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应用暴露-效应模型评估大剂量甲氨蝶呤化疗相关不良反应的发生风险 被引量:3

Evaluation of the risk of high-dose methotrexate treatment-related adverse reactions byexposure-response modeling
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摘要 目的:建立暴露-效应(exposure-response)模型考察甲氨蝶呤(MTX)的体内暴露量与化疗相关不良反应(ADR)发生概率之间的定量关系,促进个体化用药。方法:收集360例7月~14岁急性淋巴细胞白血病(ALL)患儿行大剂量MTX(HDMTX)化疗的临床资料。观察患儿在MTX给药后第1~10 d血液系统、消化系统、肝胆系统的ADR并按化疗药物常见不良反应事件评价标准(CTCAE,version 4.02)进行分级评定。首先采用非线性混合效应建模法和贝叶斯最大后验概率法获取患儿体内的MTX暴露水平。然后采用logistic回归建立暴露量与Ⅱ级以上(包括Ⅱ级)ADR发生概率之间的定量关系。分别用内部和外部数据验证最终模型的预测性能。结果:MTX在患儿体内符合二房室开放式药动学模型,群体典型值分别为:V1(中央室分布容积)=11.66 L,V2(周边室分布容积)=2.82 L,CL1(中央室表观清除率)=5.04 L·h-1,CL2(周边室清除率)=0.16 L·h-1。患儿的体质量自然对数值(lnWeight)和肾小球滤过率(GFR)对MTX的清除率有显著性影响。logistic分析显示MTX给药48 h后药时曲线下面积(AUC48-∞)与化疗相关ADR的发生概率之间相关性最强,受试者工作特征(ROC)曲线下面积Az=0.896(95%CI:0.838~0.955)。Youden指数最大(0.817)时对应的AUC48-∞最佳界值切点为2.03 h·mg·L-1,高于该值时ADR的发生概率>50%。内部和外部验证结果均表明最终模型稳定,预测结果可靠。结论:本研究成功建立了用于评估HDMTX化疗相关ADR发生风险的暴露-效应数学模型,可为临床个体化治疗提供帮助。 OBJECTIVE To establish an exposure-response model to investigate the quantitative relationship between in vivo exposure to methotrexate(MTX)and the probability of chemotherapy-related adverse reactions(ADRs),and to promote individualized medication.METHODS The clinical data of 360 children with acute lymphoblastic leukemia(ALL)aged from 7 months to 14 years treated with high-dose MTX(HDMTX)were collected.To observe the ADR of hematological system,digestive system and hepatobiliary system in children within 1-10 d after administration of MTX,and graded according to the Common Terminology Criteria for Adverse Events(CTCAE,version 4.02).Nonlinear mixed-effects modeling and Bayesian maximum a posteriori probability methods were first used to obtain MTX exposure levels in children.Logistic regression analysis was carried to evaluate the quantitative relationship of MTX exposure parameters and the probability of treatment-related ADR gradedⅡand above.The predictive performance of final model was evaluated with internal and external data respectively.RESULTS A two-compartment,open kinetic model was?tted to describe the pharmacokinetic property of MTX in children.The typical population values of pharmacokinetic parameters estimated in final model were as follows:V1(volume of the central compartment)=11.66 L,V2(volume of the peripheral compartment)=2.82 L,CL1(central compartment clearance)=5.04 L·h-1,CL2(intercompartmental clearance)=0.16 L·h-1.MTX clearance was significantly impacted by the natural logarithm of body mass(ln weight)and glomerular filtration rate(GFR)of patient..Logistic analysis showed the strongest correlation between the area under the curve(AUC48-∞)and the probability of occurrence of chemotherapy-related ADRs after 48 h of MTX administration,with the area under the receiver operating characteristic(ROC)curve Az=0.896(95%CI:0.838 to 0.955).The optimal cut-off point of AUC48-∞at the maximum Youden index(0.817)was 2.03 h·mg·L-1,above which the probability of ADR was>50%.Both internal and external validation results showed that the final model was stable and the prediction results were reliable.CONCLUSION A exposure-response mathematical model was successfully established in this study to evaluate the risk of HDMTX treatment-related ADR,which will be useful for optimization of the individualized administration protocol.
作者 汪洋 李思婵 宋小英 叶琦 梅艳 许琼 徐华 WANG Yang;LI Si-chan;SONG Xiao-ying;YE Qi;MEI Yan;XU Qiong;XU Hua(Department of Pharmacy,Wuhan Children’s Hospital,Tongji Medical College,Huazhong University of Science&Technology,Hubei Wuhan 430016,China;Department of hematology and oncology,Wuhan Children’s Hospital,Tongji Medical College,Huazhong University of Science&Technology,Hubei Wuhan 430016,China;Yichang city Yiling District Maternal and Child Health Hospital,Hubei Yichang 443400,China)
出处 《中国医院药学杂志》 CAS 北大核心 2019年第17期1779-1786,共8页 Chinese Journal of Hospital Pharmacy
基金 国家自然基金青年基金资助项目(编号:81600123) 武汉市卫生计生科研基金资助项目(编号:WX18C21)
关键词 甲氨蝶呤 急性淋巴细胞白血病 暴露量 不良反应 群体药动学 methotrexate acute lymphoblastic leukemia exposure adverse reactions population pharmacokinetics
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