Simulation-Based Assessment of the Impact of Non-Adherence on Endoxifen Target Attainment in Different Tamoxifen Dosing Strategies

• Main Authors: Anna Mueller-Schoell, Lena Klopp-Schulze, Robin Michelet, Madelé van Dyk, Thomas E. Mürdter, Matthias Schwab, Markus Joerger, Wilhelm Huisinga, Gerd Mikus, Charlotte Kloft
• Format: Article
• Language: English
• Published: MDPI AG 2021-02-01
• Series: Pharmaceuticals
• Subjects: tamoxifen; non-adherence; model-informed precision dosing; pharmacokinetics; pharmacometrics
• Online Access: https://www.mdpi.com/1424-8247/14/2/115

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} applying 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 <i>CYP2D6</i>-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 <i>CYP2D6</i> 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 <i>CYP2D6</i>-guided dosing. Adding a fixed increment to the originally selected dose is not recommended, since it inflates interindividual variability.