Isoniazid and rifampicin concentrations in children with tuberculosis, on either daily or intermittent regimen – implications for the revised RNTCP 2012 doses, in India

Background Sub-optimal plasma drug concentrations of Anti-Tubercular Therapy (ATT) could lead to delayed response and emergence of acquired drug-resistance. Objectives To determine and compare the plasma concentrations of isoniazid and rifampicin in children treated for tuberculosis (TB) on daily or intermittent ATT regimen. To study the effect of the exposure of isoniazid and rifampicin on clinical outcome at the end of therapy. Methods Forty-one children aged 2 to 16 years, initiated on either daily or three-times a week (intermittent) ATT regimen were recruited into the study. Towards the end of the intensive phase, blood specimens were collected pre-dose, followed by 0⋅5, 1, 1⋅5, 2, 2⋅5, 4 and 6 hours post-dose, and concentrations of isoniazid and rifampicin were analyzed using validated Liquid Chromatography-Mass Spectrometry (LC-MS/MS) and High-Performance Liquid Chromatography (HPLC) assays, respectively. The Cmax (maximum plasma concentration), AUC0-6h, and treatment outcome were determined. Results and Conclusion Ninety-three percent of the patients had an isoniazid Cmax above 3 µg/mL. Seventy-seven percent of the patients had a rifampicin Cmax below 8 µg/mL, and 28% of the patients had a rifampicin AUC0-24h less than 13 mg.hr/L. The exposure of isoniazid and rifampicin was not different between daily and intermittent ATT regimens, on the day of administration. All the children had a favourable outcome at the end of therapy. Since 77% children had low exposure to rifampicin, the authors recommend the routine use of therapeutic drug monitoring to prevent relapse and also to support the implementation of the Revised National Tuberculosis Control Programme 2012 doses.