Pharmacokinetic-Pharmacodynamic (PK-PD) Analysis of Second-Line Anti-Tubercular Drugs in Indian Children with Multi-Drug Resistance.

Objectives: 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 (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.

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 C range suggests the need for future investigations on pharmacogenomic aspects of drug metabolism.