Pharmacokinetics, Safety, and Tolerability of Single-Dose Intravenous Moxifloxacin in Pediatric Patients: Dose Optimization in a Phase 1 Study

Abstract

The pharmacokinetics, safety, and tolerability of a single dose of moxifloxacin were characterized in 31 pediatric patients already receiving antibiotics for a suspected or proven infection in an open-label phase 1 study. A dosing strategy for each age cohort (Cohort 1: ≥6 years to ≤14 years; Cohort 2: ≥2 years to <6 years; Cohort 3: >3 month to <2 years) was developed using physiology-based pharmacokinetic modeling combined with a stepwise dosing scheme to obtain a similar exposure to adults receiving 400 mg of moxifloxacin. Doses, adjusted to body weight and age, were gradually escalated from 5 mg/kg in Cohort 1 to 10 mg/kg in Cohort 3 based on interim analysis of the pharmacokinetic and safety data. Plasma and urine samples before and after the 60-minute infusion were collected for the analysis of moxifloxacin and its metabolites using a validated high-pressure liquid chromatography assay with tandem mass spectrometry. Moxifloxacin and metabolite concentrations in plasma were within the ranges observed in adults; however, clearance of all analytes was lower in pediatric patients compared with adults. Population pharmacokinetic analyses using the achieved exposure levels in the 3 age cohorts (with known body weight and clearance) predicted similar efficacy and safety profiles to adults. Moxifloxacin was well tolerated in all pediatric age cohorts. Adverse events related to moxifloxacin were mild or moderate in intensity and showed no correlation with increased weight-adjusted doses. Our findings guided the selection of age-appropriate clinical doses for a subsequent phase 3 clinical trial in pediatric patients with complicated intra-abdominal infections.

Keywords: dose finding; fluoroquinolone; moxifloxacin; pediatrics; pharmacokinetics/pharmacodynamics; phase 1 study.

Figure 1.

Distribution of AUC_0-24 (A)and C_max (B) derived from evaluation of pooled phase 1 study data in adults used to define the target exposure ranges for clinical efficacy based on PK/PD considerations. (Part of the data were reproduced with permission of Springer as published by Stass and Dalhoff.) AUC_0-24, area under the curve from 0 to 24 hours at steady state; C_max, maximum drug concentration in plasma; IV, intravenous.

Figure 2.

(A) Time course of moxifloxacin concentration in plasma following the administration of a single intravenous dose in Cohort 1. Data obtained with 5 mg/kg and 6 mg/kg doses are shown separately. (B) Time course of moxifloxacin concentration in plasma following the administration of a single intravenous dose in Cohort 2. Data obtained with 7-mg/kg and 8-mg/kg doses are shown separately. (C) Time course of moxifloxacin concentration in plasma following the administration of a single intravenous dose in Cohort 3. Data obtained with 9-mg/kg and 10-mg/kg doses are shown separately. LLOQ, lower limit of quantification. Note: Geometric mean (geometric standard deviation) are shown.

Figure 3.

(A) Time course of metabolite M1 concentration in plasma following the administration of a single intravenous dose of moxifloxacin in 3 age groups. Data obtained with 5 mg/kg and 6 mg/kg doses in Cohort 1, 7 mg/kg and 8 mg/kg in Cohort 2, and 9 mg/kg and 10 mg/kg in Cohort 3 are shown separately. (B) Time course of metabolite M2 concentration in plasma following the administration of a single intravenous dose of moxifloxacin in 3 age groups. Data obtained with 5 mg/kg and 6 mg/kg doses in Cohort 1, 7 mg/kg and 8 mg/kg in Cohort 2, and 9 mg/kg and 10 mg/kg in Cohort 3 are shown separately. LLOQ, lower limit of quantification. Note: Geometric mean (geometric standard deviation) are shown.

Figure 4.

(A) Predicted AUC at steady state based upon single-dose intravenous administration of moxifloxacin vs age based on final population pharmacokinetic model. Dashed lines: limits of the AUC target range (shown in Figure 1). (B) Predicted C_max at steady state based upon single-dose intravenous administration of moxifloxacin vs age based on final population PK model. Dashed lines: limits of the C_max target range (shown in Figure 1). AUC, area under the concentration curve; C_max, maximum drug concentration in plasma.