Population Pharmacokinetics of Moxifloxacin in Children

Abstract

Background/objective: Moxifloxacin is a fluoroquinolone that is commonly used in adults, but not children. Certain clinical situations compel pediatric clinicians to use moxifloxacin, despite its potential for toxicity and limited pharmacokinetics (PK) data. Our objective was to further characterize the pharmacokinetics of moxifloxacin in children.

Methods: We performed an opportunistic, open-label population PK study of moxifloxacin in children < 18 years of age who received moxifloxacin as part of standard care. A set of structural PK models and residual error models were explored using nonlinear mixed-effects modeling. Covariates with known biological relationships were investigated for their influence on PK parameters.

Results: We obtained 43 moxifloxacin concentrations from 14 participants who received moxifloxacin intravenously (n = 8) or orally (n = 6). The dose of moxifloxacin was 10 mg/kg daily in participants ≤ 40 kg and 400 mg daily in participants > 40 kg. The population mean clearance and mean volume of distribution were 18.2 L/h and 167 L, respectively. The oral absorption was described by a first-order process. The estimated extent of oral bioavailability was highly variable (range 20-91%). Total body weight was identified as a covariate on clearance and volume of distribution, and substantially reduced the random unexplained inter-individual variability for both parameters. No participants experienced suspected serious adverse reactions related to moxifloxacin.

Conclusion: These data add to the existing literature to support use of moxifloxacin in children in certain situations; however, further prospective studies on the safety and efficacy of moxifloxacin are needed.

Figure 1.. Selected Diagnostic Plots

Selected diagnostic plots for the final pharmacokinetic model.

Figure 2.. Simulations for Intravenous and Oral Moxifloxacin Dose

Simulations from the final model for an: A) intravenous; and B) oral dose of 400 mg and total body weight of 43 kg. Observed data shown are normalized (i.e., to a 400 mg dose and allometrically scaled to 43 kg). P10, 10th percentile of the model predictions; P50, median percentile of the model predictions; P90, 90th percentile of the model predictions

Figure 3.. Probabilities of Target Attainment

Based on Monte Carlo simulations of the intravenous dosage regimens administered in the study. PK-PD targets used: fAUC/MIC ≥34 for S. pneumoniae and fAUC/MIC ≥75 for Gram-negative bacteria. fAUC/MIC, area under the free concentration-time curve in a 24-hour interval/minimum inhibitory concentration; PK-PD, pharmacokinetic-pharmacodynamic