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 (E-max) of 8.80 ms (interindividual variability = 9.75 ms). Clofazimine use increased E-max 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. Weight, human immunodeficiency virus status, stunting, and formulation influence moxifloxacin pharmacokinetics in children. Moxifloxacin prolongs the QT interval, but no severe prolongation events occurred. The effect was increased with clofazimine cotreatment. Higher moxifloxacin doses are needed to match adult exposures.

Automated summary

Limited data on the pharmacokinetics and safety of moxifloxacin in children, especially in those with rifampin-resistant tuberculosis, were evaluated in this study. The results suggest that higher doses of moxifloxacin are needed to achieve adult exposures in young children, and further safety assessment is required, particularly when coadministered with other QT-prolonging agents.