Simulation-based assessment of the impact of non-adherence on endoxifen target attainment in different tamoxifen dosing strategies

Anna Mueller-Schoell, Lena Klopp-Schulze, Robin Michelet, Madelé van Dyk, Thomas E. Mürdter, Matthias Schwab, Markus Joerger, Wilhelm Huisinga, Gerd Mikus, Charlotte Kloft

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1 Citation (Scopus)

Abstract

Tamoxifen is widely used in breast cancer treatment and minimum steady-state concentrations of its active metabolite endoxifen (CSS,min ENDX) above 5.97 ng/mL have been associated with favourable disease outcome. Yet, about 20% of patients do not reach target CSS,min ENDX ap-plying conventional tamoxifen dosing. Moreover, 4–75% of patients are non-adherent, resulting in worse disease outcomes. Assuming complete adherence, we previously showed model-informed precision dosing (MIPD) to be superior to conventional and CYP2D6-guided dosing in minimising the proportion of patients with subtarget CSS,min ENDX. Given the high non-adherence rate in long-term tamoxifen therapy, this study investigated the impact of non-adherence on CSS,min ENDX target attainment in different dosing strategies. We show that MIPD allows to account for the expected level of non-adherence (here: up to 2 missed doses/week): increasing the MIPD target threshold from 5.97 ng/mL to 9 ng/mL (the lowest reported CSS,min ENDX in CYP2D6 normal metabolisers) as a safeguard resulted in the lowest interindividual variability and proportion of patients with subtarget CSS,min ENDX even in non-adherent patients. This is a significant improvement to conventional and CYP2D6-guided dosing. Adding a fixed increment to the originally selected dose is not recommended, since it inflates interindividual variability.

Original languageEnglish
Article number115
Number of pages11
JournalPharmaceuticals
Volume14
Issue number2
DOIs
Publication statusPublished - Feb 2021

Keywords

  • Model-informed precision dosing
  • Non-adherence
  • Pharmacokinetics
  • Pharmacometrics
  • Tamoxifen

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