Journal Article

DKFZ-2024-00557

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Nonlinear Mixed-Effects Model of Z-Endoxifen Concentrations in Tamoxifen-Treated Patients from the CEPAM Cohort.

Mc Laughlin, A. M. ; Helland, T. ; Klima, F. ; Koolen, S. L. W. ; van Schaik, R. H. N. ; Mathijssen, R. H. J. ; Neven, P. ; Swen, J. J. ; Guchelaar, H.-J. ; Dalenc, F. ; White-Koning, M. ; Michelet, R. ; Mikus, G. ; Schroth, W. ; Mürdter, T. ; Brauch, H.DKFZ* ; Schwab, M.DKFZ* ; Søiland, H. ; Mellgren, G. ; Thomas, F. ; Kloft, C. ; Hertz, D. L. ; Model, C. E. P. A. (Collaboration Author) ; Agema, B. C. (Contributor) ; Sanchez-Spitman, A. (Contributor) ; Almeida, T. (Contributor) ; Nardin, J. (Contributor) ; Casali-da-Rocha, J. C. (Contributor) ; Moo-Puc, R. E. (Contributor) ; Rangel-Mendez, J. A. (Contributor) ; McMillin, G. (Contributor) ; Hennig, E. E. (Contributor) ; Brewczyńska, E. (Contributor) ; Venzon Antunes, M. (Contributor) ; Haufroid, V. (Contributor) ; Thorén, L. (Contributor) ; Madlensky, L. (Contributor) ; Pierce, J. (Contributor) ; Nakaumra, Y. (Contributor) ; Kubo, M. (Contributor) ; Zembutsu, H. (Contributor) ; Bianchi Ximenez, J. P. (Contributor) ; Lanchote, V. L. (Contributor) ; Rae, J. M. (Contributor) ; Hayes, D. F. (Contributor) ; Stearns, V. (Contributor) ; Skaar, T. C. (Contributor) ; Desta, Z. (Contributor) ; Scott, S. A. (Contributor) ; Desnick, R. J. (Contributor) ; Park, I. H. (Contributor) ; Woo, H. I. (Contributor) ; Lee, S.-Y. (Contributor) ; Fernandez-Santander, A. (Contributor) ; Romero-Lorca, A. (Contributor) ; Villajos, A. N. (Contributor) ; Alonso, M. G. (Contributor) ; Johansson, H. (Contributor) ; Bonanni, B. (Contributor) ; DeCensi, A. (Contributor) ; Gurney, H. (Contributor) ; Balleine, R. (Contributor) ; Irvin, W. J. (Contributor) ; McLeod, H. L. (Contributor) ; Goetz, M. P. (Contributor) ; Reid, J. M. (Contributor) ; Suman, V. J. (Contributor) ; Areepium, N. (Contributor) ; Charoenchokthavee, W. (Contributor) ; Eccles, D. (Contributor) ; Tapper, W. (Contributor) ; Chowbay, B. (Contributor) ; Khor, C. C. (Contributor) ; Hsuen, E. L. (Contributor) ; Tfayli, A. (Contributor) ; Zgheib, N. K. (Contributor) ; Arellano, C. (Contributor)

2024
Wiley-Blackwell Hoboken, NJ

Abstract: Tamoxifen is widely used in patients with hormone receptor-positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z-endoxifen. The Z-endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been proposed but not validated, and prospective trials of individualized tamoxifen treatment to achieve Z-endoxifen concentration thresholds are considered infeasible. Therefore, we aim to validate the association between Z-endoxifen concentration and tamoxifen treatment outcomes, and identify a Z-endoxifen concentration threshold of tamoxifen efficacy, using pharmacometric modeling and simulation. As a first step, the CYP2D6 Endoxifen Percentage Activity Model (CEPAM) cohort was created by pooling data from 28 clinical studies (> 7,000 patients) with measured endoxifen plasma concentrations. After cleaning, data from 6,083 patients were used to develop a nonlinear mixed-effect (NLME) model for tamoxifen and Z-endoxifen pharmacokinetics that includes a conversion factor to allow inclusion of studies that measured total endoxifen but not Z-endoxifen. The final parent-metabolite NLME model confirmed the primary role of CYP2D6, and contributions from body weight, CYP2C9 phenotype, and co-medication with CYP2D6 inhibitors, on Z-endoxifen pharmacokinetics. Future work will use the model to simulate Z-endoxifen concentrations in patients receiving single agent tamoxifen treatment within large prospective clinical trials with long-term survival to identify the Z-endoxifen concentration threshold below which tamoxifen is less efficacious. Identification of this concentration threshold would allow personalized tamoxifen treatment to improve outcomes in patients with hormone receptor-positive breast cancer.

Note: 2024 Sep;116(3):690-702

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Tübingen (TU01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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