title: Concomitant use of tamoxifen and endoxifen in postmenopausal early breast cancer: prediction of plasma levels by physiologically-based pharmacokinetic modeling.
abstract: OBJECTIVE
  To overcome cytochrome P450 2D6 (CYP2D6) mediated tamoxifen resistance in postmenopausal early breast cancer, CYP2D6 phenotype-adjusted tamoxifen dosing in patients with impaired CYP2D6 metabolism and/or the application of endoxifen, the most potent tamoxifen metabolite, are alternative treatment options. To elucidate both strategies comprehensively we used a physiologically-based pharmacokinetic (PBPK) modeling approach.
  
  
  METHODS
  Firstly simulation of increasing tamoxifen dosages was performed by a virtual clinical trial including populations of CYP2D6 poor (PM), intermediate (IM) and extensive metabolizers (EM) (N = 8,000). Secondly we performed PBPK-simulations under consideration of tamoxifen use plus concomitant increasing dosages of endoxifen (N = 7,000).
  
  
  RESULTS
  Our virtual study demonstrates that dose escalation of tamoxifen in IMs resulted in endoxifen steady-state plasma concentrations similar to CYP2D6 EMs whereas PMs did not reach EM endoxifen levels. Steady-state plasma concentrations of tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen were similar in CYP2D6 IMs and PMs versus EMs using once daily dosing of 20 mg tamoxifen and concomitant CYP2D6 phenotype-adjusted endoxifen dosing in IMs and PMs (1 mg/d and 3 mg/d, respectively).
  
  
  CONCLUSIONS
  In conclusion, we suggest that co-administration of endoxifen in tamoxifen treated early breast cancer women with impaired CYP2D6 metabolism is a promising alternative to reach plasma concentrations comparable to CYP2D6 EM patients.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Klinische Pharmazie, Westfälische Wilhelms-Universität Münster, Corrensstrasse 48, Münster, 48149 Germany ; Computational Systems Biology, Bayer Technology Services GmbH, Building 9115, Leverkusen, 51368 Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Dickschen
authors.affiliation: Computational Systems Biology, Bayer Technology Services GmbH, Building 9115, Leverkusen, 51368 Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Eissing
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University Tübingen, Auerbachstrasse 112, Stuttgart, 70376 Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mürdter
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University Tübingen, Auerbachstrasse 112, Stuttgart, 70376 Germany ; Department of Clinical Pharmacology, University Hospital Tübingen, Auf der Morgenstelle 8, Tübingen, 72076 Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Computational Systems Biology, Bayer Technology Services GmbH, Building 9115, Leverkusen, 51368 Germany ; Clinical Pharmacometrics, Bayer Pharma AG, Aprather Weg 18a, Wuppertal, 42113 Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Willmann
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Klinische Pharmazie, Westfälische Wilhelms-Universität Münster, Corrensstrasse 48, Münster, 48149 Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Hempel
keywords: CYP2D6 genotype; PBPK modeling; Postmenopausal breast cancer; Tamoxifen-endoxifen-combination