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

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...

Full description

Saved in:
Bibliographic Details
Published in:Clinical infectious diseases Vol. 74; no. 8; p. 1372
Main Authors: Radtke, Kendra K, Hesseling, Anneke C, Winckler, J L, Draper, Heather R, Solans, Belen P, Thee, Stephanie, Wiesner, Lubbe, van der Laan, Louvina E, Fourie, Barend, Nielsen, James, Schaaf, H Simon, Savic, Radojka M, Garcia-Prats, Anthony J
Format: Journal Article
Language:English
Published: United States 28.04.2022
Subjects:
Adult
Child
Child, Preschool
Electrocardiography
Fluoroquinolones - adverse effects
HIV Infections
Humans
Moxifloxacin - adverse effects
Rifampin - adverse effects
Rifampin - pharmacokinetics
Tuberculosis - drug therapy
Tuberculosis, Multidrug-Resistant - drug therapy
pharmacokinetics
pediatrics
tuberculosis
moxifloxacin
ISSN:1537-6591, 1537-6591
Online Access:Get more information
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. 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. 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. 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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1537-6591
1537-6591
DOI:10.1093/cid/ciab641