基于计算机仿真模拟结果推荐老年人左奥硝唑给药方案

Dosage regime Optimization of Levornidazole for Elderly Based on Computational Simulation

中文关键词: 老年人  左奥硝唑氯化钠注射液  药动学  计算机模拟  药动/药效学

英文关键词: elderly  levornidazole and sodium chloride injection  pharmacokinetic  computational simulation  pharmacokinetics/pharmacodynamics (PK/PD)

中文摘要:

      目的 观察左奥硝唑氯化钠注射液在健康老年人体内的药代动力学,利用计算机模拟不同给药方案的药动学参数,结合药动/药效学(PK/PD)分析,推荐左奥硝唑老年人给药方案.方法 本研究临床试验部分为单中心、开放、单剂量给药试验设计,评价老年受试者单剂静脉滴注左奥硝唑氯化钠注射液500 mg的药动学特征;采用WinNonlin软件模拟500 mg,q 12h和750mg,q24 h连续7d给药后老年人体内的药动学参数;利用Matlab进行Monte Carlo模拟预测多剂静脉滴注左奥硝唑不同给药方案达稳态时,不同MIC水平下的的达标概率及对脆弱拟杆菌的累积反应分数.结果 大于65岁老年人单次静脉注射左奥硝唑氯化钠注射液500 mg后主要药动学参数:C～为(11.97±1.16) μg/mL,AUC0-96为(171.24±20.43)μg·h/mL,AUC0-∞为(172.16±20.88)μg· h/mL,t1/2为(12.46±1.85)h.多剂静脉滴注500 mg和750 mg左奥硝唑达稳态后的药动学参数模拟结果如下:Cmax,ss分别为(20.6±1.9) μg/mL和(20.5±1.6) μg/mL,AUG0-τ别为(166.1±19.6)μg· h/mL和(251.0±29.6)μg·h/mL,t11/2分别为(11.75±1.87)h和(11.75-±-1.87)h,2种给药方案达稳态后Cmax,ss无统计学差异(P＞0.05),而750mg组的AUC0-τ明显降低(P＜0.05).Monte Carlo模拟结果表明,当靶值为AUC0-24/MIC≥157.6及C呲/MIC≥14.1时,500 mg,q 12h和750 mg,q24h给药方案对脆弱拟杆菌达到靶值的CFR均≥96％,对于MIC≤1μtg/mL的病原菌,2种给药方案的达标概率均可达到100％.结论 左奥硝唑氯化钠注射液500mg,q 12h和750mg,q24h均可用于老年患者厌氧菌感染的治疗.

英文摘要:

      Objective To evaluate different dose regimens of levornidazole in healthy elderly through computational simulations and PK/PD analysis.Methods An single-center,open-label,single-dose study was conducted to investigate pharmacokinetic (PK) characteristics of single dose levornidazole for injection,500 mg,by intravenous drip infusion in healthy elderly.WinNonlin software was applied in simulating 7-day dosing regimens of 500 mg,q 12 h and 750 mg,q 24 h in the elderly and the pharmacokinetic parameters were observed;Monte Carlo simulation was used in estimating the probability of target attainment and cumulative fraction of response to Bacteroides fragilis of both dosing regimens under various MIC levels.Results The main pharmacokinetic parameters in the elderly over 65 years old after a single dose of 500 mg levornidazole were recorded as follows:Cmax:(11.97±1.16) μg/mL,AUC0-96:(171.24 ±20.43) μg·h/mL,AUC0-∞:(172.16 ±20.88) μg·h/mL,t1/2:(12.46 ± 1.85) h while those in the elderly after multi-dose regimens of 500 mg and 750 mg were as follows:Cmax:(20.6±1.9) μg/mLand (20.5-±-1.6) μg/mL respectively,AUC0-τ:(166.1±19.6) μg·h/mLand (251.0±29.6) μg·h/mL,t1/2:(11.8±1.9) h of both;the results of the Monte Carlo simulation showed that for both dose regimes of 750 mg,q 24 h and 500 mg,q 12 h to Bacteroides fragilis,the CFR for AUC0-24MIC＞ 157.6 and Cmax/MIC≥ 14.1 were over 96％,and the pharmacodynamic target value probability reached 100 ％ when the MIC ≤ 1 μg/mL.Conclusions Both of 500 mg,q 12 h and 750 mg q 24 h dose regimens of levornidazole are recommended for the treatment of anaerobic infection in elderly patients.