干细胞移植患者白消安暴露量的估算模型研究  

Estimation model for exposure of intravenous busulfan in patients receiving autologous hematopoietic stem cell transplantation

作　　者：李晋文 徐燕 王晓丹 廖应熙 何帅 徐姗 章萍 苗文娟 LI Jin-wen;XU Yan;WANG Xiao-dan;LIAO Ying-xi;HE Shuai;XU Shan;ZHANG Ping;MIAO Wen-juan(Institute of Hematology&Blood Diseases Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College,Tianjin 300020,China)

机构地区：[1]中国医学科学院血液病医院(中国医学科学院血液学研究所),天津300020

出　　处：《中国药理学通报》2024年第6期1193-1198,共6页Chinese Pharmacological Bulletin

基　　金：天津市卫生健康科技项目(No TJWJ2021QN074)。

摘　　要：目的采用有限采样法建立接受自体造血干细胞移植(autologous stem cell transplantation,ASCT)的淋巴瘤患者体内白消安暴露量-药时曲线下面积(area under the concentration-time curve,AUC)的估算模型。方法选取12名适合接受ASCT的淋巴瘤患者,采用含白消安105 mg·m^(-2),静脉滴注3 h的预处理方案,分别于白消安第1剂输注开始后1 h,输注结束后5 min,1、2、4、6、18 h采集血样,采用液质联用法进行白消安血药浓度测定。采用传统药动学方法计算白消安的临床药动学参数后,采用多元线性逐步回归分析法,建立有限采样法的白消安的AUC 0-t估算模型。以Jackknife法和Bootstrap法进行模型内部验证,采用Bland-Altman图评价经典药动学方法与有限采样法的一致性。结果采取有限采样法得出以AUC对C 60min、C 180min、C 300min进行多元线性回归的方程分析,方程的线性关系和预测效果最好,为AUC 0-t=295.003C 60min+233.050C 180min+273.163C 300min-1202.713,其中r 2为0.995,平均预测误差为-0.87%,均方根误差为2.40%。结论采用三点法估算的有限采样法模型,可以用于接受ASCT的淋巴瘤患者体内白消安AUC 0-t的估算,为临床合理应用白消安提供参考。Aim To establish limited sampling strategy to estimate area under the drug concentration versus time curve(AUC 0-t)of lymphoma patients treated with autologous stem cell transplantation(ASCT)who had busulfan intravenous infusion.Methods Twelve lymphoma patients treated with ASCT received a conditioning regimen containing busulfan 105 mg·m^(-2),IV infusion for 3 h.Blood samples were obtained 1 h after the start of the first dose of the busulfan infusion,at 5 min,1 h,2 h,4 h,6 h and 18 h after the end of the drug administration.LC-MS/MS was used to determine the busulfan serum concentration.After obtaining the clinical pharmacokinetic parameters of busulfan by traditional pharmacokinetic method,multiple linear stepwise regression analysis was used to establish the AUC 0-t estimation model of busulfan based on limited sampling method.The model was further verified by Jackknife and Bootstrap method.Bland-Altman plots were used to evaluate the consistency between the limited sampling method and the classical pharmacokinetic method.Results The multiple linear regression equation analysis of C 60min,C 180min and C 300min was obtained by the limited sampling method.The regression equation was AUC 0-t=295.003C 60min+233.050C 180min+273.163C 300min-1202.713,r 2=0.995,MPE=-0.87%,RMSE=2.40%.Conclusion The limited sampling model with three-point estimation can be used to estimate the AUC 0-t of busulfan exposure in lymphoma patients with ASCT to provide reference for clinical application of busulfan.

关 键 词：白消安 有限采样法 Jackknife法 BOOTSTRAP法 自体造血干细胞移植 药时曲线下面积 治疗药物监测 

分 类 号：R617[医药卫生—外科学] R733.4[医药卫生—临床医学] R969.1R979.11