Progressive tools and critical strategies for development of best fit PBPK model aiming better in vitro-in vivo correlation.

ABSTRACT

Nowadays, conducting discriminative dissolution experiments employing physiologically based pharmacokinetic modeling (PBPK) or physiologically based biopharmaceutical modeling (PBBM) is gaining significant importance in quantitatively predicting oral absorption of drugs. Mechanistic understanding of each process involved in drug absorption and its impact on the performance greatly facilitates designing a formulation with high confidence. Unfortunately, the biggest challenge scientists are facing in current days is the lack of standardized protocol for integrating dissolution experiment data during PBPK modeling. However, in vitro-in vivo drug release interrelation can be improved with the consideration and development of appropriate biorelevant dissolution media that closely mimic physiological conditions. Multiple reported dissolution models have described nature and functionality of different regions of the gastrointestinal tract (GI) to more accurately design discriminative dissolution media. Dissolution experiment data can be integrated either mechanistically or without a mechanism depending primarily on the formulation type, biopharmaceutics classification system (BCS) class and particle size of the drug substance. All such parameters are required to be considered for selecting the appropriate functions during PBPK modeling to produce a best fit model. The primary focus of this review is to critically discuss various progressive dissolution models and tools, existing challenges and approaches for establishing best fit PBPK model aiming better in vitro-in vivo correlation (IVIVC). Strategies for proper selection of dissolution models as an input function in PBPK/PBBM modeling have also been critically discussed. Logical and scientific pathway for selection of different type of functions and integration events in the commercially available in silico software has been described through case studies.