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Pharmacokinetics, Safety, and Tolerability of Single‐Dose Intravenous Moxifloxacin in Pediatric Patients: Dose Optimization in a Phase 1 Study
Author(s) -
Stass Heino,
Lettieri John,
Vanevski Konstantina M.,
Willmann Stefan,
James Laura P.,
Sullivan Janice E.,
Arrieta Antonio C.,
Bradley John S.
Publication year - 2019
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1358
Subject(s) - medicine , moxifloxacin , pharmacokinetics , tolerability , dosing , cohort , adverse effect , pharmacodynamics , population , pharmacology , antibiotics , environmental health , microbiology and biotechnology , biology
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.