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首页> 美国卫生研究院文献>Antimicrobial Agents and Chemotherapy >Population Modeling and Monte Carlo Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Rifampin in Lungs
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Population Modeling and Monte Carlo Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Rifampin in Lungs

机译：利福平在肺部的药代动力学和抗结核药代动力学的种群建模和蒙特卡洛模拟研究

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摘要

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 (Cmax)/MIC ratio and the area under the concentration-time curve from time zero to 24 h (AUC0-24)/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 Cmax/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 (AUC0-24/MIC ≥ 271) but only 54.5% in ELF (AUC0-24/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.
机译：关于抗结核药的肺药理学信息很少。我们使用群体药代动力学模型和蒙特卡罗模拟来描述和探索利福平（RIF；利福平）的肺部药代动力学和药效学。使用非参数自适应网格（NPAG）算法，建立了一个能够充分描述血浆，上皮衬里液（ELF）和肺泡细胞（AC）浓度的34人志愿者中RIF的人群药代动力学模型。估计的浓度与测得的浓度具有很好的相关性，并且几乎没有偏差和良好的精度。然后将使用NPAG算法获得的结果导入到Matlab软件中，以执行10,000个对象的蒙特卡洛模拟。通过计算达到最大药物最大浓度（Cmax）/ MIC比的特定目标值的受试者的比例以及该区域下的面积，来评估RIF抑制耐药性发展并诱导足够的抗结核分枝杆菌杀菌作用的能力。浓度-时间曲线从零时间到24小时（AUC0-24）/ MIC比。在最低MIC（0.01 mg / L）下，口服600 mg口服后，AC中Cmax / MIC（≥175）的目标达成率分别为95％，血浆中48.8％和35.9％。 ELF。在相同条件下，杀灭目标的目标结果是血浆（AUC0-24 / MIC≥271）为100％，而ELF（AUC0-24 / MIC≥665）只有54.5％。使用1200 mg RIF剂量可以达到更好的目标达成效果。总体结果表明，在大多数受试者中，使用标准RIF剂量获得的肺部浓度过低。这项工作支持需要评估更大剂量的RIF以治疗结核病患者的需求。

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