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

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.