Relationship between Pulmonary Adverse Events and Everolimus Exposure in Japanese and Non-Japanese Patients: A Meta-Analysis of Oncology Trials.
Relationship between Pulmonary Adverse Events and Everolimus Exposure in Japanese and Non-Japanese Patients: A Meta-Analysis of Oncology Trials.
复制标题
日本和非日本患者肺部不良事件与依维莫司暴露之间的关系：肿瘤学试验的荟萃分析。
作者：
3.Noguchi S;Shinohara N;Ito T;Ohtsu A;Ravaud A;Jerusalem G;Ohno N;Gallo J;Bouillaud E;Fan J et al
目的：本荟萃分析探讨了依维莫司最小（Cmin）和最大（Cmax）暴露量与日本和非日本患者肺部不良事件（ae）风险之间的关系。方法：使用Cox回归模型评估晚期实体瘤试验中每日依维莫司治疗患者的患者水平数据，按癌症类型或治疗组分层，以对数转换的时间平均Cmin或Cmax作为时变协变量。Kaplan-Meier分析评价肺ae与药代动力学参数的关系。结果：确定了30项研究。在Cmin人群（n = 1962）中，日本患者的全级别肺部AE发生率明显高于非日本患者（19.9% vs. 9.4%）。日本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% CI: 1.141-2.918）和非日本患者（风险比：1.406;95% CI: 1.156-1.710）发生首次任何级别肺部AE的风险。结论：肺部不良反应的发生与依维莫司暴露有关。当地监测和报告的差异可能解释了日本患者与非日本患者相比报告的低级别依维莫司相关肺部不良事件发生率显著较高的原因。应仔细监测患者肺部不良反应的早期症状，并实施适当的医疗管理。
Aims: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.Methods: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.Results: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).Conclusions: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.