Development of a novel physiologically based biopharmaceutics modeling (PBBM) framework using the open systems...

Physiologically Based Biopharmaceutics Modeling (PBBM) links in vitro solubility and dissolution kinetics of oral drugs to Physiologically Based Pharmacokinetic (PBPK) models, enabling the prediction of drug bioavailability. This approach reduces reliance on animal experimentation during drug development. Part 1 of this series introduces a novel, open-source PBBM workflow using the Open Systems Pharmacology (OSP) Software Suite. It combines the newly developed OSP solubility toolbox to estimate drug aqueous solubility and bile salt micelle partitioning from in vitro data, with an updated MoBi® dissolution model that accounts for factors such as hydrodynamic diffusion layer thickness changes and micelle partitioning. This approach was applied to poorly soluble, highly permeable vericiguat, a first-in-class soluble guanylate cyclase (sGC) stimulator for the treatment of chronic heart failure. The solubility models effectively described the aqueous solubility-pH profile and bile salt partitioning, while the dissolution model captured the in vitro dissolution kinetics of various tablet formulations. Part 2 focuses on integrating developed PBBM sub-models into PBPK models using PK-Sim® to predict vericiguat's clinical pharmacokinetics after oral administration. This PBBM workflow demonstrates potential for diverse applications, including predictive bioavailability and bioequivalence assessments, in silico formulation optimization, formulation bridging, dose selection, and setting dissolution specifications.