TY  - JOUR
AU  - Mc Laughlin, Anna M
AU  - Helland, Thomas
AU  - Klima, Fenja
AU  - Koolen, Stijn L W
AU  - van Schaik, Ron H N
AU  - Mathijssen, Ron H J
AU  - Neven, Patrick
AU  - Swen, Jesse J
AU  - Guchelaar, Henk-Jan
AU  - Dalenc, Florence
AU  - White-Koning, Melanie
AU  - Michelet, Robin
AU  - Mikus, Gerd
AU  - Schroth, Werner
AU  - Mürdter, Thomas
AU  - Brauch, Hiltrud
AU  - Schwab, Matthias
AU  - Søiland, Håvard
AU  - Mellgren, Gunnar
AU  - Thomas, Fabienne
AU  - Kloft, Charlotte
AU  - Hertz, Daniel L
TI  - Nonlinear Mixed-Effects Model of Z-Endoxifen Concentrations in Tamoxifen-Treated Patients from the CEPAM Cohort.
JO  - Clinical pharmacology & therapeutics
VL  - 116
IS  - 3
SN  - 0009-9236
CY  - Hoboken, NJ
PB  - Wiley-Blackwell
M1  - DKFZ-2024-00557
SP  - 690-702
PY  - 2024
N1  - 2024 Sep;116(3):690-702
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:38494911
DO  - DOI:10.1002/cpt.3238
UR  - https://inrepo02.dkfz.de/record/289025
ER  -