伏立康唑谷浓度监测在侵袭性真菌感染治疗中的应用

Application of Voriconazole Trough Concentration Monitoring in Patients with Invasive Fungal Infection

目的建立快捷的高效液相色谱-串联质谱法(HPLC-MS/MS)测定某院侵袭性真菌感染患者血浆中伏立康唑的谷浓度,并初步考察其有效谷浓度范围。方法以氯雷他定为内标,用乙腈直接蛋白沉淀的方法,色谱柱为ZORBAX Eclipse XDB-C18柱(50 mm×4.6 mm,1.8μm),流动相为乙腈—0.1%甲酸的10 mmol·L^(-1)甲酸铵水溶液(85∶15),流速为0.4 mL·min^(-1),正离子多反应监测(MRM)模式扫描分析,检测15例侵袭性真菌感染患者的伏立康唑谷浓度,并观察其临床疗效和不良反应。结果血浆中伏立康唑浓度的线性范围为0.01~10.00μg·m L^(-1)(r=0.999 2),定量下限为0.01μg·mL^(-1),提取回收率在94.94%~104.73%之间,日内、日间精密度相对标准偏差(RSD)均小于15%。患者体内伏立康唑的血药浓度为0.739~8.763μg·mL^(-1)。结论该方法快速、灵敏,适用于伏立康唑血药浓度监测。由于伏立康唑的个体间浓度差异大,对危重患者开展常规伏立康唑谷浓度监测有助于提高临床疗效,减少不良反应的发生。

OBJECTIVE To establish a simple and quick HPLC-MS/MS method for the determination of voriconazole trough concentration in patients with invasive fungal infection, and investigate the range of proper trough concentration in our hospital. METHODS The plasma procedure involved a single-step protein precipitation by acetonitrile, then chromatographed on a ZORBAX Eclipse XDB-C18 （50 min×4.6 mm, 1.8 μm） using a mobile phase composed of acetonitrile-0.1% formic acid in 10 mmol. L-1 ammonium formate（85：15） at a flow rate of 0.4 mL. min-1,with Loratadine as internal standard.The protonated ions of analytes were detected in positive ionization in muhiple reaction monitoring （ MRM ） mode. The specificity, standard curve, lower limit of quantitation （ LLOQ ）, precision,recovery rate as well as the matrix effect were investigated. The trough concentrations of voriconazole in 15 patients with invasive fungal infection were analyzed by this method.The efficacy and adverse drug reactions during the pharmacotherapy period were observed. RESULTS The calibration curve was linear over a concentration range of 0.01 - 10.00 μg. mL-1 （ r = 0.999 2） , the lower limit of quantitation was 0.01 μg.mL-1.The extraction recovery rates ranged from 94.94%-104.73%,intra-day and inter-day RSD were all less than 15%.The plasma concentrations of voriconazole in patients were 0.739-8.763 μg.mL-1. CONCLUSION The method is quick and sensitive. It is suitable for the concentration determination of voriconazole in patients. Because of the high concentration variability among patients, routine monitoring of voriconazole trough concentration for critical patients may help to increase the probability of achieving therapeutic efficacy and decrease adverse events.