Physiologically-based pharmacokinetic modeling to support the determination of drug product bioequivalence

Physiologically-based pharmacokinetic (PBPK) modeling is an important in silico tool that bridges drug properties and in vivo pharmacokinetic (PK) behaviours. There has been an increasing interest in this computational approach, as it presents multiple applications in both drug discovery and development stages. In a drug development setting, PBPK modeling can support alternative bioequivalence (BE) approaches with reduced or no human testing. In this regard, PBPK modeling emerges with the aim of overcoming the limitations of clinical studies, presenting itself as a more cost-effective method that accelerates the drug development process. PBPK models for non-oral dosage forms are still under development compared to oral drug models, yet both still present many challenges concerning their review and evaluation, due to the difficulty in recruiting evaluators with appropriate experience and knowledge of PBPK modeling, and the lack of confidence in PBPK models for which there are no drug concentration data in the tissue/plasma to evaluate the models. Efforts have been made recently and there are already successful cases of complex generic drugs approved by the Food and Drug Administration (FDA) based on PBPK modeling for BE determination and subsequently to support regulatory decision-making. To this end, PBPK models have been properly verified and validated for their intended purpose. This chapter aims to present an overview of PBPK modeling and discuss scientific and regulatory considerations on the development, verification and validation (V&V) and application of PBPK modeling in the context of a virtual BE (VBE) assessment for generic drug products.