SCHR 1323/2-1), Germany. The authors thank the High-Performance Computing Service of ZEDAT at Freie Universitaet Berlin (https://www.zedat.fu-berlin.de/HPC/Home) for computing time. Open access funding enabled and organized by Projekt DEAL.

Funding Information:
This work was, in part, supported by the Robert Bosch Stiftung, the Bundesministerium für Bildung und Forschung (BMBF; 01EK1509A), and the Deutsche Forschungsgemeinschaft (DFG; MU 1727/2‐1 and SCHR 1323/2‐1), Germany.

Funding Information:
C.K. and W.H. report grants from an industry consortium (AbbVie Deutschland GmbH & Co. K.G., Boehringer Ingelheim Pharma GmbH & Co. K.G., Grünenthal GmbH, Astra Zeneca, F. Hoffmann‐La Roche Ltd, Merck KGaA and Sanofi) for the PharMetrX program. C.K. reports a grant for the Innovative Medicines Initiative‐Joint Undertaking (“DDMoRe”). C.K. and R.Mi. report grants from the Federal Ministry of Education and Research within the Joint Programming Initiative on Antimicrobial Resistance Initiative (JPIAMR), all outside the submitted work. All other authors declared no competing interests for this work.

Publisher Copyright:
© 2020 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics

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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. (2020). Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach. Clinical Pharmacology & Therapeutics, 108(3), 661-670. https://doi.org/10.1002/cpt.1960

@article{8c8a5220c8144eb58217996b14038269,

title = "Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach",

abstract = "Endoxifen is one of the most important metabolites of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (CSS,min ENDX) 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 CSS,min ENDX using nonlinear mixed-effects modeling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared with postmenopausal patients, premenopausal patients had a 30\% higher risk for subtarget CSS,min ENDX 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 CSS,min ENDX 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.",

author = "Anna Mueller-Schoell and Lena Klopp-Schulze and Werner Schroth and Thomas M{\"u}rdter and Robin Michelet and Hiltrud Brauch and Wilhelm Huisinga and Markus Joerger and Patrick Neven and Koolen, \{Stijn L.W.\} and Mathijssen, \{Ron H.J.\} and Ellen Copson and Diana Eccles and Sylvia Chen and Balram Chowbay and Arafat Tfayli and Zgheib, \{Nathalie K.\} and Matthias Schwab and Charlotte Kloft",

note = "Funding Information: This work was, in part, supported by the Robert Bosch Stiftung, the Bundesministerium f{\"u}r Bildung und Forschung (BMBF; 01EK1509A), and the Deutsche Forschungsgemeinschaft (DFG; MU 1727/2-1 and SCHR 1323/2-1), Germany. The authors thank the High-Performance Computing Service of ZEDAT at Freie Universitaet Berlin (https://www.zedat.fu-berlin.de/HPC/Home) for computing time. Open access funding enabled and organized by Projekt DEAL. Funding Information: This work was, in part, supported by the Robert Bosch Stiftung, the Bundesministerium f{\"u}r Bildung und Forschung (BMBF; 01EK1509A), and the Deutsche Forschungsgemeinschaft (DFG; MU 1727/2‐1 and SCHR 1323/2‐1), Germany. Funding Information: C.K. and W.H. report grants from an industry consortium (AbbVie Deutschland GmbH \& Co. K.G., Boehringer Ingelheim Pharma GmbH \& Co. K.G., Gr{\"u}nenthal GmbH, Astra Zeneca, F. Hoffmann‐La Roche Ltd, Merck KGaA and Sanofi) for the PharMetrX program. C.K. reports a grant for the Innovative Medicines Initiative‐Joint Undertaking (“DDMoRe”). C.K. and R.Mi. report grants from the Federal Ministry of Education and Research within the Joint Programming Initiative on Antimicrobial Resistance Initiative (JPIAMR), all outside the submitted work. All other authors declared no competing interests for this work. Publisher Copyright: {\textcopyright} 2020 The Authors Clinical Pharmacology \& Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics",

