新生儿万古霉素的群体药动学研究

李静静,刘艺茜,唐莲,翁小红,王三南,焦正,尚尔宁

中国药学杂志 ›› 2017, Vol. 52 ›› Issue (16) : 1434-1441.

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中国药学杂志
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中国药学杂志 ›› 2017, Vol. 52 ›› Issue (16) : 1434-1441. DOI: 10.11669/cpj.2017.16.012
论著

新生儿万古霉素的群体药动学研究

  • 李静静1,刘艺茜2,3,唐莲1,翁小红1,王三南4,焦正2*,尚尔宁1*
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Population Pharmacokinetics of Vancomycin in Chinese Neonates

  • LI Jing-jing1, LIU Yi-xi2,3, TANG Lian1, WENG Xiao-hong1, WANG San-nan4, JIAO Zheng2*, SHANG Er-ning1*
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摘要

目的 应用非线性混合效应模型(NONMEM)考察中国新生儿患者万古霉素群体药动学特征。方法 回顾性收集南京医科大学附属苏州医院新生儿患者91例,154个谷浓度数据建立群体药动学模型。采用一级消除的一室模型进行数据拟合,并引入生理成熟度模型考察体重和年龄对清除率的影响。采用自举法和正态预测分布误差法(NPDE)进行最终模型评价。在模型应用时,应用最终模型及参数估算值,结合Monte Carlo法模拟,评价MIC为1 mg·L-1时不同孕周、日龄和血清肌酐水平的典型患儿在不同给药方案下的AUC0-24 h/MIC≥400的比例。结果 最终模型确定体重、矫正孕周和血清肌酐为影响清除率的主要因素。模型评价表明,模型参数估算可靠、模型稳定。此外,血清肌酐低水平(15 μmol·L-1)组有96%的患儿在指南推荐给药方案下AUC0-24 h/MIC未达标,可根据所建立的模型计算给药剂量。结论 本研究建立的新生儿万古霉素群体药动学模型可为国人新生儿人群的万古霉素的个体化给药提供参考。

Abstract

OBJECTIVE To investigate the population pharmacokinetics of vancomycin (VAN) in Chinese neonates by nonlinear mixes-effects modeling software (NONMEM). METHODS One hundred and fifty-four VAN serum trough data from 91 neonatal patients were retrospectively collected from Suzhou Hospital Affiliated to Nanjing Medical University. A one-compartment model with first order elimination was used to describe structure pharmacokinetic model, and physiological maturity model was employed to screen covariates. The stability and prediction of the final model were evaluated by Bootstrap and normalized prediction distribution error (NPDE). The final model was applied to evaluate the percentage of AUC0-24 h/MIC ≥ 400 in neonatal patients by Monte Carlo Simulation, who were stratified according to gestational weeks, age and serum creatinine. RESULTS The weight, postmenstrual age and serum creatinine were identified as the most significant covariate on clearance. Bootstrap and NPDE showed the satisfactory stability and prediction performance of the final model. Moreover, the final model indicated that 96% of neonates with low serum creatinine (15 μmol·L-1) were not getting AUC0-24 h/MIC≥400, according to the current guidelines. CONCLUSION The population pharmacokinetic model of vancomycin in neonates is established successfully and could provide basis for the individualized therapy in neonatal patients.

关键词

万古霉素 / 群体药动学 / 新生儿

Key words

vancomycin / population pharmacokinetics / neonate

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李静静,刘艺茜,唐莲,翁小红,王三南,焦正,尚尔宁. 新生儿万古霉素的群体药动学研究[J]. 中国药学杂志, 2017, 52(16): 1434-1441 https://doi.org/10.11669/cpj.2017.16.012
LI Jing-jing, LIU Yi-xi, TANG Lian, WENG Xiao-hong, WANG San-nan, JIAO Zheng, SHANG Er-ning. Population Pharmacokinetics of Vancomycin in Chinese Neonates[J]. Chinese Pharmaceutical Journal, 2017, 52(16): 1434-1441 https://doi.org/10.11669/cpj.2017.16.012
中图分类号： R969.1   

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基金

苏州市科技发展计划项目(SYSD2014148)
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