重症患者体内米卡芬净暴露量有限采样法估算模型的建立  

Establishment of a limited sampling strategy to estimate micafungin exposure in critically ill patients

作　　者：何杰[1] 刘冬雪 钟羚君 邵华[1] 胡琳璘 HE Jie;LIU Dongxue;ZHONG Lingjun;SHAO Hua;HU Linlin(Department of Pharmacy,Zhongda Hospital,Southeast University,Nanjing 210009,Jiangsu,China;School of Basic Medicine and Clinical Pharmacy,China Pharmaceutical University,Nanjing 211198,Jiangsu,China;Office of Clinical Trial Institution,Zhongda Hospital,Southeast University,Nanjing 210009,Jiangsu,China)

机构地区：[1]东南大学附属中大医院药学部,江苏京210009 [2]中国药科大学基础医学与临床药学学院,江苏南京211198 [3]东南大学附属中大医院临床试验机构办公室,江苏南京210009

出　　处：《中国临床药理学与治疗学》2022年第11期1264-1271,共8页Chinese Journal of Clinical Pharmacology and Therapeutics

基　　金：2021年南京市药学会项目(2021YX020);江苏省药学会-奥赛康临床药学基金(A201904);北京慈华医学发展基金会科研项目(CHSJDC001)。

摘　　要：目的:建立超高效液相色谱法监测重症感染患者米卡芬净血药浓度,并采用有限采样法估算其AUC。方法:重症感染患者静脉输注米卡芬净150 mg,每日1次,输注时间为1 h,稳态后分别于给药前、给药后1、2、4、8、12和24 h收集患者血液样本,建立UPLC法测定米卡芬净血药浓度,并采用Phoenix WinNonlin 6.4软件计算药动学参数,用SPSS 22.0软件对2~4个采血点的药物浓度进行多元线性回归方程建立有限采样模型。结果:血浆中米卡芬净线性范围为1.0~50 mg/L(r^(2)=0.994),定量下限为1.0 mg/L,米卡芬净提取回收率为73.20%,精密度相对标准偏差(RSD)均小于15%。分别采用2~4个时间点的血药浓度估算AUC,其中2个时间点的方案C4、C12,3个时间点的方案C4、C12、C24,4个时间点的方案C4、C8、C12、C24预测性能良好,r^(2)分别为0.986,0.995,0.996。结合预测精准性和可操作性,推荐3个时间点方案,其方程为4.578+7.263×C4+9.684×C12+6.411×C24。结论:本研究建立的测定方法专属性强、准确度高,操作简便,灵敏度高,可用于临床米卡芬净血药浓度的测定,并通过所建立的有限采样模型推荐给药后4、12、24 h的浓度估算AUC_(0-24),为优化米卡芬净给药方案提供基础。AIM:To establish an ultra high performance liquid chromatography(UPLC)method for the determination of micafungin in plasma of critically ill patients.And to establish a model for estimating the area under the concentration-time curve(AUC)of micafungin by limited sampling strategy.METHODS:Patients with severe infection were administrated with micafungin once a day,1 h for each infusion.The blood samples were collected before administration and 1,2,4,8,12,24 h after administration and were measured by UPLC.The pharmacokinetic parameters were calculated by Phoenix winnonlin 6.4,and the drug concentrations at 2-4 blood collection points were analyzed with SPSS 22.0 to establish limited sampling models.RESULTS:The calibration curve was linear over a concentration range of 1.0 to 50μg/mL(r^(2)=0.994)and the lower limit of quantification was 1.0 mg/L.The recovery rate was 73.20%,and the precision relative standard deviation(RSD)were both lower than 15%.AUC was estimated by blood drug concentration at 2-4 time points,of which C4,C12 at 2 time points,C4,C12,C24 at 3 time points,C4,C8,C12,C24 at 4 time points had good prediction performance,and r^(2) was 0.986,0.995,0.996 respectively.Combining the prediction accuracy and operability,the recommended 3 time-point scheme equation was 4.578+7.263×C4+9.684×C12+6.411×C24.CONCLUSION:The method is simple and quick,with high specificity and sensitivity,therefore it is suitable for the detection of micafungin in the human plasma.The AUC_( 0-24) can be accurately estimated by the concentration of micafungin at 4,12,24 h after administration,which can be applicable to the guidance for individualized micafungin use in clinical practice.

关 键 词：米卡芬净 超高效液相色谱法 治疗药物浓度监测 有限采样法 

分 类 号：R969.4[医药卫生—药理学] R978.1[医药卫生—药学]