基于胱抑素C评估肾功能的万古霉素群体药动学研究

盛长城,沈祥春,唐才林,熊世娟,白雪,张家兴,钱鑫,谢娟,焦正

中国药学杂志 ›› 2018, Vol. 53 ›› Issue (21) : 1847-1855.

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中国药学杂志
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中国药学杂志 ›› 2018, Vol. 53 ›› Issue (21) : 1847-1855. DOI: 10.11669/cpj.2018.21.009
论著

基于胱抑素C评估肾功能的万古霉素群体药动学研究

  • 盛长城1,2,沈祥春3,唐才林1,熊世娟1,白雪1,张家兴1,钱鑫1,谢娟1*,焦正2*
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Analysis of Population Pharmacokinetics of Vancomycin Using Cystatin C as a Marker of Renal Function

  • SHENG Chang-cheng1,2, SHEN Xiang-chun3, TANG Cai-lin1, XIONG Shi-juan1, BAI Xue1, ZHANG Jia-xing1, QIAN Xin1, XIE Juan1*, JIAO Zheng2*
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摘要

目的 建立成年患者的万古霉素群体药动学模型,考察影响万古霉素清除的因素。方法 以半胱氨酸蛋白酶抑制剂C为评估肾功能的指标,用非线性混合效应模型考察成年患者中万古霉素的群体特征,采用正向递加和逆向剔除法确定最终模型,采用图形结合统计学方法评价模型拟合优度、稳定性、内部有效性和预测效能。结果 用95例患者147个谷浓度数据,建立了最终模型。清除率和表观分布容积的群体典型值分别为3.57 L·h-1和63.30 L,其中肾功能是影响万古霉素清除率最主要的因素。验证表明,模型稳定,参数估算可靠,预测性能良好。结论 本试验所建立的万古霉素群体模型可用于协助制定和优化给药方案。

Abstract

OBJECTIVE To establish a population pharmacokinetics(PPK) model of vancomycin in adult patients and investigate the factors influencing vancomycin clearance.METHODS The nonlinear mixed-effect model(NONMEM) was used to investigate the population characteristics of vancomycin in adult patients and the serum cystatin C was used as a marker of renal function. The final model was built by forward inclusion approach and backward elimination method. Fitting effect of the model was evaluated by the goodness of fit plots(GOFs). Nonparametric Bootstraps and normalized prediction distribution errors(NPDE) were performed to evaluate the robustness and predictive efficacy of the final model. External model evaluation was conducted using an independent dataset to evaluate the model predictability. RESULTS Vancomycin PPK model was set up via 147 serum trough concentration data from 95 adult patients. The estimated population typical values of clearance rate and apparent volume of distribution were 3.57 L·h-1 and 63.30 L, respectively. The main factor influencing clearance was renal function. The GOFs showed that the final model was stable and effective, and the fitting degree of the final model was better than that of the base model. The robust rate verified by Bootstrap was 99.45%. All of the relative biases between the median of parameters validated by Bootstrap and the estimated parameters of final model were within ±3%, and the 95% confidence intervals of these validated parameters did not include zero. The NPDE followed the N(0,1) distribution with a global adjust P value of 0.334, which indicated that the model had a high predictive accuracy. External evaluation was performed via an independent dataset of 40 concentration data from 20 patients. The mean prediction error(MPE) and mean absolute prediction error(MAPE) based on population predictions(PRED) was -1.90% and 24.34%, respectively. CONCLUSION Vancomycin PPK model established in the study is of as a good stability and high predictive accuracy, as a reference for developing individualized administration regimens.

关键词

万古霉素 / 半胱氨酸蛋白酶抑制剂C / 群体药动学 / 非线性混合效应模型 / 个体化给药

Key words

vancomycin / cystatin C / population pharmacokinetics / nonlinear mixed-effect model / individualized administration

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盛长城,沈祥春,唐才林,熊世娟,白雪,张家兴,钱鑫,谢娟,焦正. 基于胱抑素C评估肾功能的万古霉素群体药动学研究[J]. 中国药学杂志, 2018, 53(21): 1847-1855 https://doi.org/10.11669/cpj.2018.21.009
SHENG Chang-cheng, SHEN Xiang-chun, TANG Cai-lin, XIONG Shi-juan, BAI Xue, ZHANG Jia-xing, QIAN Xin, XIE Juan, JIAO Zheng. Analysis of Population Pharmacokinetics of Vancomycin Using Cystatin C as a Marker of Renal Function[J]. Chinese Pharmaceutical Journal, 2018, 53(21): 1847-1855 https://doi.org/10.11669/cpj.2018.21.009
中图分类号： R969.1   

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基金

贵州省卫生计生委科学技术基金项目资助(gzwjkj2015-1-076)
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