Comparison of Drug Concentration of Isoniazid and Rifampicin between Daily and Intermittent Anti-Tubercular (ATT) Regimen, in Children treated for Tuberculosis

OBJECTIVES : 1. To measure the drug exposure as the area under the concentration time curve to six hours (AUC0-6h) for both isoniazid and rifampicin in children treated by either daily or intermittent ATT regimen. 2. To determine the inter-patient variability in plasma concentrations, as well to determine the basic pharmacokinetic parameters, for isoniazid and rifampicin in above population. METHODS : Children aged 2 to 16 years, initiated on either daily or intermittent (thrice weekly) ATT were recruited into the study, after obtaining informed consent. 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 6hrs post-dose. The concentrations of isoniazid and rifampicin were analyzed using a validated LC-MS/MS and HPLC assays, respectively. Results were analyzed using non parametric methods with R version 3.1.2. RESULTS : The median dose (mg/kg) *for isoniazid was 10.13 versus 8.10 (p=0.005) in the intermittent and daily dose regimens respectively. The C0 (μg/mL) * was below the limit of detection versus 0.15 (p=0.0009). The Cmax(μg/mL) * was 6.8 versus 6.86, C2(μg/mL) * was 5.1 versus 5.54 and C6(μg/mL) * was 2.01 versus 2.18. None of these were significantly different. Median AUC0-6h(mg.hr/L) *was 22.18 versus 24.55 (p =0.879) The median dose (mg/kg) * for rifampicin was 10.26 versus 10.77. C0(μg/mL) * was below the limit of detection, versus 0.01 (p=0.4), Cmax(μg/mL)* was 6.19 versus 5.59, C2(μg/mL)* was 4.3 versus 4.4 and C6(μg/mL) *was 1.01 versus 1.68. However, there was no significant difference. Median AUC0-6h (mg.hr/L) * was 16.87 versus 16.51 (p =0.879). CONCLUSION : All the patients (except 2) had isoniazid Cmax above 3μg/mL (recommended range: 3-6μg/mL) and 83% of the patients had rifampicin Cmax less than recommended range (8-24μg/mL). 31% of the patients had a very low Cmax for rifampicin, which is