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

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BACKGROUND: High-dose isoniazid (INHH) (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 INHH 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 (AUC0–24) and maximum concentration (Cmax). AUC and Cmax 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 AUC0–24 was 19.46 µgh/mL (IQR 10.76–50.06) and Cmax 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 AUC0–24 (geometric mean ratio GMR 0.19, 95% CI 0.15–0.26; P < 0.001) and Cmax (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.

Keywords: drugs; paediatric; prevention; therapy

Document Type: Research Article

Affiliations: 1: Desmond Tutu TB Centre, Department of Paediatrics, Stellenbosch University, Cape Town, South Africa 2: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa

Publication date: November 1, 2021

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