year = "2020",

month = sep,

doi = "10.1002/cpt.1960",

language = "English",

volume = "108",

pages = "661--670",

journal = "Clinical Pharmacology \& Therapeutics",

issn = "0009-9236",

publisher = "Wiley-Blackwell",

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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, SLW , Mathijssen, RHJ, Copson, E, Eccles, D, Chen, S, Chowbay, B, Tfayli, A, Zgheib, NK, Schwab, M & Kloft, C 2020, 'Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach', Clinical Pharmacology & Therapeutics, vol. 108, no. 3, pp. 661-670. https://doi.org/10.1002/cpt.1960

TY - JOUR

T1 - Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients

T2 - A Pharmacometric Simulation Approach

AU - Mueller-Schoell, Anna

AU - Klopp-Schulze, Lena

AU - Schroth, Werner

AU - Mürdter, Thomas

AU - Michelet, Robin

AU - Brauch, Hiltrud

AU - Huisinga, Wilhelm

AU - Joerger, Markus

AU - Neven, Patrick

AU - Koolen, Stijn L.W.

AU - Mathijssen, Ron H.J.

AU - Copson, Ellen

AU - Eccles, Diana

AU - Chen, Sylvia

AU - Chowbay, Balram

AU - Tfayli, Arafat

AU - Zgheib, Nathalie K.

AU - Schwab, Matthias

AU - Kloft, Charlotte

N1 - Funding Information: This work was, in part, supported by the Robert Bosch Stiftung, the Bundesministerium für Bildung und Forschung (BMBF; 01EK1509A), and the Deutsche Forschungsgemeinschaft (DFG; MU 1727/2-1 and SCHR 1323/2-1), Germany. The authors thank the High-Performance Computing Service of ZEDAT at Freie Universitaet Berlin (https://www.zedat.fu-berlin.de/HPC/Home) for computing time. Open access funding enabled and organized by Projekt DEAL. Funding Information: This work was, in part, supported by the Robert Bosch Stiftung, the Bundesministerium für Bildung und Forschung (BMBF; 01EK1509A), and the Deutsche Forschungsgemeinschaft (DFG; MU 1727/2‐1 and SCHR 1323/2‐1), Germany. Funding Information: C.K. and W.H. report grants from an industry consortium (AbbVie Deutschland GmbH & Co. K.G., Boehringer Ingelheim Pharma GmbH & Co. K.G., Grünenthal GmbH, Astra Zeneca, F. Hoffmann‐La Roche Ltd, Merck KGaA and Sanofi) for the PharMetrX program. C.K. reports a grant for the Innovative Medicines Initiative‐Joint Undertaking (“DDMoRe”). C.K. and R.Mi. report grants from the Federal Ministry of Education and Research within the Joint Programming Initiative on Antimicrobial Resistance Initiative (JPIAMR), all outside the submitted work. All other authors declared no competing interests for this work. Publisher Copyright: © 2020 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics

PY - 2020/9

Y1 - 2020/9

N2 - Endoxifen is one of the most important metabolites of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (CSS,min ENDX) 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 CSS,min ENDX using nonlinear mixed-effects modeling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared with postmenopausal patients, premenopausal patients had a 30% higher risk for subtarget CSS,min ENDX 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 CSS,min ENDX 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.

AB - Endoxifen is one of the most important metabolites of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (CSS,min ENDX) 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 CSS,min ENDX using nonlinear mixed-effects modeling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared with postmenopausal patients, premenopausal patients had a 30% higher risk for subtarget CSS,min ENDX 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 CSS,min ENDX 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.

UR - https://www.scopus.com/pages/publications/85088300651

U2 - 10.1002/cpt.1960

DO - 10.1002/cpt.1960

M3 - Article

C2 - 32578187

SN - 0009-9236

VL - 108

SP - 661

EP - 670

JO - Clinical Pharmacology & Therapeutics

JF - Clinical Pharmacology & Therapeutics

IS - 3

ER -

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

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