Noguchi Shinzaburo, Shinohara Nobuo, Ito Tetsuhide, Ohtsu Atsushi, Ravaud Alain, Jerusalem Guy, Ohno Nobutsugu, Gallo Jorge, Bouillaud Emmanuel, Fan Jenna, Nonomura Norio
Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
Oncology. 2017;92(5):243-254. doi: 10.1159/000457904. Epub 2017 Feb 21.
This meta-analysis explores the relationship between the everolimus minimum (Cmin) and maximum (Cmax) exposure and the risk for pulmonary adverse events (AEs) in Japanese versus non-Japanese patients.
Patient-level data from patients treated with daily everolimus in advanced solid tumor trials were evaluated using a Cox regression model, stratified by cancer type or treatment arm, with log-transformed time-averaged Cmin or Cmax as a time-varying covariate. Kaplan-Meier analysis was used to evaluate the relationship between pulmonary AEs and pharmacokinetic parameters.
Thirty studies were identified. In the Cmin population (n = 1,962), all-grade pulmonary AE incidence was significantly higher in Japanese versus non-Japanese patients (19.9 vs. 9.4%). Pharmacokinetic parameters were similar between Japanese and non-Japanese patients. A 2-fold increase in everolimus Cmin significantly increased the risk for the first any-grade pulmonary AE in Japanese (risk ratio: 1.824; 95% CI: 1.141-2.918) and non-Japanese patients (risk ratio: 1.406; 95% CI: 1.156-1.710).
The risk for pulmonary AEs is related to everolimus exposure. Local monitoring and reporting differences might account for the significantly higher reported incidence of low-grade everolimus-associated pulmonary AEs in Japanese versus non-Japanese patients. Patients should be carefully monitored for early signs of pulmonary AEs, and appropriate medical management should be implemented.
本荟萃分析探讨了依维莫司最低（Cmin）和最高（Cmax）血药浓度暴露与日本患者和非日本患者肺部不良事件（AE）风险之间的关系。
在晚期实体瘤试验中，使用Cox回归模型对接受每日依维莫司治疗患者的个体水平数据进行评估，按癌症类型或治疗组分层，将对数转换后的时间平均Cmin或Cmax作为时变协变量。采用Kaplan-Meier分析评估肺部AE与药代动力学参数之间的关系。
共纳入30项研究。在Cmin人群（n = 1962）中，日本患者的所有级别肺部AE发生率显著高于非日本患者（19.9%对9.4%）。日本患者和非日本患者的药代动力学参数相似。依维莫司Cmin增加2倍显著增加了日本患者（风险比：1.824；95%置信区间：1.141 - 2.918）和非日本患者首次发生任何级别肺部AE的风险（风险比：1.406；95%置信区间：1.156 - 1.710）。
肺部AE风险与依维莫司暴露有关。局部监测和报告差异可能是日本患者与非日本患者中依维莫司相关的低级别肺部AE报告发生率显著更高的原因。应密切监测患者肺部AE的早期迹象，并实施适当的医疗管理。
