Pharmacokinetics of isoniazid, rifampicin, pyrazinamide and ethambutol in Indian children

Background: The available pharmacokinetic data on anti-tubercular drugs in children raises the concern of suboptimalplasma concentrations attained when doses extrapolated from adult studies are used. Also, there is lack of consensus regarding the effect of malnutrition on pharmacokinetics of anti-tubercular drugs in children. We conducted this study with the aims of determining the plasma concentrations of isoniazid, rifampicin, pyrazinamide and ethambutol achieved with different dosage of the anti-tubercular drugs so as to provide supportive evidence to the revised dosages and to evaluate the effects of malnutrition on the pharmacokinetics of these drugs in children. We also attempted to correlate the plasma concentrations of these drugs with clinical outcome of therapy. Method: Prospective drug estimation study was conducted in two groups of children, age 6 months to 15 years, with tuberculosis, with or without severe malnutrition, receiving different dosage of daily anti-tubercular therapy. The dosage (range) of isoniazid was 5 (4-6) and 10 (7-15) mg/kg in the two groups, respectively, that of rifampicin-10 (8-12) and 15 (10-12) mg/kg, respectively, both the groups received same dose of pyrazinamide (30-35 mg/kg) and ethambutol (20-25 mg/kg). All four drugs were simultaneously estimated by liquid chromatography-mass spectrometry (LC-MS/MS). Results and conclusion: The median (IQR) C-max of isoniazid increased significantly from 0.6 (0.3,1.2) mu g/mL to 3.4 (1.8, 5.0) mu g/mL with increase in the dose. Plasma rifampicin concentrations increased only marginally on increasing the dose [median (IQR) C-max: 10.4 (7.2, 13.9) mu g/mL vs. 12.0 (6.1, 24.3) mu g/mL, p = 0.08]. For ethambutol, 55.9% of the children had inadequate 2-hour concentrations. Two-hour plasma concentrations of at least one drug were low in 59 (92.2%) and 54 (85.7%) children in the two dosing regimen, respectively. We did not observe any effect of malnutrition on pharmacokinetic parameters of the drugs studied. We did not observe an association between low plasma drug concentrations and poor outcome. We may have to be cautious while increasing the doses and strive to asses other factors influencing the drug concentrations and treatment outcomes in children.