Population Pharmacokinetic Modeling Using Polymyxin B Free Plasma Concentrations From Published Reports and Evaluation of Dosage Regimens Based on Monte Carlo Simulation in Critically Ill Patients

药代动力学 医学 药理学 非金属 人口 药效学 最小抑制浓度 养生 多粘菌素B 治疗药物监测 内科学 抗生素 微生物学 生物 环境卫生
作者
You Zheng,Baohua Xu,Shengyang Chen,Maobai Liu,Huiping Huang,Jingting Wang,Xuemei Wu
出处
期刊:The Journal of Clinical Pharmacology [Wiley]
卷期号:63 (9): 1036-1044 被引量:7
标识
DOI:10.1002/jcph.2261
摘要

A population pharmacokinetic (pop PK) model of polymyxin B was developed using nonlinear mixed-effects (NONMEM) modeling based on free plasma concentrations to determine whether dose adjustment is required in critically ill patients. One thousand pharmacokinetic profiles for virtual patients with a body weight of 70 kg were simulated using Monte Carlo simulation at different dose scenarios, and area under the concentration-time curve of free drug (fAUC) was computed. The probability of target attainment (PTA) at each minimum inhibitory concentration (MIC) was calculated using fAUC/MIC as a pharmacokinetic/pharmacodynamic (PK/PD) index. The final population PK model was a 2-compartment model. PTA showed that 3.5 mg/kg/day regimens of polymyxin B effectively achieved the fAUC/MIC target of 10 (one log10 kill) against Pseudomonas aeruginosa strains with MIC of 1 mg/L or less (PTA, 90.7% or greater), while the dose regimen were ineffective against strains with an MIC of 2 mg/L or greater (PTA, 56.9% or less). For Klebsiella pneumoniae, the fAUC/MIC target of 17.4 (one log10 kill) was achieved in more than 90.4% of cases for MIC of 0.5 mg/L or less with 3 mg/kg/day regimens. However, the PTA decreased dramatically as MICs increased above 1 mg/L (PTA, 56.1% or less). The polymyxin B dosage regimen of 3.5 mg/kg/day and 3 mg/kg/day are sufficient to treat P. aeruginosa infections with an MIC of 1 mg/L or less and K. pneumoniae infections with an MIC of 0.5 mg/L or less, respectively. The current recommended dose (1.5-3 mg/kg/day) of polymyxin B appears inadequate to attain the PK/PD target for therapeutic efficacy against infections caused by P. aeruginosa and K. pneumoniae isolates when MIC is above the values.
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