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

• Main Authors: Anna Mueller-Schoell (Author), Lena Klopp-Schulze (Author), Robin Michelet (Author), Madelé van Dyk (Author), Thomas E. Mürdter (Author), Matthias Schwab (Author), Markus Joerger (Author), Wilhelm Huisinga (Author), Gerd Mikus (Author), Charlotte Kloft (Author)
• Format: Book
• Published: MDPI AG, 2021-02-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph14020115; 1424-8247
• Keywords: tamoxifen; non-adherence; model-informed precision dosing; pharmacokinetics; pharmacometrics; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 14, Iss 2, p 115 (2021)

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.