Pharmacy Department, Division of Medicines, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain.
Liver Unit, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain.
J Antimicrob Chemother. 2020 Dec 1;75(12):3619-3624. doi: 10.1093/jac/dkaa362.
Meropenem pharmacokinetics (PK) may be altered in patients with cirrhosis, hampering target attainment. We aimed to describe meropenem PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target.
Serum concentrations and covariates were obtained from patients with severe infections under meropenem treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate meropenem exposure to assess the PTA.
Fifty-four patients were enrolled in the study. Data were best described by a one-compartment linear model. The estimated typical mean value for clearance (CL) was 8.35 L/h and the estimated volume of distribution (V) was 28.2 L. Creatinine clearance (CLCR) and MELD score significantly influenced meropenem CL, and acute-on-chronic liver failure (ACLF) significantly affected V. Monte Carlo simulations showed that a lower meropenem dose would be needed as CLCR decreases and as the MELD score increases. Patients with ACLF would have lower peak meropenem concentrations but similar steady-state concentrations compared with patients with no ACLF.
Our study identified two new covariates that influence meropenem PK in patients with decompensated cirrhosis in addition to CLCR: MELD score and ACLF. Dosing regimens are recommended to reach several PK/PD targets considering these clinical variables and any MIC within the susceptibility range.
肝硬化患者的美罗培南药代动力学（PK）可能发生改变，从而影响目标药物浓度的达到。本研究旨在描述失代偿期肝硬化合并严重细菌感染患者的美罗培南 PK 特征，确定 PK 变异性的来源，并评估不同给药方案的性能，以优化 PK/药效学（PD）目标。
从接受美罗培南治疗的严重感染患者中获得血清浓度和协变量数据。采用非线性混合效应模型进行群体 PK 分析，使用最终模型模拟美罗培南暴露情况，以评估治疗药物浓度时间曲线下面积（PTA）。
本研究共纳入 54 例患者。数据最好用单室线性模型来描述。估计的典型平均清除率（CL）值为 8.35 L/h，估计的分布容积（V）为 28.2 L。肌酐清除率（CLCR）和 MELD 评分显著影响美罗培南 CL，而慢加急性肝衰竭（ACLF）显著影响 V。蒙特卡罗模拟结果显示，随着 CLCR 降低和 MELD 评分增加，美罗培南的剂量需要降低。与无 ACLF 的患者相比，ACLF 患者的美罗培南峰浓度较低，但稳态浓度相似。
本研究除了 CLCR 外，还发现了两个新的影响失代偿期肝硬化患者美罗培南 PK 的协变量：MELD 评分和 ACLF。建议根据这些临床变量和任何处于敏感范围内的 MIC，制定给药方案以达到多个 PK/PD 目标。
