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

Abstract

Background Moxifloxacin is a priority 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, QT-interval prolongation and evaluate optimal dosing in children with RR-TB. Methods Pharmacokinetic data were pooled from two observational studies in South African children 0-17 years of age 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 <2 years of age, and 8 (9%) were HIV-positive. 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 infection 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 (inter-individual 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 co-administered with other QT-prolonging agents.

Multidrug-resistant tuberculosis in children: A practical update on epidemiology, diagnosis, treatment and prevention

“…Higher maximum doses have been utilized when there is low-level resistance, such as in the presence of a 90Val gyrA mutation that is typically associated with an moxifloxacin MIC of < 1, though the efficacy of this approach has recently been questioned [45] . The maximum dose for moxifloxacin is 15 mg/kg daily capped at 600–800 mg per dose and for levofloxacin is 20 mg/kg daily capped at 1250–1500 mg per day [48] , [49] , [50] . Modeling studies suggest that current dose bands may result in lower drug exposure in children and doses > 20 mg/kg daily may be more optimal [51] , [52] .…”

What's new in childhood tuberculosis

“…Drug-resistant-TB in children has traditionally required treatment for up to 18 months, using drug regimens with high pill burdens and suboptimal side effect profiles. Recent progress in the treatment of drug-resistant-TB in adults and accumulation of safety and pharmacokinetic data from paediatric studies have meant that shorter, safer and more tolerable drug-resistant-TB treatment regimens for children are now being recommended and implemented globally [53 ▪ ,54 ▪ ,55,56 ▪ ,57].…”

QT Interval Prolongation and Second-line Antituberculosis Medicines in Children: An Update and Practical Considerations for Noncardiologists

“…In a prospective observational study of 70 children receiving treatment for RR-TB disease with levofloxacin-based regimens, 41 children had ECG data available and none had QTcF >450 msec recorded over the 2 hours post-treatment administration. 4 A mean change in QTcF of 4.7 ms was recorded; 5 (13%) children had QTcF change 30–60 ms and 1 had a change >60 ms. Only 1 child received another QT-prolonging drug, clofazimine, and they had a QTcF change of 44 ms. 4 Across 2 observational studies where 85 children received moxifloxacin (mean dose 11 mg/kg/day) within treatment regimens for RR-TB, 5 children had a QTcF ≥450 to <500 ms (4 of 5 were receiving clofazimine), but no child had QTcF >500 ms. 5 As moxifloxacin has a short half-life, the maximum QT effects would be expected within a few days of starting treatment.…”