Population Pharmacokinetics of Trametinib and Impact of Nonadherence on Drug Exposure in Oncology Patients as Part of the Optimizing Oral Targeted Anticancer Therapies Study

Simple Summary Poor adherence to trametinib, an oral anticancer drug, may be the consequence of side effects that severely impact the patient's quality of life. The significant interindividual variability associated with poor adherence results in suboptimal drug exposure and consequently in unfavourable patient outcomes. By characterizing the pharmacokinetics of trametinib, this study aims to assess (i) the adequacy of recommended doses to achieve efficacy thresholds and (ii) the impact of non-adherence on drug exposure. The latter was assessed by simulating different scenarios of missing one or more doses per week to highlight the risk of treatment failure associated with poor adherence. These results promote interprofessional collaboration and patient partnership to address patients' needs in order to ensure adherence to trametinib and in fine therapeutic success.Abstract Trametinib is a targeted therapy used for the treatment of solid tumours, with significant variability reported in real-life studies. This variability increases the risk of suboptimal exposure, which can lead to treatment failure or increased toxicity. Using model-based simulation, this study aims to characterize and investigate the pharmacokinetics and the adequacy of the currently recommended doses of trametinib. Additionally, the simulation of various suboptimal adherence scenarios allowed for an assessment of the impact of patients' drug adherence on the treatment outcome. The population data collected in 33 adult patients, providing 113 plasmatic trametinib concentrations, were best described by a two-compartment model with linear absorption and elimination. The study also identified a significant positive effect of fat-free mass and a negative effect of age on clearance, explaining 66% and 21% of the initial associated variability, respectively. Simulations showed that a maximum dose of 2 mg daily achieved the therapeutic target in 36% of male patients compared to 72% of female patients. A dose of 1.5 mg per day in patients over 65 years of age achieved similar rates, with 44% and 79% for male and female patients, respectively, reaching the therapeutic target. Poor adherence leads to a significant drop in concentrations and a high risk of subtherapeutic drug levels. These results underline the importance of interprofessional collaboration and patient partnership along the patient's journey to address patients' needs regarding trametinib and support medication adherence.