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...

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Veröffentlicht in:Clinical infectious diseases Jg. 74; H. 8; S. 1372
Hauptverfasser: 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
Sprache:Englisch
Veröffentlicht: United States 28.04.2022
Schlagworte:
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
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:1537-6591
1537-6591
DOI:10.1093/cid/ciab641