PBPK modeling coupled with biorelevant dissolution to forecast the oral performance of amorphous solid dispersion formulations.

The aim of this research was to develop an in silico modeling and simulation approach to predict the oral performance of a poorly soluble drug candidate, T2CP, formulated as an amorphous solid dispersion and an amorphous powder. The dissolution and precipitation profiles of T2CP of the two amorphous formulations were evaluated in biorelevant media using USP 2 paddle apparatus. Three equations, the Noyes-Whitney equation for dissolution and separate equations describing nucleation and crystal growth, were fitted simultaneously to the in vitro profiles to estimate the dissolution and precipitation parameters for each formulation. The in silico prediction model for the amorphous formulations was designed using STELLA Professional software and the simulated profiles were compared with the observed plasma profiles in dogs. The STELLA model was able to describe the complex characteristics of in vitro dissolution and precipitation of the amorphous formulations well. The predicted plasma concentration profiles using the estimated dissolution and precipitation parameters of the two amorphous formulations were close to the profiles observed in dogs. This research paves the way for further application of biorelevant in vitro methods in combination with in silico tools to mechanistically forecast the in vivo performance of enhanced formulations.