目的 建立中国成年患者的替考拉宁(teicoplanin,TEC)群体药动学(population pharmacokinetics,PPK)模型,考察TEC药动学参数的影响因素。方法 前瞻性收集139例革兰阳性球菌感染患者静脉注射TEC后的222份常规监测血药浓度和相关信息,采用一级消除的一室模型进行数据拟合,并应用非线性混合效应模型(nonlinear mixed effect model,NONMEM)程序建立PPK模型。采用Bootstrap、正态预测分布误差法(normalized predictive distribution error,NPDE)进行最终模型评价。利用蒙特卡洛模拟法对给药方案进行优化。结果 确定了肌酐清除率(creatinine clearance,CLcr)、白蛋白(albumin,ALB)为影响TEC清除率的主要因素。最终模型为:CL(L·h-1)=1.24×(CLcr/77)0.564×31/ALB;V(L)=69.2。验证表明,模型稳定、有效,且有较好的预测效能。对于不同ALB和CLcr的多数患者起始负荷剂量400 mg/q12h,iv,3次,维持剂量400～800 mg·d-1的给药方案可达有效治疗谷浓度。严重感染者需调整负荷剂量至800 mg/q12h,iv,3次,维持剂量400～800 mg·d-1的给药方案来确保血药浓度达到15 mg·L-1以上。结论 本实验报道了CLcr、ALB对TEC清除率有显著影响,所建模型对TEC在中国成人患者中实现个体化给药具有重要应用价值。
Abstract
OBJECTIVE To establish a population pharmacokinetics(PPK) model of teicoplanin(TEC) in Chinese adult patients and investigate the factors influencing TEC pharmacokinetic parameters. METHODS A total of 222 blood samples and related information were prospectively collected from 139 inpatients with Gram-positive bacterial infection receiving TEC intravenously. A one-compartment model with first order elimination was used to perform the PPK analysis and the PPK model of TEC was developed via nonlinear mixed effects modeling(NONMEM) approach. The stability and prediction of the final model were evaluated by Bootstrap and normalized predictive distribution error (NPDE). Monte Carlo simulation was used to evaluate the effective of currently recommended dosing regimen. RESULTS The creatinine clearance(CLcr) and albumin(ALB) were identified as the most significant covariate on the clearance rate of TEC. The established final model was: CL(L·h-1)=1.24×(CLcr/77)0.564×31/ALB;V(L)=69.2. It is verified that the established final model is stable, effective and predictable. For most patients with different serum albumin concentration and CLcr, the initial loading dose of 400 mg/q12h, iv, 3 times, and the maintenance dose of 400-800 mg·d-1 can achieve effective treatment of trough concentration. Severe infections need to adjust the loading dose to 800 mg/q12h, iv, 3 times, and maintain a dose of 400-800 mg·d-1 of the dosing regimens to ensure that the blood concentration reached 15 mg·L-1. CONCLUSION This study reports that CLcr, ALB has a significant effect on TEC clearance and the model has important value for the individualization of TEC therapy in Chinese adult patients.
关键词
替考拉宁 /
中国成人患者 /
群体药动学 /
非线性混合效应模型 /
蒙特卡洛模拟法
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Key words
teicoplanin /
Chinese adult patient /
population pharmacokinetics /
nonlinear mixed effect model /
Monte Carlo simulation
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中图分类号：
R969.1
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脚注
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基金
福建省科技计划项目资助(2018J01394);福建省科技厅引导性项目资助(2017Y0033);厦门市医疗卫生指导性项目资助(3502Z20199125)
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