基于验证的群体药代动力学模型开发重症患者美罗培南持续输注剂量列线图。

Development of a dosing nomogram for continuous-infusion meropenem in critically ill patients based on a validated population pharmacokinetic model.

机构信息

Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169 Berlin, Germany.

Graduate Research Training program PharMetrX, Freie Universitaet Berlin, Berlin, Germany, and Universitaet Potsdam, Potsdam, Germany.

出版信息

J Antimicrob Chemother. 2018 May 1;73(5):1330-1339. doi: 10.1093/jac/dkx526.

DOI:10.1093/jac/dkx526

PMID:29425283

Abstract

BACKGROUND

Optimal antibiotic exposure is a vital but challenging prerequisite for achieving clinical success in ICU patients.

OBJECTIVES

To develop and externally validate a population pharmacokinetic model for continuous-infusion meropenem in critically ill patients and to establish a nomogram based on a routinely available marker of renal function.

METHODS

A population pharmacokinetic model was developed in NONMEM® 7.3 based on steady-state meropenem concentrations (CSS) collected during therapeutic drug monitoring. Different serum creatinine-based markers of renal function were compared for their influence on meropenem clearance (the Cockcroft-Gault creatinine clearance CLCRCG, the CLCR bedside estimate according to Jelliffe, the Chronic Kidney Disease Epidemiology Collaboration equation and the four-variable Modification of Diet in Renal Disease equation). After validation of the pharmacokinetic model with independent data, a dosing nomogram was developed, relating renal function to the daily doses required to achieve selected target concentrations (4/8/16 mg/L) in 90% of the patients. Probability of target attainment was determined for efficacy (CSS ≥8 mg/L) and potentially increased likelihood of adverse drug reactions (CSS >32 mg/L).

RESULTS

In total, 433 plasma concentrations (3.20-48.0 mg/L) from 195 patients (median/P0.05 - P0.95 at baseline: weight 77.0/55.0-114 kg, CLCRCG 63.0/19.6-168 mL/min) were used for model building. We found that CLCRCG best described meropenem clearance (CL = 7.71 L/h, CLCRCG = 80 mL/min). The developed model was successfully validated with external data (n = 171, 73 patients). According to the nomogram, daily doses of 910/1480/2050/2800/3940 mg were required to reach a target CSS = 8 mg/L in 90% of patients with CLCRCG = 20/50/80/120/180 mL/min, respectively. A low probability of adverse drug reactions (<0.5%) was associated with these doses.

CONCLUSIONS

A dosing nomogram was developed for continuous-infusion meropenem based on renal function in a critically ill population.

摘要

背景

在 ICU 患者中，获得临床成功的关键前提是使抗生素暴露达到最佳。

目的

建立并验证重症患者中持续输注美罗培南群体药动学模型，并基于常规肾功能标志物建立列线图。

方法

采用 NONMEM®7.3 软件建立基于美罗培南治疗药物监测时稳态浓度（CSS）的群体药动学模型。比较不同的血清肌酐肾功能标志物对美罗培南清除率（基于 Cockcroft-Gault 肌酐清除率 CLCRCG、Jelliffe 床边估计 CLCR、慢性肾脏病流行病学合作研究方程和 4 变量改良肾脏病饮食研究方程）的影响。使用独立数据验证药动学模型后，根据肾功能与达到 90%患者所选目标浓度（4/8/16 mg/L）所需的日剂量之间的关系，建立剂量列线图。测定疗效（CSS≥8 mg/L）和潜在增加药物不良反应（CSS＞32 mg/L）的目标达成概率。

结果

共纳入 195 例患者（中位值/P0.05-P0.95 基线值：体重 77.0/55.0-114 kg，CLCRCG 63.0/19.6-168 mL/min）的 433 个血药浓度（3.20-48.0 mg/L）用于模型构建。我们发现 CLCRCG 可最佳描述美罗培南清除率（CL=7.71 L/h，CLCRCG=80 mL/min）。使用外部数据（n=171，73 例患者）成功验证了该模型。根据列线图，当 CLCRCG 为 20/50/80/120/180 mL/min 时，分别需要 910/1480/2050/2800/3940 mg 的日剂量才能使 90%的患者达到目标 CSS=8 mg/L。这些剂量与药物不良反应的低概率（＜0.5%）相关。