Evaluation of the GastroPlus™ Advanced Compartmental and Transit (ACAT) Model in Early Discovery

Abstract

The generic GastroPlus ACAT model provided reasonable predictions especially for BCS class 1 compounds. For compounds of other classes, the model may be refined by obtaining more information on solubility and permeability in secondary assays. This increases confidence that such a model can be used in discovery projects to understand the parameters limiting absorption and extrapolate predictions across species. Also, when predictions disagree with the observations, the model can be updated to test hypotheses and understand oral absorption.

Physiologically Based Pharmacokinetic Modeling to Evaluate Formulation Factors Influencing Bioequivalence of Metoprolol Extended‐Release Products

“…Once developed and qualified, the intravenous infusion model was expanded to an oral absorption model in GastroPlus TM using the ACAT module to account for absorption and presystemic metabolism. In order to distinguish between the impact of drug‐related and formulation‐related factors on absorption and PK, we started out with the development of an absorption model for 50‐mg metoprolol IR tablets under fasted conditions . Particle size distribution, physicochemical properties (solubility, pK a , diffusion coefficient, log P , and permeability), and PK model parameter values are summarized in Table S1.…”

“…In order to distinguish between the impact of drug-related and formulation-related factors on absorption and PK, we started out with the development of an absorption model for 50-mg metoprolol IR tablets under fasted conditions. 19,[21][22][23] Particle size distribution, physicochemical properties (solubility, pK a , diffusion coefficient, log P, and permeability), and PK model parameter values are summarized in Table S1. The model developed for 50-mg metoprolol IR tablets was externally qualified by overlaying model-based prediction for 100-mg IR tablets with actual observation following administration of the same dose strength.…”

Non-animal approaches for toxicokinetics in risk evaluations of food chemicals

“…PBPK models are generally evaluated on a case-by-case basis. Those using input of in vitro kinetic data show adequate quantitative predictions of in vivo kinetics, including C max , AUC and bioavailability (Flanagan et al, 2016;Gobeau et al, 2016;Rietjens et al, 2010). An evaluation of the various risk evaluations (Fig.…”

Physiology of the Neonatal Gastrointestinal System Relevant to the Disposition of Orally Administered Medications

“…These transporters, in a complex interplay with both active and passive processes in the intestinal epithelium, act on hydrophilic compounds, resulting in a net flux of the majority of the drug back to the lumen of the GIT or into the portal blood supply. Findings from the Caco-2 cells bout intestinal permeability have been incorporated in advanced compartmental and transit (Gobeau et al, 2016), or similar, algorithms, which are complex sets of equations describing key features of the GIT as a drug is emptied from the stomach (gastric emptying time) into the small intestine. Ultimately, the advanced compartmental and transit algorithms predict the concentration of drug that is transported across the intestinal epithelium by mechanisms previously described at a rate determined empirically by Caco-2 cells.…”