Population Modeling and Monte Carlo Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Rifampin in Lungs
Population Modeling and Monte Carlo Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Rifampin in Lungs
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DOI：
10.1128/aac.01520-08
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发表时间：
2009-07-01
影响因子：
4.9
通讯作者：
Jelliffe, Roger W.
中科院分区：
文献类型：
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作者：
Goutelle, Sylvain;Bourguignon, Laurent;Jelliffe, Roger W.
关于抗结核药物的肺药理学信息很少。我们使用群体药代动力学建模和蒙特卡罗模拟来描述和探索利福平（rifampicin; rifampicin）的肺药代动力学和药效学。利用非参数自适应网格（NPAG）算法建立了一个群体药代动力学模型，该模型充分描述了34名人类志愿者的血浆、上皮衬里液（ELF）和肺泡细胞（AC）中RIF的浓度。估计浓度与测量浓度相关性好，偏差小，精度高。然后将NPAG算法得到的结果导入到Matlab软件中，进行10,000受试者的蒙特卡罗模拟。通过分别计算达到最大药物浓度(C(max))/MIC比特定目标值的受试者比例和时间0 ~ 24 h浓度-时间曲线下面积(AUC(0 ~ 24))/MIC比特定目标值的受试者比例，评价RIF抑制结核分枝杆菌耐药发展和诱导充分杀菌作用的能力。在最低MIC （0.01 mg/l）时，口服1次600 mg给药后，ac组C(max)/MIC（>= 175）达标率为95%，血浆组为48.8%，ELF组为35.9%。在相同条件下，血浆（AUC(0-24)/MIC >= 271）杀灭效果达到100%，ELF （AUC(0-24)/MIC >= 665）杀灭效果仅达到54.5%。使用1200毫克RIF剂量与更好的目标实现结果相关。总体结果表明，在大多数受试者中，标准RIF剂量获得的肺浓度过低。这项工作支持有必要评估更高剂量的RIF用于治疗结核病患者。
Little information exists on the pulmonary pharmacology of antituberculosis drugs. We used population pharmacokinetic modeling and Monte Carlo simulation to describe and explore the pulmonary pharmacokinetics and pharmacodynamics of rifampin (RIF; rifampicin). A population pharmacokinetic model that adequately described the plasma, epithelial lining fluid (ELF), and alveolar cell (AC) concentrations of RIF in a population of 34 human volunteers was made by use of the nonparametric adaptive grid (NPAG) algorithm. The estimated concentrations correlated well with the measured concentrations, and there was little bias and good precision. The results obtained with the NPAG algorithm were then imported into Matlab software to perform a 10,000-subject Monte Carlo simulation. The ability of RIF to suppress the development of drug resistance and to induce a sufficient bactericidal effect against Mycobacterium tuberculosis was evaluated by calculating the proportion of subjects achieving specific target values for the maximum concentration of drug (C(max))/MIC ratio and the area under the concentration-time curve from time zero to 24 h (AUC(0-24))/MIC ratio, respectively. At the lowest MIC (0.01 mg/liter), after the administration of one 600-mg oral dose, the rates of target attainment for C(max)/MIC (>= 175) were 95% in ACs, 48.8% in plasma, and 35.9% in ELF. Under the same conditions, the target attainment results for the killing effect were 100% in plasma (AUC(0-24)/MIC >= 271) but only 54.5% in ELF (AUC(0-24)/MIC >= 665). The use of a 1,200-mg RIF dose was associated with better results for target attainment. The overall results suggest that the pulmonary concentrations obtained with the standard RIF dose are too low in most subjects. This work supports the need to evaluate higher doses of RIF for the treatment of patients with tuberculosis.