Nonlinear Mixed-Effects Model of Z-Endoxifen Concentrations in Tamoxifen-Treated Patients from the CEPAM Cohort
© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Clinical pharmacology and therapeutics - (2024) vom: 18. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mc Laughlin, Anna M [VerfasserIn] |
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Date Revised 18.03.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1002/cpt.3238 |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Nonlinear Mixed-Effects Model of Z-Endoxifen Concentrations in Tamoxifen-Treated Patients from the CEPAM Cohort |
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| 520 | |a © 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Klima, Fenja |e verfasserin |4 aut | |
| 700 | 1 | |a Koolen, Stijn L W |e verfasserin |4 aut | |
| 700 | 1 | |a van Schaik, Ron H N |e verfasserin |4 aut | |
| 700 | 1 | |a Mathijssen, Ron H J |e verfasserin |4 aut | |
| 700 | 1 | |a Neven, Patrick |e verfasserin |4 aut | |
| 700 | 1 | |a Swen, Jesse J |e verfasserin |4 aut | |
| 700 | 1 | |a Guchelaar, Henk-Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Dalenc, Florence |e verfasserin |4 aut | |
| 700 | 1 | |a White-Koning, Melanie |e verfasserin |4 aut | |
| 700 | 1 | |a Michelet, Robin |e verfasserin |4 aut | |
| 700 | 1 | |a Mikus, Gerd |e verfasserin |4 aut | |
| 700 | 1 | |a Schroth, Werner |e verfasserin |4 aut | |
| 700 | 1 | |a Mürdter, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Brauch, Hiltrud |e verfasserin |4 aut | |
| 700 | 1 | |a Schwab, Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a Søiland, Håvard |e verfasserin |4 aut | |
| 700 | 1 | |a Mellgren, Gunnar |e verfasserin |4 aut | |
| 700 | 1 | |a Thomas, Fabienne |e verfasserin |4 aut | |
| 700 | 1 | |a Kloft, Charlotte |e verfasserin |4 aut | |
| 700 | 1 | |a Hertz, Daniel L |e verfasserin |4 aut | |
| 700 | 0 | |a CYP2D6 Endoxifen Percentage Activity Model (CEPAM) Consortium |e verfasserin |4 aut | |
| 700 | 1 | |a Agema, Bram C |e investigator |4 oth | |
| 700 | 1 | |a Sanchez-Spitman, Anabel |e investigator |4 oth | |
| 700 | 1 | |a Almeida, Thais |e investigator |4 oth | |
| 700 | 1 | |a Nardin, Jeanine |e investigator |4 oth | |
| 700 | 1 | |a Casali-da-Rocha, José Claudio |e investigator |4 oth | |
| 700 | 1 | |a Moo-Puc, Rosa Esther |e investigator |4 oth | |
| 700 | 1 | |a Rangel-Mendez, Jorge Aarón |e investigator |4 oth | |
| 700 | 1 | |a McMillin, Gwendolyn |e investigator |4 oth | |
| 700 | 1 | |a Hennig, Ewa E |e investigator |4 oth | |
| 700 | 1 | |a Brewczyńska, Elżbieta |e investigator |4 oth | |
| 700 | 1 | |a Venzon Antunes, Marina |e investigator |4 oth | |
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| 700 | 1 | |a Gurney, Howard |e investigator |4 oth | |
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