Pharmacokinetics of isoniazid in Ethiopian children with tuberculosis in relation to the N-acetyltransferase 2 (NAT2) genotype

Until recently, the dose of isoniazid used to treat tuberculosis was the same for all patient groups. However, the pharmacokinetic profile of isoniazid varies across different populations. A comparative, observational, single-dose, 5 h study was conducted evaluating the pharmacokinetics of isoniazid in Ethiopian children. Pharmacokinetic parameters for a dose of 5 mg/kg and NAT2 genotype were determined in 29 children with tuberculosis (<15 years, with mean age of 8.6). Initially, univariate analyses evaluated covariates that exhibited associations (p < 0.2) with isoniazid pharmacokinetic parameters. Covariates with associations, acetylator genotype (p < 0.01) and age (p < 0.1) were further analysed with multiple linear regression. Sixteen (55%) were genotyped as rapid and 13 (45%) as slow acetylators. Four rapid acetylators had 2 and 3 h post-dose concentrations of < 3 and 1.5 ug/ml, respectively. Multiple linear regression analyses revealed acetylator status to be the only predictor of k, area under the curve (AUC2→5h), and isoniazid concentrations at 2, 3, 4 and 5 h. The mean values of these variables were also found to differ between genotypes (p < 0.0025). These findings reaffirm that 5 mg/kg isoniazid dose may not provide adequate plasma drug levels in all paediatric patients. Thus, isoniazid dose for children should be higher than 5 mg/kg body weight to cover the diverse acetylation kinetics. Key words: Acetylator status, paediatric tuberculosis, isoniazid, pharmacokinetics, NAT2, Ethiopia.