Use of Monte Carlo simulation to design an optimized pharmacodynamic dosing strategy for meropenem
Use of Monte Carlo simulation to design an optimized pharmacodynamic dosing strategy for meropenem
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DOI：
10.1177/0091270003257225
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发表时间：
2003-10-01
影响因子：
2.9
通讯作者：
Nicolau, DP
中科院分区：
文献类型：
--
作者：
Kuti, JL;Dandekar, PK;Nicolau, DP
延长美罗培南的输注超过3小时增加了药物浓度保持在最小抑制浓度（MIC）以上的给药间隔的百分比，从而使该药剂的药效学最大化并遵守药物稳定性约束。采用Monte Carlo模拟确定几种延长输注（PI）美罗培南给药方案与传统30分钟输注（TI）相比对肠杆菌科、不动杆菌属和铜绿假单胞菌种群的药效学目标达到率。对10，000名受试者模拟1000 mg TI q8h、2000 mg TI q8h、500 mg PI q8h、1000 mg PI q12h、1000 mg PI q8h、2000 mg PI q12h和2000 mg PI q8h暴露高于MIC（% T>MIC）的时间百分比。药代动力学参数和MIC分布的变异性分别来自健康志愿者研究和MYSTIC监测项目。对于针对肠杆菌科种群的所有给药方案，达到抑菌（30% T>MIC）和杀菌（50% T>MIC）暴露的概率都很高。针对不动杆菌属和铜绿假单胞菌，2000 mg PI q8h给药方案提供了最高的目标达成率。对于由肠杆菌科引起的轻度至中度感染，500 mg PI q8h和1000 mg PI q12h的延长输注方案将提供与传统30分钟输注相同的目标达到率，同时在24小时内需要更少的药物。对于可能由不动杆菌属或铜绿假单胞菌引起的更严重感染，推荐剂量为2000 mg PI q8h，因为其对这些病原体的杀菌目标达到率较高。建议在临床试验中进一步研究这些剂量建议。(C)2003年，美国临床药理学学会。
Prolonging the infusion of meropenem over 3 hours increases the percentage of the dosing interval that drug concentrations remain above the minimum inhibitory concentration (MIC), thereby maximizing the pharmacodynamics of this agent and adhering to drug stability constraints. Monte Carlo simulation was employed to determine pharmacodynamic target attainment rates for several prolonged infusion (PI) meropenem dosage regimens as compared with the traditional 30-minute infusion (TI) against Enterobacteriaceae, Acinetobacter species, and Pseudomonas aeruginosa populations. Percent time above the MIC (% T>MIC) exposures for 1000 mg TI q8h, 2000 mg TI q8h, 500 mg PI q8h, 1000 mg PI q12h, 1000 mg PI q8h, 2000 mg PI q12h, and 2000 mg PI q8h were simulated for 10,000 subjects. Variability in pharmacokinetic parameters and MIC distributions were derived from studies in healthy volunteers and the MYSTIC surveillance program, respectively. The probabilities of attaining bacteriostatic (30% T>MIC) and bactericidal (50% T>MIC) exposures were high for all dosage regimens against populations of Enterobacteriaceae. Against Acinetobacter species and Pseudomonas aeruginosa, the 2000-mg PI q8h dosage regimen provided the highest target attainment rates. For mild to moderate infections caused by Enterobacteriaceae, prolonged infusion regimens of 500 mg PI q8h and 1000 mg PI q12h would provide equivalent target attainment rates to the traditional 30-minute infusion while requiring less drug over 24 hours. For more serious infections presumably caused by Acinetobacter species or Pseudomonas aeruginosa, a dose of 2000 mg PI q8h is recommended because of its high bactericidal target attainment rate against these pathogens. Further study of these dosage recommendations in clinical trials is suggested. (C) 2003 the American College of Clinical Pharmacology.