Age-dependent oral drug absorption in children: Assessment of a bottom-up modelling approach

Paediatric drug development poses significant challenges due to the unique physiological and ethical considerations in children. Physiologically Based Pharmacokinetic (PBPK) modelling has emerged as a valuable tool for predicting paediatric drug absorption and optimising dosing strategies. This study aimed to refine PBPK modelling for paediatric applications by developing a customised PK-Sim-based paediatric PBPK (pPBPK) model for four drugs that are part of the Model List of Essential Medicines for Children by the World Health Organisation: paracetamol, ibuprofen, darunavir, and itraconazole. The model incorporated age-specific gastrointestinal parameters for four paediatric age groups, minimising the need for parameter interpolation or scaling. The effect of food on drug absorption was investigated by extending the absorption model to account for bile and excipient solubilisation. A literature review identified gaps in the understanding of paediatric intestinal parameters necessary for pPBPK modelling. Biorelevant in vitro dissolution and solubility data were integrated to enhance prediction accuracy. Validation with clinical pharmacokinetic data demonstrated the model's reliability across different paediatric age groups. Sensitivity analyses highlighted the influence of gastric emptying time, small intestinal transit, and bile salt concentration on drug pharmacokinetics. This research underscores the potential of pPBPK modelling to inform paediatric dosing strategies while addressing current gaps and challenges.