Efficacy of isoniazid in pediatric tuberculosis: an individual participant data meta-analysis.
Academic Article
Overview
abstract
BACKGROUND: Isoniazid is a cornerstone of management therapy for tuberculosis. The aim was to determine the association between isoniazid exposure and clinical outcomes, to develop a pharmacokinetic model, and to optimize the dosing regimen in children treated for drug-susceptible tuberculosis. METHODS: For this individual participant data meta-analysis, PubMed was searched for observational studies, involving children (0-18 years), being treated for drug susceptible tuberculosis. The relationship between isoniazid exposure and clinical outcomes was analyzed using a mixed-effects logistic regression model. Pharmacokinetic parameters were described using nonlinear mixed effects modeling. Pharmacokinetic target was the median adult area under the concentration time curve (AUCss) of 23.4 mg.h·L-1. RESULTS: Six studies provided clinical outcomes, including 405 patients, of which 21% had unfavorable outcomes. Sixteen studies (1255 patients) were included in the pharmacokinetic model. Unfavorable outcomes were only related to lower BMI for age Z-score (OR 0.96, 95% CI 0.93-0.99, p<0.05). Isoniazid exposure was impacted by NAT2 genotype, weight, age, and nutritional status (using BMI for age Z-score). With currently recommended WHO doses, isoniazid exposure was similar to that of adults. Pharmacokinetic target attainment was 71.7% and 29.5% for slow and fast metabolizers, respectively (p<0.05); 50.5% for patients with a BAZ>0 and 42.6% for malnourished patients (BAZ<-2) (p<0.05). Model-informed dosing regimen showed that fast metabolizers could benefit from higher isoniazid dosing, especially in malnourished children. CONCLUSION: Our findings showed that the only predictor of unfavorable clinical outcomes was a lower BMI for age Z-score. We support the current WHO-recommended dosing regimen for isoniazid. To equalize and attain our pharmacological target for all children, dosing regimens could be adjusted on NAT2 genotype and nutritional status.
