The application of preclinical in vitro and in silico models can help formulation scientists to predict the in vivo performance of a drug in an early stage of oral drug product development. An important aspect is that these models should include equations that represent mechanisms that are biorelevant and are sensitive to changes in parameter values. Human gastrointestinal (GI) physiology involves many processes that change as a function of time. In this work, a dynamic fluid and pH model was applied in GastroPlus™ to simulate intraluminal and systemic concentrations of the weak base posaconazole in a biorelevant manner. Simulated results were compared with observed data, extracted from a previously reported human in vivo GI aspiration study. Three different formulations were explored (i.e., one solution (20 mg dose strength) and two suspensions (both 40 mg dose strength)). Simulated results were compared and in line with the observed results for different intraluminal (e.g., precipitated fraction) and systemic parameters (e.g., plasma C_max). The optimization of the advanced compartmental and absorption transit (ACAT) model related to fluid dynamics and dynamic pH in this work creates perspectives to validate this model with other reference data derived from aspiration/magnetic resonance imaging (MRI) studies.

By Bart Hens & Michael B. Bolger