Population pharmacokinetics and dosing of dispersible moxifloxacin formulation in children with rifampicin-resistant tuberculosis

Abstract

Aims: Moxifloxacin is a priority drug for treating rifampicin-resistant tuberculosis (RR-TB). We assessed the pharmacokinetics of a child-friendly, dispersible 100 mg tablet moxifloxacin formulation (dispersed in water) compared to the standard 400 mg non-dispersible formulation (crushed and suspended in water) in children and evaluated current dosing recommendations.

Methods: The CATALYST trial investigated the pharmacokinetics of moxifloxacin in children with RR-TB. Children were enrolled in South Africa, India and the Philippines. Intensive pharmacokinetic sampling was undertaken while children were taking the standard non-dispersible 400 mg moxifloxacin tablet formulation and repeated after switching to the novel dispersible formulation. Pharmacokinetic data were analysed using population pharmacokinetic modelling. Simulations were performed to evaluate moxifloxacin exposures in children compared to consensus adult reference exposures using current World Health Organization (WHO)-recommended doses and more recent model-based doses.

Results: Thirty-six children were enrolled [median age 4.8 (range 0.4-15) years and weight 15.6 (range 6.9-42.1) kg]. A two-compartment disposition model with first-order elimination and delayed absorption was developed. The bioavailability of dispersible versus standard formulations fulfilled standard bioequivalence criterion (ratio 1.05 with 90% confidence interval 0.95-1.15). Simulations showed WHO-recommended doses achieved exposures similar to those in adults in children >10 kg, while children <10 kg may require 33%-56% higher doses to reach adult reference exposures.

Conclusions: Dosing recommendations for children can be the same for the dispersible paediatric and standard non-dispersible adult moxifloxacin formulation. The current WHO dosing recommendation risks underdosing moxifloxacin in children <10 kg. We propose optimized moxifloxacin doses for both formulations.

Keywords: child‐friendly formulation; moxifloxacin; paediatric dosing; paediatric tuberculosis; population pharmacokinetics.

FIGURE 1

CATALYST study schematic.

FIGURE 2

Visual predictive checks on the final model of moxifloxacin in normal scale (upper) and log scale (lower), separated by formulations. Observations are represented by open circles.

FIGURE 3

Noncompartment‐analysis posterior predictive check histogram of simulated pharmacokinetic metrics (area under concentration–time curve from 0 to 24 h [AUC_0–24] and maximum concentration [C_max]) of moxifloxacin from 300 model‐simulated trials separated by formulations (left‐hand side for nondispersible tablets and right‐hand side for dispersible tablets), compared with the observed pharmacokinetic metrics represented by the red lines.

FIGURE 4

Simulated steady state area under concentration–time curve from 0 to 24 h (AUC_0–24,ss; upper) and maximum concentration (C_max; lower) of moxifloxacin vs. World Health Organization (WHO) weight bands using the final model, for 400‐mg nondispersible tablet (left) and 100‐mg dispersible tablet (right). In the dosing table legend, “previously suggested” refers to Radtke et al.; “proposed” refers to the newly proposed dosing in this work; “WHO” refers to WHO dosing which CATALYST follows. The reference AUC range is a median 37 mg h/L (solid red line) with 95% coverage of the adult population from 15 to 76 mg h/L (shaded area); the reference C_max range is correspondingly 3.06 (1.36–6.72) mg/L. The range of boxes represents 25th and 75th percentiles and the range of whiskers represents 2.5th and 97.5th percentiles. The upper percentage in red represents the proportion of simulated patients above the reference range, while the lower in cyan represents those below the reference range; numbers from left to right in a weight band correspond to the sequence of dosing tables.