%0 Journal Article
%A Mc Laughlin, Anna M
%A Helland, Thomas
%A Klima, Fenja
%A Koolen, Stijn L W
%A van Schaik, Ron H N
%A Mathijssen, Ron H J
%A Neven, Patrick
%A Swen, Jesse J
%A Guchelaar, Henk-Jan
%A Dalenc, Florence
%A White-Koning, Melanie
%A Michelet, Robin
%A Mikus, Gerd
%A Schroth, Werner
%A Mürdter, Thomas
%A Brauch, Hiltrud
%A Schwab, Matthias
%A Søiland, Håvard
%A Mellgren, Gunnar
%A Thomas, Fabienne
%A Kloft, Charlotte
%A Hertz, Daniel L
%T Nonlinear Mixed-Effects Model of Z-Endoxifen Concentrations in Tamoxifen-Treated Patients from the CEPAM Cohort.
%J Clinical pharmacology & therapeutics
%V 116
%N 3
%@ 0009-9236
%C Hoboken, NJ
%I Wiley-Blackwell
%M DKFZ-2024-00557
%P 690-702
%D 2024
%Z 2024 Sep;116(3):690-702
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:38494911
%R 10.1002/cpt.3238
%U https://inrepo02.dkfz.de/record/289025