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 ss ) 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 N -acetyltransferase 2 (NAT2) genotype, weight, age and nutritional status (using BAZ).
Dosing exposure and clinical outcomes in paediatric DS-TB: an IPD synthesis
The estimated odds ratio per unit decrease in BAZ was 0.96 (95% CI 0.93–0.99), indicating higher risk with poorer growth status.