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

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 fedstate 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.

The Use of Population Pharmacokinetics to Extrapolate Food Effects from Human Adults and Beagle Dogs to the Pediatric Population Illustrated with Paracetamol as a Test Case

“…The beagle dogs and the human adults were able to adequately simulate the pediatric paracetamol concentration–time curves ( Figure 4 ). The simulation results obtained using popPK were comparable with the results retrieved from a similar PBPK exercise performed by Statelova et al [ 14 , 15 ]. In this current analysis, for the simulations starting from the human adult results, it was decided to use the popPK parameters, scaled allometrically, since it is known that body weight is an important covariate on PK parameters.…”

“…PopPK models describing the PK of paracetamol in both species were constructed to gain more insights into the drug’s performance based on different dosing conditions (fasted, reference meal (RM), and infant formula (IF)) and to verify these insights using the available (published) data on the pediatric population. The results obtained with the present popPK analysis were compared with a similar PBPK exercise performed by Statelova et al [ 14 , 15 ].…”

“…Ethical committee approval was obtained from the ethical committee of Janssen R&D (approval number 512). A detailed description of the beagle dog study can be found in Statelova et al [ 14 ]. Six clinically healthy beagle dogs (Marshall BioResources, Lyon, France) were included in this present study with a median age of 1.9 years (a minimum of 1.7 and a maximum of 4.0 years) and a median body weight of 9.70 kg (a minimum of 7.90 and a maximum of 13.3 kg).…”

“… Paracetamol plasma concentration–time curves in beagle dogs [ 14 ] and human adults [ 16 ]. RM: reference meal; IF: infant formula; RM200: 100 g (200 kcal); RM100: 50 g (100 kcal); IF100: 150 mL (100 kcal); INF200: 300 mL (200 kcal); RM: 990 kcal; and IF: 520 kcal.…”

“…This current manuscript does not contain any original clinical or preclinical data. The data were extracted from Statelova et al, 2019 (human adults) [ 16 ], and Statelova et al, 2023 (beagle dogs) [ 14 ].…”