Usefulness of the Beagle Model in the Evaluation of Paracetamol and Ibuprofen Exposure after Oral Administration to Pediatric Populations: An Exploratory Study

Marina Statelova, René Holm, Nikoletta Fotaki, Christos Reppas, Maria Vertzoni

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Abstract

The present study aimed to explore the usefulness of beagle dogs in combination with physiologically based pharmacokinetic (PBPK) modeling in the evaluation of drug exposure after oral administration to pediatric populations at an early stage of pharmaceutical product development. An exploratory, single-dose, crossover bioavailability study in six beagles was performed. A paracetamol suspension and an ibuprofen suspension were coadministered in the fasted-state conditions, under reference-meal fed-state conditions, and under infant-formula fed-state conditions. PBPK models developed with GastroPlus v9.7 were used to inform the extrapolation of beagle data to human infants and children. Beagle-based simulation outcomes were compared with published human-adult-based simulations. For paracetamol, fasted-state conditions and reference-meal fed-state conditions in beagles appeared to provide adequate information for the applied scaling approach. Fasted-state and/or reference-meal fed-state conditions in beagles appeared suitable to simulate the performance of ibuprofen suspension in pediatric populations. Contrary to human-adult-based translations, extrapolations based on beagle data collected under infant-formula fed-state conditions appeared less useful for informing simulations of plasma levels in pediatric populations. Beagle data collected under fasted and/or reference-meal fed-state conditions appeared to be useful in the investigation of pediatric product performance of the two investigated highly permeable and highly soluble drugs in the upper small intestine. The suitability of the beagle as a preclinical model to understand pediatric drug product performance under different dosing conditions deserves further evaluation with a broader spectrum of drugs and drug products and comparisons with pediatric in vivo data.

Original languageEnglish
Pages (from-to)2836-2852
Number of pages17
JournalMolecular Pharmaceutics
Volume20
Issue number6
Early online date1 May 2023
DOIs
Publication statusPublished - 5 Jun 2023

Bibliographical note

Funding Information:
This work was supported by the Horizon 2020 Marie Sklodowska-Curie Innovative Training Networks programme under grant agreement no. 674909.

Keywords

  • beagle bioavailability study
  • extrapolation to pediatric populations
  • food effect
  • ibuprofen
  • infant formula
  • paracetamol
  • pediatrics
  • physiologically based pharmacokinetic (PBPK) model

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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