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Nonlinear Mixed-Effects Model of Z-Endoxifen Concentrations in Tamoxifen-Treated Patients from the CEPAM Cohort.
Mc Laughlin, Anna M; Helland, Thomas; Klima, Fenja; Koolen, Stijn L W; van Schaik, Ron H N; Mathijssen, Ron H J; Neven, Patrick; Swen, Jesse J; Guchelaar, Henk-Jan; Dalenc, Florence; White-Koning, Melanie; Michelet, Robin; Mikus, Gerd; Schroth, Werner; Mürdter, Thomas; Brauch, Hiltrud; Schwab, Matthias; Søiland, Håvard; Mellgren, Gunnar; Thomas, Fabienne; Kloft, Charlotte; Hertz, Daniel L.
Afiliação
  • Mc Laughlin AM; Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.
  • Helland T; PharMetrX Graduate Research Training Program, Berlin/Potsdam, Germany.
  • Klima F; Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan, USA.
  • Koolen SLW; Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway.
  • van Schaik RHN; Department of Clinical Science, University of Bergen, Bergen, Norway.
  • Mathijssen RHJ; Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.
  • Neven P; PharMetrX Graduate Research Training Program, Berlin/Potsdam, Germany.
  • Swen JJ; Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • Guchelaar HJ; Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • Dalenc F; Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • White-Koning M; Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • Michelet R; Department of Gynecological Oncology and Multidisciplinary Breast Center, University Hospitals Leuven, Leuven, Belgium.
  • Mikus G; Department Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, the Netherlands.
  • Schroth W; Department Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, the Netherlands.
  • Mürdter T; Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole, Toulouse, France.
  • Brauch H; Cancer Research Center of Toulouse (CRCT), Inserm U1037, Université Paul Sabatier, Toulouse, France.
  • Schwab M; Cancer Research Center of Toulouse (CRCT), Inserm U1037, Université Paul Sabatier, Toulouse, France.
  • Søiland H; Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.
  • Mellgren G; Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.
  • Thomas F; Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany.
  • Kloft C; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
  • Hertz DL; University Tübingen, Tübingen, Germany.
Clin Pharmacol Ther ; 116(3): 690-702, 2024 Sep.
Article em En | MEDLINE | ID: mdl-38494911
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tamoxifeno / Neoplasias da Mama / Dinâmica não Linear / Antineoplásicos Hormonais / Citocromo P-450 CYP2D6 Limite: Aged / Female / Humans / Middle aged Idioma: En Revista: Clin Pharmacol Ther Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tamoxifeno / Neoplasias da Mama / Dinâmica não Linear / Antineoplásicos Hormonais / Citocromo P-450 CYP2D6 Limite: Aged / Female / Humans / Middle aged Idioma: En Revista: Clin Pharmacol Ther Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha