Applications of PBPK/PBBM modeling in generic product development: An industry perspective

Physiologically based pharmacokinetic (PBPK) modeling and physiologically based biopharmaceutics modeling (PBBM) are invaluable tools with wide applications during drug discovery and development stages. At the drug discovery setting, PBPK modeling is used for first in human pharmacokinetics prediction, food effect assessment, and preclinical modeling. During generic formulation development, PBPK and PBBM modeling can be utilized for suitable formulation design in order to achieve bioequivalence with a Reference Listed Drug (RLD). The purpose of this review is to lay down the applications of PBPK from the generic product development perspective. Evolution of PBPK models and regulatory perspectives in terms of PBPK modeling and simulation guidelines from the USFDA and EMA are critically reviewed. Applications of PBPK modeling in generic industry are discussed in detail. Utility of PBPK modeling for formulation development for modified release formulation development, biowaiver and API particle size impact, food effect studies are emphasized in detail with case studies. Applications related to dissolution safe space, justification of dissolution specifications and development of clinically relevant dissolution specifications are discussed with specific case examples. Further, insight is provided into modeling applications with regard to non-oral routes of administrations such as ocular, pulmonary, transdermal and parenteral. Finally, future perspectives for modeling & simulations for both oral and non-oral formulations and requirements for harmonization of PBPK guidelines are discussed. [Display omitted]