Physiologically based pharmacokinetic modelling for the characterization of bipharmaceutical properties

The development of pharmaceuticals aims to ensure their efficacy and safety by understanding the processes of absorption, distribution, metabolism, and excretion (ADME). Pharmacometrics, through mathematical models, allows for predicting drug behaviour and optimizing treatments. PBPK modelling is a branch of pharmacometrics that integrates physiological and anatomical information into pharmacokinetics, improving drug behaviour predictions. These models are useful for multiple applications, such as risk assessment, bioequivalence analysis, studying interactions and extrapolating data across species being a key tool in the drug development critical path. This broad range of applications has driven their development and increased their use in regulatory and clinical settings, opening new application avenues toward personalized treatments, such as digital twins and virtual bioequivalence. The main aim of this thesis is to develop and apply PBPPK models to characterize the biopharmaceutical properties of drugs and improve their application in the clinical and regulatory fields. The present thesis will start with the development of a mechanistic modelling framework for ADME processes within the PhysPK® platform for drugs classified as BCS I-IV. Further, it will be evaluated the predictive capability of the MOOM methodology compared to models based on ordinary differential equations (ODE). Secondly in this work it will be implemented the Two-Stage δ GSA method in PhysPK® and it will be analysed the impact of uncertainty on the pharmacokinetic parameters of the PBPK model. In addition, it will be assessed the iterative two-stage estimation method to enhance parameter precision with different sampling strategies. Finally, in the last part of the present work, focusing on the PBPK applications, specifically in the regulatory field, it will be developed a PBPK model for the enantiomers of racemic ibuprofen and it will be analized the influence of chirality on bioequivalence and absorption based on particle size.