文章：

曲美替尼在肿瘤患者中的群体药代动力学及不依从性对药物暴露的影响——优化口服靶向抗癌治疗研究的一部分

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

原文发布日期：11 June 2024

DOI: 10.3390/cancers16122193

类型: Article

开放获取: 是

英文摘要：

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.

摘要翻译： 

曲美替尼是一种用于治疗实体瘤的靶向疗法，真实世界研究显示其药代动力学存在显著个体差异。这种差异会增加暴露不足的风险，进而可能导致治疗失败或毒性增加。本研究采用基于模型的模拟方法，旨在系统描述并探讨曲美替尼当前推荐剂量的药代动力学特征及其合理性。此外，通过模拟不同依从性不足的场景，评估了患者用药依从性对治疗效果的影响。研究收集了33例成年患者的群体数据，共获得113个血浆曲美替尼浓度值，采用具有线性吸收和消除的二室模型能最优描述其药代动力学特征。研究发现去脂体重对清除率具有显著正向影响，而年龄则呈负向影响，分别解释了初始相关变异性的66%和21%。模拟结果显示，每日2mg最大剂量可使36%的男性患者达到治疗目标，而女性患者达标率可达72%。对于65岁以上患者，每日1.5mg剂量可使男性达标率达44%，女性达79%。依从性不佳会导致血药浓度显著下降，并大幅增加亚治疗水平风险。这些结果凸显了在患者治疗全程中，通过跨专业协作和医患合作来满足曲美替尼治疗需求、支持用药依从性的重要性。

原文链接：

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