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

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（r2=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，r2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AUC0-24，为优化米卡芬净给药方案提供基础。

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

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 50 μg/mL (r2=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 r2 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 AUC0-24 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.