Efficacy of isoniazid in paediatric tuberculosis: an individual participant data meta-analysis

Abstract

Background Isoniazid is a cornerstone of management therapy for tuberculosis (TB). Our aim was to determine the association between isoniazid exposure and clinical outcomes, to develop a pharmacokinetic model, and to optimise the dosing regimen in children treated for drug-susceptible (DS)-TB. Methods For this individual participant data meta-analysis, PubMed was searched for observational studies, involving children (aged 0–18 years), being treated for DS-TB. The relationship between isoniazid exposure and clinical outcomes was analysed using a mixed effects logistic regression model. Pharmacokinetic parameters were described using non-linear mixed effects modelling. The pharmacokinetic target was the median adult area under the concentration–time curve at steady-state (AUC<inf>ss</inf>) of 23.4 mg·h·L⁻¹. Results Six studies provided clinical outcomes, including 405 patients, of which 21% had unfavourable outcomes. 16 studies (1255 patients) were included in the pharmacokinetic model. Unfavourable outcomes were only related to lower body mass index (BMI) for age z-score (BAZ) (OR 0.96, 95% CI 0.93–0.99; p<0.05). Isoniazid exposure was impacted by N-acetyltransferase 2 (NAT2) genotype, weight, age and nutritional status (using BAZ). With currently recommended World Health Organization (WHO) doses, isoniazid exposure was similar to that of adults. Pharmacokinetic target attainment was 71.7% and 29.5% for slow and fast metabolisers, respectively (p<0.05); 50.5% for patients with BAZ >0 and 42.6% for malnourished patients (BAZ < −2) (p<0.05). The model-informed dosing regimen showed that fast metabolisers could benefit from higher isoniazid dosing, especially in malnourished children. Conclusion Our findings showed that the only predictor of unfavourable clinical outcomes was a lower BAZ. We support the current WHO-recommended dosing regimen for isoniazid. To equalise and attain our pharmacological target for all children, dosing regimens could be adjusted on NAT2 genotype and nutritional status.