Moxifloxacin in Pediatric Patients With Complicated Intra-abdominal Infections

Abstract

MXF treatment was well tolerated in children with cIAIs. However, a lower clinical cure rate was observed with MXF treatment compared with COMP. This study does not support a recommendation of MXF for children with cIAIs when alternative more efficacious antibiotics with better safety profile are available.

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

“…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 . After the completion of both trials, a pediatric popPK model for moxifloxacin was developed, and the resulting PK parameters were compared with the initial PBPK predictions to (i) retrospectively evaluate the PBPK model predictability, (ii) confirm the proposed dosing schedule of moxifloxacin in children, and (iii) support PK‐related clinical safety/efficacy questions (confirmation step).…”

“…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 …”

“…A switch to oral treatment was done in 28 subjects. The doses were selected to target exposure equivalent to that observed after the recommended 400 mg dose for adults . The studies were conducted in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice.…”

“…The PBPK‐predicted AUC inf and C max distributions for children were compared with the target exposure ranges for moxifloxacin from adult data to provide appropriate starting doses for the phase I clinical trial . During and after conclusion of the phase I trial followed by an assessment of the PK and safety data observed for the starting doses, the dosing regimens for a subsequent phase III clinical trial were defined as described in detail in ref . In addition to the PBPK predictions that related pediatric doses to the expected exposure of moxifloxacin in children, a plethora of other aspects relevant for safety and efficacy were also taken into consideration …”

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.…”