Abstract：
OBJECTIVE: To conduct a thorough pharmacokinetic (PK) - pharmacodynamic (PD) analysis of second-line anti-tubercular therapy (ATT) in children diagnosed with multi-drug resistant tuberculosis (MDR-TB).
METHODS: Twenty-seven children undergoing second-line ATT, including kanamycin (KM, n = 13), fluoroquinolones (FQs, n = 26), ethionamide (ETH, n = 20), para amino salicylic acid (PASA, n = 4), and cycloserine (CS, n = 15), were sampled at 0 (pre-dose), 1, 2, 3, and 4 h post-drug administration. Plasma drug levels were determined using a mass spectrometer and the collected dataset underwent non-compartmental PK analysis using PK solver ver2.0. PK/PD assessments involved individual drug simulation studies on 1000 subjects using Modviz Pop ver 1.0 in R-software.
RESULTS: A total of 22 and 5 children were considered as responders and non-responders, respectively. Non-compartmental PK analysis revealed mean plasma drug levels of this study cohort attained the targeted maximum drug plasma concentration (Cmax). The ratio of Cmax /minimum inhibitory concentration (MIC) or the area under the curve (AUC)/MIC of the studied drugs had not shown a significant difference between responders and non-responders. Non-responders of ETH and ofloxacin had shown deviation from the derived dose-response profile for the simulated population.
CONCLUSIONS: The management of MDR-TB with second-line ATT following national guidelines had cured the majority of the children (> 80%) who participated in the study. Inter-individual variability in few children from the targeted Cmax range suggests the need for future investigations on pharmacogenomic aspects of drug metabolism.
METHODS: Twenty-seven children undergoing second-line ATT, including kanamycin (KM, n = 13), fluoroquinolones (FQs, n = 26), ethionamide (ETH, n = 20), para amino salicylic acid (PASA, n = 4), and cycloserine (CS, n = 15), were sampled at 0 (pre-dose), 1, 2, 3, and 4 h post-drug administration. Plasma drug levels were determined using a mass spectrometer and the collected dataset underwent non-compartmental PK analysis using PK solver ver2.0. PK/PD assessments involved individual drug simulation studies on 1000 subjects using Modviz Pop ver 1.0 in R-software.
RESULTS: A total of 22 and 5 children were considered as responders and non-responders, respectively. Non-compartmental PK analysis revealed mean plasma drug levels of this study cohort attained the targeted maximum drug plasma concentration (Cmax). The ratio of Cmax /minimum inhibitory concentration (MIC) or the area under the curve (AUC)/MIC of the studied drugs had not shown a significant difference between responders and non-responders. Non-responders of ETH and ofloxacin had shown deviation from the derived dose-response profile for the simulated population.
CONCLUSIONS: The management of MDR-TB with second-line ATT following national guidelines had cured the majority of the children (> 80%) who participated in the study. Inter-individual variability in few children from the targeted Cmax range suggests the need for future investigations on pharmacogenomic aspects of drug metabolism.
摘要：
目的：对诊断为耐多药结核病（MDR-TB）的儿童进行二线抗结核治疗（ATT）的药代动力学（PK）-药效学（PD）分析。
方法：27名接受二线ATT的儿童，包括卡那霉素(KM，n=13),氟喹诺酮类(FQs，n=26),乙硫酰胺（ETH，n=20),对氨基水杨酸（PASA，n=4),和环丝氨酸(CS，n=15),在0（给药前）采样，给药后1、2、3和4小时。使用质谱仪测定血浆药物水平,并且使用PK求解器ver2.0对收集的数据集进行非隔室PK分析。PK/PD评估涉及使用R软件中的ModvizPopver1.0对1000名受试者进行的个体药物模拟研究。
结果：共有22名和5名儿童被视为应答者和非应答者，分别。非房室PK分析显示，该研究队列的平均血浆药物水平达到了目标最大药物血浆浓度（Cmax）。研究药物的Cmax/最小抑制浓度（MIC）或曲线下面积（AUC）/MIC之比在响应者和非响应者之间没有显着差异。ETH和氧氟沙星的非响应者显示出与模拟人群的衍生剂量反应曲线的偏差。
结论：按照国家指南使用二线ATT治疗耐多药结核病已治愈了参与研究的大多数儿童（>80％）。在目标Cmax范围内的少数儿童中，个体间的差异表明需要对药物代谢的药物基因组学方面进行未来的研究。
方法：27名接受二线ATT的儿童，包括卡那霉素(KM，n=13),氟喹诺酮类(FQs，n=26),乙硫酰胺（ETH，n=20),对氨基水杨酸（PASA，n=4),和环丝氨酸(CS，n=15),在0（给药前）采样，给药后1、2、3和4小时。使用质谱仪测定血浆药物水平,并且使用PK求解器ver2.0对收集的数据集进行非隔室PK分析。PK/PD评估涉及使用R软件中的ModvizPopver1.0对1000名受试者进行的个体药物模拟研究。
结果：共有22名和5名儿童被视为应答者和非应答者，分别。非房室PK分析显示，该研究队列的平均血浆药物水平达到了目标最大药物血浆浓度（Cmax）。研究药物的Cmax/最小抑制浓度（MIC）或曲线下面积（AUC）/MIC之比在响应者和非响应者之间没有显着差异。ETH和氧氟沙星的非响应者显示出与模拟人群的衍生剂量反应曲线的偏差。
结论：按照国家指南使用二线ATT治疗耐多药结核病已治愈了参与研究的大多数儿童（>80％）。在目标Cmax范围内的少数儿童中，个体间的差异表明需要对药物代谢的药物基因组学方面进行未来的研究。
