Pharmacokinetics of high-dose isoniazid in children affected by multidrug-resistant TB

BACKGROUND: High-dose isoniazid (INH H ) (15–20 mg/kg/day) could be administered to overcome low-level INH resistance, but pharmacokinetic data are sparse. METHODS: This observational study included South African children (<15 years) receiving INH H as preventive therapy, or treatment for multidrug-resistant TB (MDR-TB) exposure or disease. Pharmacokinetic sampling was performed after an INH dose of 20 mg/kg. Non-compartmental analysis and multivariable regression models were used to evaluate associations of key covariates with area under the curve (AUC 0–24 ) and maximum concentration (C max ). AUC and C max values were compared against proposed adult targets. RESULTS: Seventy-seven children were included, with median age of 3.7 years; 51 (66%) had MDR-TB disease and 26 (34%) had MDR-TB exposure. Five were HIV-positive, of whom four were ≥5 years old. The median AUC 0–24 was 19.46 µgh/mL (IQR 10.76–50.06) and C max was 5.14 µg/mL (IQR 2.69–13.2). In multivariable analysis of children aged <5 years, MDR-TB disease (vs. exposure) was associated with considerably lower AUC 0–24 (geometric mean ratio GMR 0.19, 95% CI 0.15–0.26; P < 0.001) and C max (GMR 0.20, 95% CI 0.15–0.26; P < 0.001). CONCLUSIONS: INH concentrations in children with MDR-TB disease were much lower than expected, but comparable to previous reports in children with MDR-TB exposure. Further studies should confirm these findings and explore possible causes.