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000289025 1001_ $$00000-0002-5936-1877$$aMc Laughlin, Anna M$$b0
000289025 245__ $$aNonlinear Mixed-Effects Model of Z-Endoxifen Concentrations in Tamoxifen-Treated Patients from the CEPAM Cohort.
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000289025 520__ $$aTamoxifen is widely used in patients with hormone receptor-positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z-endoxifen. The Z-endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been proposed but not validated, and prospective trials of individualized tamoxifen treatment to achieve Z-endoxifen concentration thresholds are considered infeasible. Therefore, we aim to validate the association between Z-endoxifen concentration and tamoxifen treatment outcomes, and identify a Z-endoxifen concentration threshold of tamoxifen efficacy, using pharmacometric modeling and simulation. As a first step, the CYP2D6 Endoxifen Percentage Activity Model (CEPAM) cohort was created by pooling data from 28 clinical studies (> 7,000 patients) with measured endoxifen plasma concentrations. After cleaning, data from 6,083 patients were used to develop a nonlinear mixed-effect (NLME) model for tamoxifen and Z-endoxifen pharmacokinetics that includes a conversion factor to allow inclusion of studies that measured total endoxifen but not Z-endoxifen. The final parent-metabolite NLME model confirmed the primary role of CYP2D6, and contributions from body weight, CYP2C9 phenotype, and co-medication with CYP2D6 inhibitors, on Z-endoxifen pharmacokinetics. Future work will use the model to simulate Z-endoxifen concentrations in patients receiving single agent tamoxifen treatment within large prospective clinical trials with long-term survival to identify the Z-endoxifen concentration threshold below which tamoxifen is less efficacious. Identification of this concentration threshold would allow personalized tamoxifen treatment to improve outcomes in patients with hormone receptor-positive breast cancer.
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000289025 7001_ $$00000-0002-8681-9601$$aHelland, Thomas$$b1
000289025 7001_ $$00009-0002-8504-9788$$aKlima, Fenja$$b2
000289025 7001_ $$00000-0002-0973-7530$$aKoolen, Stijn L W$$b3
000289025 7001_ $$00000-0003-1864-2151$$avan Schaik, Ron H N$$b4
000289025 7001_ $$00000-0001-5667-5697$$aMathijssen, Ron H J$$b5
000289025 7001_ $$aNeven, Patrick$$b6
000289025 7001_ $$00000-0002-3965-5552$$aSwen, Jesse J$$b7
000289025 7001_ $$00000-0002-7085-1383$$aGuchelaar, Henk-Jan$$b8
000289025 7001_ $$aDalenc, Florence$$b9
000289025 7001_ $$00000-0001-5072-5489$$aWhite-Koning, Melanie$$b10
000289025 7001_ $$00000-0002-5485-607X$$aMichelet, Robin$$b11
000289025 7001_ $$00000-0003-1783-133X$$aMikus, Gerd$$b12
000289025 7001_ $$00000-0003-1412-4592$$aSchroth, Werner$$b13
000289025 7001_ $$aMürdter, Thomas$$b14
000289025 7001_ $$00000-0001-7531-2736$$aBrauch, Hiltrud$$b15
000289025 7001_ $$0P:(DE-He78)0321c153233e619c095d93d9d5546c9d$$aSchwab, Matthias$$b16
000289025 7001_ $$00000-0002-9285-2774$$aSøiland, Håvard$$b17
000289025 7001_ $$aMellgren, Gunnar$$b18
000289025 7001_ $$00000-0001-9886-412X$$aThomas, Fabienne$$b19
000289025 7001_ $$00000-0001-9344-8514$$aKloft, Charlotte$$b20
000289025 7001_ $$00000-0003-0501-1035$$aHertz, Daniel L$$b21
000289025 7001_ $$aModel, CYP2D6 Endoxifen Percentage Activity$$b22$$eCollaboration Author
000289025 7001_ $$aAgema, Bram C$$b23$$eContributor
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