Abstract
BackgroundThe available pharmacokinetic data on anti-tubercular drugs in children raises the concern of suboptimal plasma 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.MethodProspective 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 conclusionThe median (IQR) Cmax of isoniazid increased significantly from 0.6 (0.3,1.2) μg/mL to 3.4 (1.8, 5.0) μg/mL with increase in the dose. Plasma rifampicin concentrations increased only marginally on increasing the dose [median (IQR) Cmax: 10.4 (7.2, 13.9) μg/mL vs. 12.0 (6.1, 24.3) μg/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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-015-0862-7) contains supplementary material, which is available to authorized users.
Highlights
The available pharmacokinetic data on anti-tubercular drugs in children raises the concern of suboptimal plasma concentrations attained when doses extrapolated from adult studies are used
The pharmacokinetic data on anti-tubercular drugs in children raises the concern of suboptimal plasma concentrations attained when the same mg/kg dose used in adults is extrapolated to children [6,7,8,9,10,11]
Children with known HIV infection or any history, symptoms or signs suggestive of HIV infection, with poor general condition with high chances of mortality, known hepatic or renal dysfunction, Treatment Category based anti-tubercular therapy as recommended by Revised National Tuberculosis Control Program (RNTCP) was administered [21], daily therapy was followed - four drugs in intensive phase for first two months followed by two drugs for four months during maintenance phase
Summary
The available pharmacokinetic data on anti-tubercular drugs in children raises the concern of suboptimal plasma concentrations attained when doses extrapolated from adult studies are used. The pharmacokinetic data on anti-tubercular drugs in children raises the concern of suboptimal plasma concentrations attained when the same mg/kg dose used in adults is extrapolated to children [6,7,8,9,10,11]. Though isoniazid has been studied extensively, there are relatively fewer studies on rifampicin, pyrazinamide and ethambutol in children These studies vary in the type of assay used for measurement of drug concentrations, sampling schedule adopted, type of anti-tubercular therapy (ATT)
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