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

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.

Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines

“…A proposed PZA adult target range of 20 to 60 g/ml has been suggested (23), but a study from Botswana showed that a C max of less than 35 g/ml was associated with a poor outcome in adult pulmonary TB patients (39). Our results were similar to other pediatric studies reporting peak concentrations of 34.6 to 47.8 g/ml when dosed at 30 to 40 mg/kg (8,13,28,32).…”

“…The peak RMP concentrations of 4.0 and 2.2 g/ml for the two different RMP formulations, respectively, were similar to those reported in other pediatric studies, documenting low peak concentrations of 2.8, 2.9, 3.5, 3.8, and 3.9 g/ml following an oral administration of 10 to 20 mg/kg (27-31). Higher median RMP peak concentrations of 10 and 12 g/ml were achieved when dosed at 10 and 15 mg/kg (P ϭ 0.008), respectively, in Indian children (32). RMP mean peak concentrations of 6.4 and 11.7 g/ml, when dosed at 10 and 15 mg/kg (P ϭ 0.005), respectively, were observed in 11 South African children younger than 2 years of age using a different RMP formulation.…”

“…Other pediatric studies reported similarly low concentrations of between 0.78 and 2.1 g/ml when dosed at 10 to 20 mg/kg (27,28,32,40,41). Increasing EMB dosage in children has been reported to result in higher peak concentrations (42,43); however, dose-dependent ocular toxicity is a limiting factor in dosing increases (44) especially in young children, in whom clinical evaluation is more challenging.…”

“…Hiruy et al documented an ALT range of 9 to 71 U/liter in 31 children younger than 10 years at the revised higher doses (27). Two (3.1%) of 64 children developed hepatitis on the previously recommended lower doses, and 3 (4.8%) of 63 children did so on the revised higher doses in a study conducted in Indian children younger than 15 years of age (32).…”

Integration of childhood TB into guidelines for the management of acute malnutrition in high burden countries

“…33 Data on the pharmacokinetics of TB medicines among malnourished children are also needed, as differences have been reported. [34][35][36][37] Further research into anti-tuberculosis treatment in the setting of malnutrition can guide the development of recommendations for the optimal timing for the initiation of treatment, dosing, and follow-up of children with malnutrition and TB.…”