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

Tamoxifen is widely used in breast cancer treatment and minimum steady-state concentrations of its active metabolite endoxifen (C_{SS,min ENDX}) above 5.97 ng/mL have been associated with favourable disease outcome. Yet, about 20% of patients do not reach target C_{SS,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 C_{SS,min ENDX}. Given the high non-adherence rate in long-term tamoxifen therapy, this study investigated the impact of non-adherence on C_{SS,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 C_{SS,min ENDX} in CYP2D6 normal metabolisers) as a safeguard resulted in the lowest interindividual variability and proportion of patients with subtarget C_{SS,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.