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@ARTICLE{McLaughlin:289025,
      author       = {A. M. Mc Laughlin and T. Helland and F. Klima and S. L. W.
                      Koolen and R. H. N. van Schaik and R. H. J. Mathijssen and
                      P. Neven and J. J. Swen and H.-J. Guchelaar and F. Dalenc
                      and M. White-Koning and R. Michelet and G. Mikus and W.
                      Schroth and T. Mürdter and H. Brauch$^*$ and M. Schwab$^*$
                      and H. Søiland and G. Mellgren and F. Thomas and C. Kloft
                      and D. L. Hertz},
      collaboration = {C. E. P. A. Model},
      othercontributors = {B. C. Agema and A. Sanchez-Spitman and T. Almeida and J.
                          Nardin and J. C. Casali-da-Rocha and R. E. Moo-Puc and J. A.
                          Rangel-Mendez and G. McMillin and E. E. Hennig and E.
                          Brewczyńska and M. Venzon Antunes and V. Haufroid and L.
                          Thorén and L. Madlensky and J. Pierce and Y. Nakaumra and
                          M. Kubo and H. Zembutsu and J. P. Bianchi Ximenez and V. L.
                          Lanchote and J. M. Rae and D. F. Hayes and V. Stearns and T.
                          C. Skaar and Z. Desta and S. A. Scott and R. J. Desnick and
                          I. H. Park and H. I. Woo and S.-Y. Lee and A.
                          Fernandez-Santander and A. Romero-Lorca and A. N. Villajos
                          and M. G. Alonso and H. Johansson and B. Bonanni and A.
                          DeCensi and H. Gurney and R. Balleine and W. J. Irvin and H.
                          L. McLeod and M. P. Goetz and J. M. Reid and V. J. Suman and
                          N. Areepium and W. Charoenchokthavee and D. Eccles and W.
                          Tapper and B. Chowbay and C. C. Khor and E. L. Hsuen and A.
                          Tfayli and N. K. Zgheib and C. Arellano},
      title        = {{N}onlinear {M}ixed-{E}ffects {M}odel of {Z}-{E}ndoxifen
                      {C}oncentrations in {T}amoxifen-{T}reated {P}atients from
                      the {CEPAM} {C}ohort.},
      journal      = {Clinical pharmacology $\&$ therapeutics},
      volume       = {116},
      number       = {3},
      issn         = {0009-9236},
      address      = {Hoboken, NJ},
      publisher    = {Wiley-Blackwell},
      reportid     = {DKFZ-2024-00557},
      pages        = {690-702},
      year         = {2024},
      note         = {2024 Sep;116(3):690-702},
      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.},
      cin          = {TU01},
      ddc          = {610},
      cid          = {I:(DE-He78)TU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38494911},
      doi          = {10.1002/cpt.3238},
      url          = {https://inrepo02.dkfz.de/record/289025},
}