基于药代动力学/药效学模型优化新生儿美罗培南给药方案

doi:10.6040/j.issn.1671-7554.0.2025.0098

摘要/Abstract

摘要： 目的分析中国新生儿群体的药代动力学/药效学(population pharmacokinetics /pharmacodynamics, PPK/PD)特点,优化新生儿美罗培南给药方案。方法选取2023年1月1日至2024年6月30日期间,于山东第一医科大学附属省立医院确诊细菌感染并接受静脉美罗培南治疗的新生儿50例,按临床常规方案给予美罗培南并采集血液。采用高效液相色谱分析技术测定血浆中美罗培南的浓度,非线性混合效应建模软件NONMEM V7.4对美罗培南进行群体药代动力学分析,基于蒙特卡罗模拟评估在不同剂量方案下美罗培南的药效学达标率(the probability of target attainment, PTA)。结果群体药代动力学分析结果显示,美罗培南的药代动力学特征最符合一级消除单室模型。药代动力学参数的群体典型值为:清除率0.301 L/h, 分布容积0.885 L。影响新生儿美罗培南代谢的最重要的协变量是当前体质量、胎龄与生后月龄。药效学分析结果显示,对于最低抑菌浓度(minimum inhibitory concentration, MIC)≤2 mg/L的细菌,最小有效给药方案为15 mg/kg静脉输注1 h,每8 h给药1次, PTA为70.76%。对于MIC=4 mg/L的细菌,最小有效给药方案分别为20 mg/kg静脉输注3 h、25 mg/kg静脉输注2 h、30 mg/kg静脉输注1 h,均每8 h给药1次,PTA分别为74.74%、72.67%和70.76%。当致病菌为MIC=8 mg/L的高耐药菌时,最小有效给药方案为35 mg/kg静脉输注3 h,每8 h给药1次,PTA为71.69%。对于MIC=16 mg/L的细菌,美罗培南各单药治疗方案的PTA均低于70%。结论基于治疗药物实际监测数据以及PPK/PD分析可以为优化新生儿美罗培南治疗提供重要依据。

关键词: 美罗培南, 群体药代动力学/药效学, 新生儿, 剂量优化

Abstract: Objective To analyze the population pharmacokinetics/pharmacodynamics(PPK/PD)characteristics of meropenem in Chinese neonates and to optimize the dosing regimen for neonatal Meropenem therapy. Methods A total of 50 neonates with confirmed bacterial infections, who received intravenous meropenem treatment at the Affiliated Provincial Hospital of Shandong First Medical University between January 1, 2023, and June 30, 2024, were included in this study. Blood samples were collected following the standard clinical dosing regimen of meropenem. Plasma concentrations of meropenem were determined using high-performance liquid chromatography. Nonlinear mixed-effect modeling software NONMEM V7.4 was employed for population pharmacokinetic analysis of meropenem. Monte Carlo simulations were used to evaluate the probability of target attainment(PTA)under different dosage regimens. Results Population pharmacokinetic analysis revealed that the pharmacokinetic characteristics of meropenem were best described by a first-order elimination, one-compartment model. The typical population pharmacokinetic parameters were a clearance rate of 0.301 L/h and a distribution volume of 0.885 L. The most significant covariates affecting the metabolism of meropenem in neonates were current body weight, gestational age, and birth age. Pharmacodynamic analysis showed that for bacteria with a minimum inhibitory concentration(MIC)≤2 mg/L, the minimum effective dosing regimen was 15 mg/kg administered as a 1-hour intravenous infusion every 8 hours, with a PTA of 70.76%. For bacteria with an MIC of 4 mg/L, the minimum effective dosing regimens were 20 mg/kg as a 3-hour intravenous infusion, 25 mg/kg as a 2-hour intravenous infusion, and 30 mg/kg as a 1-hour intravenous infusion, all administered every 8 hours, with PTAs of 74.74%, 72.67%, and 70.76%, respectively. When the pathogen was a highly resistant strain with an MIC of 8 mg/L, the minimum effective dosing regimen was 35 mg/kg as a 3-hour intravenous infusion every 8 hours, with a PTA of 71.69%. For bacteria with an MIC of 16 mg/L, the PTA of each monotherapy regimen of meropenem was below 70%. Conclusion Treatment optimization of meropenem for neonates can be significantly informed by actual therapeutic drug monitoring data and PPK/PD analysis.

Key words: Meropenem, Population pharmacokinetics/pharmacodynamics, Neonates, Dose optimization

中图分类号:

R722.13

王翠翠,郑凤家,张雅慧,王小康,于瑞花,郝薇. 基于药代动力学/药效学模型优化新生儿美罗培南给药方案[J]. 山东大学学报 (医学版), 2026, 64(4): 83-91.

WANG Cuicui, ZHENG Fengjia, ZHANG Yahui, WANG Xiaokang, YU Ruihua, HAO Wei. Optimizing neonatal meropenem dosage regimens based on pharmacokinetic/pharmacodynamic models[J]. Journal of Shandong University (Health Sciences), 2026, 64(4): 83-91.

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