Moxifloxacin Pharmacokinetics, Cardiac Safety, and Dosing for the Treatment of Rifampicin-Resistant Tuberculosis in Children.

BACKGROUND: Moxifloxacin is a recommended drug for rifampin-resistant tuberculosis (RR-TB) treatment, but there is limited pediatric pharmacokinetic and safety data, especially in young children. We characterize moxifloxacin population pharmacokinetics and QT interval prolongation and evaluate optimal dosing in children with RR-TB. METHODS: Pharmacokinetic data were pooled from 2 observational studies in South African children with RR-TB routinely treated with oral moxifloxacin once daily. The population pharmacokinetics and Fridericia-corrected QT (QTcF)-interval prolongation were characterized in NONMEM. Pharmacokinetic simulations were performed to predict expected exposure and optimal weight-banded dosing. RESULTS: Eighty-five children contributed pharmacokinetic data (median [range] age of 4.6 [0.8-15] years); 16 (19%) were aged <2 years, and 8 (9%) were living with human immunodeficiency virus (HIV). The median (range) moxifloxacin dose on pharmacokinetic sampling days was 11 mg/kg (6.1 to 17). Apparent clearance was 6.95 L/h for a typical 16-kg child. Stunting and HIV increased apparent clearance. Crushed or suspended tablets had faster absorption. The median (range) maximum change in QTcF after moxifloxacin administration was 16.3 (-27.7 to 61.3) ms. No child had QTcF ≥500 ms. The concentration-QTcF relationship was nonlinear, with a maximum drug effect (Emax) of 8.80 ms (interindividual variability = 9.75 ms). Clofazimine use increased Emax by 3.3-fold. Model-based simulations of moxifloxacin pharmacokinetics predicted that current dosing recommendations are too low in children. CONCLUSIONS: Moxifloxacin doses above 10-15 mg/kg are likely required in young children to match adult exposures but require further safety assessment, especially when coadministered with other QT-prolonging agents.

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

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.