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.

Application of Physiologically‐Based and Population Pharmacokinetic Modeling for Dose Finding and Confirmation During the Pediatric Development of Moxifloxacin

“…administered moxifloxacin in children of different ages. Based on the known pharmacological profile of moxifloxacin and a therapeutic target range established in adults, an age‐dependent dosing scheme for moxifloxacin could be proposed (learning step) and tested in the first‐in‐children trial . The analysis of the uncertainties associated with model‐based predictions using phase I results as a reference resulted in refined doses that were confirmed in the larger phase III study investigating moxifloxacin treatment for cIAIs in children .…”

“…During conduction of the phase I and III studies, these dose recommendations were subject to clinical validation and assessment through independent safety boards, allowing for the adjustment of the recommended doses if deemed necessary. The details of the clinical dose adjustment steps are presented in the clinical papers describing the phase I and III trials of moxifloxacin in children …”

“…(as 60‐minute infusion) or p.o. administration of 400 mg moxifloxacin: The minimum and maximum that were observed in adults were 11.8 and 71.7 mg·hour/L for AUC (0–24 h) and 1.5 and 6.9 mg/L for C max , with more than 95% between 20–60 mg · hour/L and 2–6.5 mg/L, respectively …”

“…The primary target achievement criterion for predicting a clinically effective dose was a narrower AUC range of 30–60 mg · hour/L (representing more than 90% of the observed study values). In relation to the PK/PD relationship, this is a more conservative approach to avoid dose predictions that may increase the risk of emerging resistance in clinical trials as a result of exposure and decrease the likelihood of exceeding the maximum exposure observed in adults.…”

Predictive Pediatric Modeling and Simulation Using Ontogeny Information

“…Figure shows the single‐dose exposure (expressed as area under the concentration‐time curve [AUC]) predicted for children with a PBPK model in comparison to the data observed in the first clinical trial with rivaroxaban in children . Another example is the fluoroquinolone antibiotic moxifloxacin the clearance of which was predicted in children by PBPK modeling before the conduction of pediatric trials and compared with individual data observed in 2 pediatric trials . In both case examples, PBPK modeling in children using previous ontogeny information has been proven to be very helpful to guide the development of suitable dosing regimens in pediatric development programs.…”