美罗培南在CVVHDF重症感染患者中的药代动力学研究

The Study of Pharmacokinetics of Meropenem in Patients with CVVHDF Severe Infection

目的 建立美罗培南体内血药浓度的测定方法,并研究其在持续静脉-静脉血液滤过透析(CVVHDF)重症感染患者中的药代动力学特点。方法 通过UPLC-MS/MS法测定两组需行CVVHDF治疗的肝炎危重症/重症感染患者的美罗培南的血药浓度,A组美罗培南1 g,q8h,B组美罗培南1 g,q12h,两组均持续泵入3 h,用Win Nonlin8.1软件计算药代动力学参数,并针对不同的MIC计算PK/PD靶值。结果 应用非房室模型得出主要药代动力学参数,A组:Cmax为(39.97±7.16)μg/m L,AUC为(235.70±51.19)μg/(m L·h),T1/2(h)为(8.10±1.78),Vz为(39.0±9.11)L;B组:Cmax为(37.78±12.42)μg/m L,AUC为(171.79±55.86)μg/(m L·h),T1/2(h)为(4.46±1.19),Vz为(34.01±13.62)L。MIC为4、8、16μg/m L时,A组的%T> MIC均值分别为(275.00±63.34)(,173.00±45.48),(72.00±33.69),B组的%T> MIC均值分别为(110.00±30.88),(73.52±23.74),(37.62±21.38)。两组美罗培南的药代动力学参数与PK/PD参数比较,除了Cmax、Vz外,其余指标差异均有统计学意义(P <0.05)。结论 该方法准确、简便、专属性好,可用于美罗培南的药代动力学研究。美罗培南在CVVHDF重症感染患者中药代动力学与健康受试者有较大差异,1 g,q8h给药与1 g,q12h给药同样存在一定差异,在高MIC下,可能需要调整剂量或者减少给药间隔,才能达到有效的杀菌靶值。

Objective To establish a method for the determination of meropenem in human plasma, and study its pharmacokinetic characteristics in severe infection patients receiving continuous veno-venous hemodiafiltration(CVVHDF) therapy. Methods Ultra performance liquid chromatography-tandem mass spectrometry( UPLC-MS/MS) method was used to determine the blood concentration of meropenem in the two groups of hepatitis patients with critical or severe infection requiring CVVHDF therapy. Meropenem 1 g q8h in group A and 1 g q12h in group B were pumped continuously for 3 hours. Pharmacokinetic parameters were calculated with WinNonlin 8.1 software. Pharmacokinetics/Pharmacodynamic(PK/PD) target values were calculated for different MIC value. Results The main pharmacokinetic parameters were obtained by non-atrioventricular model. In group A, Cmax was(39.97±7.16) μg/mL, AUC was(235.70±51.19) μg/(mL·h), T1/2(h) was(8.10±1.78), Vz was(39.00±9.11) L.Group B: Cmax was(37.78±12.42) μg/mL, AUC was(171.79±55.86)μg/(mL·h), T1/2(h) was(4.46±1.19), Vz was(34.01±13.62) L. When MIC was 4, 8, 16 μg/mL, the %T>MIC mean values of group A were respectively(275.00±63.34),(173.00±45.48),(72.00±33.69). The %T>MIC mean values of group B were respectively(110.00±30.88),(73.52±23.74),(37.62±21.38). The pharmacokinetic parameters of the two groups of meropenem were compared with the PK/PD parameters, and the differences in the other indicators were statistically significant except for Cmax and Vz(P<0.05). Conclusion The method is accurate, simple and specific, and can be used to study the pharmacokinetics of meropenem.The pharmacokinetics of meropenem in patients with CVVHDF severe infection were significantly different from those of healthy subjects, and there was also a certain difference between 1.0 g meropenem every 8-hour administration and 1.0 g meropenem every 12-hour administration. Under high MIC, it may be necessary to adjust the dose or reduce the interval of administration to achieve the effective sterilization target value.