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

Research output: Contribution to journalArticleAcademicpeer-review

19 Citations (Scopus)
14 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)661-670
Number of pages10
JournalClinical Pharmacology & Therapeutics
Volume108
Issue number3
DOIs
Publication statusPublished - 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

Research programs

  • EMC OR-01

Fingerprint

Dive into the research topics of 'Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach'. Together they form a unique fingerprint.

Cite this