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

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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.

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Mueller-Schoell, A., Klopp-Schulze, L., Michelet, R., van Dyk, M., Mürdter, T. E., Schwab, M., … Kloft, C. (2021). Simulation-based assessment of the impact of non-adherence on endoxifen target attainment in different tamoxifen dosing strategies. Pharmaceuticals, 14(2), 1–11. https://doi.org/10.3390/ph14020115

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