Mukherjee Aparna, Gowtham Lakshminarayanan, Kabra Sushil Kumar, Lodha Rakesh, Velpandian Thirumurthy
Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
Ocular Pharmacology and Pharmacy Division, All India Institute of Medical Sciences, New Delhi, 110029, India.
Indian J Pediatr. 2024 May 28. doi: 10.1007/s12098-024-05135-9.
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).
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.
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 (C). The ratio of C /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.
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 C range suggests the need for future investigations on pharmacogenomic aspects of drug metabolism.
对确诊为耐多药结核病（MDR-TB）的儿童进行二线抗结核治疗（ATT）的全面药代动力学（PK）-药效学（PD）分析。
27名接受二线抗结核治疗的儿童，包括使用卡那霉素（KM，n = 13）、氟喹诺酮类（FQs，n = 26）、乙硫异烟胺（ETH，n = 20）、对氨基水杨酸（PASA，n = 4）和环丝氨酸（CS，n = 15），在给药前（0小时）、给药后1、2、3和4小时进行采样。使用质谱仪测定血浆药物水平，并使用PK solver ver2.0对收集的数据集进行非房室PK分析。PK/PD评估包括在R软件中使用Modviz Pop ver 1.0对1000名受试者进行个体药物模拟研究。
分别有22名和5名儿童被视为有反应者和无反应者。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血浆药物浓度（C）。所研究药物的C/最低抑菌浓度（MIC）或曲线下面积（AUC）/MIC之比在有反应者和无反应者之间未显示出显著差异。ETH和氧氟沙星的无反应者显示出与模拟人群得出的剂量反应曲线存在偏差。
按照国家指南使用二线抗结核治疗管理耐多药结核病治愈了参与研究的大多数儿童（>80%）。少数儿童的个体间差异超出目标C范围，提示未来需要对药物代谢的药物基因组学方面进行研究。
