Population pharmacokinetic modelling of total and unbound cefazolin plasma concentrations as a guide for dosing in preterm and term neonates
Population pharmacokinetic modelling of total and unbound cefazolin plasma concentrations as a guide for dosing in preterm and term neonates
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DOI：
10.1093/jac/dkt527
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发表时间：
2014-05-01
影响因子：
5.2
通讯作者：
Knibbe, C. A. J.
中科院分区：
文献类型：
--
作者：
De Cock, R. F. W.;Smits, A.;Knibbe, C. A. J.
头孢唑啉经常用于抗菌预防和感染治疗。在新生儿中，药代动力学观察有限且给药方案可变。本研究的目的是根据总浓度和未结合浓度描述新生儿中头孢唑林的药代动力学，以优化头孢唑林剂量。 36 名新生儿 [中位出生体重 2720（范围 5404200）g，当前体重 (cBW) 2755 (8304200) g，出生后年龄 (PNA) 9 (130) 天]接受静脉注射包括头孢唑啉（50 mg/kg/8 h）。基于 119 个总血浆浓度和未结合血浆浓度，进行了群体药代动力学分析和协变量分析。进行蒙特卡罗模拟的目的是使所有患者的未结合浓度高于 8 mg/L（60 次）。开发了一种单室药代动力学模型，其中总浓度和未结合浓度通过 136 mg/L 的最大蛋白结合 (B-max) 和 46.5 mg/L 的头孢唑啉蛋白结合解离常数 (K-D) 连接起来。 cBW 被确定为分布容积 (V)、bBW 和 PNA（清除率）以及 B-max 血浆白蛋白浓度的协变量，分别解释了 V、清除率和 B-max 的个体间变异性 50、58 和 41。基于蒙特卡罗模拟，提出了一种适应体重和 PNA 的给药方案，该方案在不同体重和年龄组中产生相似的暴露量。确定了考虑到总和未结合头孢唑啉浓度以及可饱和血浆蛋白结合的新生儿药代动力学模型。由于 cBW 和 PNA 是最重要的协变量，因此它们可用于新生儿的个体化剂量。
Cefazolin is frequently administered for antimicrobial prophylaxis and treatment of infections. In neonates, pharmacokinetic observations are limited and dosing regimens variable. The aim of this study was to describe the pharmacokinetics of cefazolin in neonates based on total and unbound concentrations to optimize cefazolin dosing.Thirty-six neonates [median birth body weight 2720 (range 5404200) g, current body weight (cBW) 2755 (8304200) g and postnatal age (PNA) 9 (130) days] receiving intravenous cefazolin (50 mg/kg/8 h) were included. Based on 119 total and unbound plasma concentrations, a population pharmacokinetic analysis with a covariate analysis was performed. Monte Carlo simulations were performed aiming for unbound concentrations above an MIC of 8 mg/L (60 of the time) in all patients.A one-compartment pharmacokinetic model was developed in which total and unbound concentrations were linked by maximum protein binding (B-max) of 136 mg/L and a dissociation constant (K-D) for cefazolin protein binding of 46.5 mg/L. cBW was identified as covariate for volume of distribution (V), bBW and PNA for clearance and albumin plasma concentration for B-max, explaining 50, 58 and 41 of inter-individual variability in V, clearance and B-max, respectively. Based on Monte Carlo simulations, a body weight- and PNA-adapted dosing regimen that resulted in similar exposure across different weight and age groups was proposed.A neonatal pharmacokinetic model taking into account total and unbound cefazolin concentrations with saturable plasma protein binding was identified. As cBW and PNA were the most important covariates, these may be used for individualized dosing in neonates.