PDF(Pubmed)
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.
摘要：
曲美替尼是一种用于治疗实体瘤的靶向疗法，在现实生活中的研究中报告了显著的变异性。这种可变性增加了次优暴露的风险，这可能导致治疗失败或毒性增加。使用基于模型的仿真，本研究旨在表征和研究曲美替尼目前推荐剂量的药代动力学和适宜性.此外,通过模拟各种次优依从性情景,可以评估患者药物依从性对治疗结果的影响.收集了33名成年患者的人口数据，提供113血浆曲美替尼浓度，最好用具有线性吸收和消除的两室模型来描述。该研究还确定了无脂肪质量的显着积极影响和年龄对清除率的负面影响，解释了66%和21%的初始相关变异性，分别。模拟显示,与72%的女性患者相比,每天2mg的最大剂量在36%的男性患者中达到治疗目标。在65岁以上的患者中，每天1.5mg的剂量达到了相似的比率，男性和女性患者分别占44％和79％，分别,达到治疗目标。较差的依从性导致浓度的显著下降和亚治疗药物水平的高风险。这些结果强调了跨专业合作和患者伙伴关系在患者的旅程中的重要性，以满足患者对曲美替尼的需求并支持药物依从性。
