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

Kendra K Radtke, Anneke C Hesseling, J L Winckler, Heather R Draper, Belen P Solans, Stephanie Thee, Lubbe Wiesner, Louvina E van der Laan, Barend Fourie, James Nielsen, H Simon Schaaf, Radojka M Savic, Anthony J Garcia-Prats, Kendra K Radtke, Anneke C Hesseling, J L Winckler, Heather R Draper, Belen P Solans, Stephanie Thee, Lubbe Wiesner, Louvina E van der Laan, Barend Fourie, James Nielsen, H Simon Schaaf, Radojka M Savic, Anthony J Garcia-Prats

Abstract

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.

Keywords: moxifloxacin; pediatrics; pharmacokinetics; tuberculosis.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.
Figure 1.
Moxifloxacin pharmacokinetic profiles in children treated for rifampicin-resistant tuberculosis. Gray lines connect individual observed concentrations (circle = MDR-PK1; triangle = MDR-PK2) over time at unique sampling occasions. Mean concentrations over time are shown with bold lines (blue = MDR-PK1; pink = MDR-PK2). Trough concentrations are shown as the actual time after the previous recorded dose.
Figure 2.
Figure 2.
Moxifloxacin AUC24(A, C) and apparent clearance (B, D) by nutritional status and body weight. Nutritional status is shown by HAZ and body weight by WHO weight band. AUC24 is adjusted for the milligram per kilogram dose. CL/F is adjusted for body weight. The sample size (n) of each group is displayed in text, and the size of the center point represents the relative sample size. Center points represent the median. Lines represent the 2.5th to 97.5th percentile range. Abbreviations: AUC, area under the curve; CL/F, moxifloxacin oral clearance; HAZ, height-for-age z score; WHO, World Health Organization.
Figure 3.
Figure 3.
QTcF profiles in children treated with moxifloxacin for rifampicin-resistant tuberculosis as (A) QTcF interval over time and (B) maximum change in QTcF during the dosing interval in children receiving clofazimine (n = 29) and not (n = 27). (A) Gray lines represent distinct children and sampling occasions with individual observations as triangles (MDR-PK1) or circles (MDR-PK2). The bold line (pink = clofazimine group; blue = no clofazimine group) is the population mean. (B) Box plots represent the median, interquartile range, and whiskers show 95th and 5th percentile. Abbreviations: AE, adverse event; QTcF, Fridericia-corrected QT interval.
Figure 4.
Figure 4.
Simulated moxifloxacin (A) AUC24 and (B) maximum concentration at steady state with weight band dosing according to current WHO recommendations (blue) and model-informed optimized doses (yellow, 400 mg maximum dose; orange, no maximum dose). Data are based on 500 simulations. Weight band doses are shown in Table 3. Dashed line in (A) represents the target AUC24. Abbreviations: AUC24, area under the curve at steady state over 24-hours; WHO, World Health Organization.

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Source: PubMed

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