Pharmacokinetics, Safety, and Dosing of Novel Pediatric Levofloxacin Dispersible Tablets in Children with Multidrug-Resistant Tuberculosis Exposure

Abstract

This study characterized the pharmacokinetics of novel 100-mg levofloxacin dispersible tablets in 24 children aged <5 years who had household multidrug-resistant tuberculosus (MDR-TB) exposure. The current data were pooled with previously published data from children (n = 109) with MDR-TB receiving adult (250-mg) levofloxacin tablets, using nonlinear mixed-effects modelling. The adult tablets had 41% lower bioavailability than the novel dispersible tablets, resulting in much higher exposures with the dispersible tablets with the same dose.

Keywords: bioavailability; children; dispersible tablets; formulation; levofloxacin; multidrug-resistant tuberculosis; pharmacokinetics.

FIG 1

Visual predictive check of the levofloxacin concentration versus time after dose for the historical 109 controls receiving adult 250-mg standard levofloxacin tablets (5) (left) versus the 24 patients on the pediatric 100-mg scored dispersible tablets (right). Solid and dashed lines, 50th, 5th, and 95th percentiles of the observed data; shaded areas, model-predicted 95% confidence intervals for the same percentiles. Circles, observed concentrations.

FIG 2

Simulated steady-state levofloxacin C_max and AUC_0–24 versus body weight using weight-banded dosing of pediatric levofloxacin 100-mg scored dispersible tablets. The dashed line for AUC (96.8 mg · h/liter) is the median AUC from adults with TB receiving 1,000 mg daily in the study by Peloquin et al. (8) after linearly rescaling the dose from 1,000 to 750 mg/day, because the pharmacokinetics of levofloxacin have been reported to be linear in this dose range. The dashed line for C_max (15.55 mg/liter) is the median C_max in adults receiving 1,000 mg/day from the same study. C_max was not rescaled to a 750-mg/day dose, because the C_max values achieved with the 1,000-mg dose were safe in adults over 7 days in that study. In selecting doses for children, it is helpful to know that the C_max values expected in children with the proposed doses are not well beyond what has been demonstrated to be safe in adults.