Predicting in vivo performance of piroxicam and apalutamide drug nanocrystals from in vitro flux measurements combined with in silico modelling.

The development and optimization of pharmaceutical nanocrystal formulations is often complex and resource-intensive, as particle properties depend on composition, manufacturing parameters, and batch variability, all of which influence in vivo performance. Predictive in vitro-in silico approaches can streamline formulation development by reducing the need for extensive animal and clinical testing. This study reports on a methodological evaluation of an integrated workflow combining dissolution-permeation data with a mechanistic absorption model based on the gastrointestinal unified theoretical framework. Two drugs with distinct properties, piroxicam (PRX) and apalutamide (APA), were investigated across multiple species to assess the framework's ability to predict their pharmacokinetic (PK) behaviour. The incorporation of in vivo relevant dosing for in vitro testing together with corrections for the particle drifting effect and dissolution rate coefficient enabled generation of predicted plasma concentration vs time profiles. The in silico predictions reproduced key PK parameters, including area under the curve (AUC), time to maximum concentration (tmax), maximum concentration (Cmax), and captured formulation-specific differences in PK behaviour - in particular, the enhanced performance of APA and PRX nanocrystals over the reference products. Overall, these findings imply that this workflow potentially can identify formulation- and species-dependent rate-limiting factors governing bioavailability, indicating its potential as predictive tool for nanocrystal drug development and supporting further evaluation of the methods performance for other drugs.