GastroPlus

Simulation methods have also been developed that include physiologically based pharmacokinetic modeling (PBPK) and methods such as Cloe PK, OMPPPlus, GastroPlus , SimCYP , and others [122] that are described elsewhere in this book. It is likely that the computational metabolism predictions could be integrated with these to assist in deriving more accurate predictions of human pharmacokinetic parameters. 

Other than the different approaches mentioned above, commercial packages such as GastroPlus (Simulations Plus, Lancaster, CA) [19] and IDEA (LionBioscience, Inc. Cambridge, MA) [19] are available to predict oral absorption and other pharmacokinetic properties. They are both based on the advanced compartmental absorption and transit (CAT) model [20], which incorporates the effects of drug moving through the gastrointestinal tract and its absorption into each compartment at the same time (see also Chapter 22). 

Parrott N, Lave T. Prediction of intestinal absorption comparative assessment of GASTROPLUS and IDEA . Eur J Pharm Sci 2002 17 51-61... 

There have been considerable efforts toward modeling ADME/Tox properties and the biophysical properties of molecules (see chapters 18-20, 22, 28), including numerous commercial software solutions. Simulations Plus (http //www.simulations-plus.com/) have developed GastroPlus, a product... 

GastroPlus. For further information visit http //www.simulations-plus.com. 

The mechanistic simulation ACAT model was modified to account automatically for the change in small intestinal and colon k as a function of the local (pH-dependent) log D of the drug molecule. The rank order of %HIA from GastroPlus was directly compared with rank order experimental %HIA with this correction for the log D of each molecule in each of the pH environments of the small intestine. A significant Spearman rank correlation coefficient for the mechanistic simulation-based method of 0.58 (p < 0.001) was found. The mechanistic simulation produced 71% of %HIA predictions within 25% of the experimental values. 

Fig. 18.5. Correlation of simulated %HIA and experimental %HIA. The fraction absorbed was simulated using GastroPlus with input values of permeability, solubility, diffusivity, and pKa values calculated purely in silico.

Figure 21.3 Schematic representation of the absorption processes modelled in GastroPlus .

In a limited independent evaluation of GastroPlus , Hendriksen et al. [22] used literature data on solubility together with calculated human permeability values to predict the human Fabs for 21 drugs for which observed human FabS... 

GastroPlus, Simulations Plus, Inc., http //www.simulations-plus.com Pathway Prism, Physiome Sciences, Inc., http //www.physiome.com Physiolab, Entelos, Inc., http //www.entelos.com/... 

GastroPlus [137] and IDEA [138] are absorption-simulation models based on in vitro input data like solubility, Caco-2 permeability and others. They are based on advanced compartmental absorption and transit (ACAT) models in which physicochemical concepts are incorporated. Both approaches were recently compared and are shown to be suitable to predict the rate and extent of human absorption [139]. 

Furthermore, the Pefr data can be integrated with solubility/dissolution data to predict the oral absorption from the solid dosage form (see Chapter 10). Gastrointestinal transit absorption model (GITA) [12, 13], advanced compartmental absorption and transit model (ACAT, GastroPlus), advanced drug absorption and metabolism model (ADAM, SimCYP) and so on have been reported as useful integration models (see Chapter 10). 

In a second stage GastroPlus was used to simulate oral absorption, and oral profiles were produced by feeding this predicted input into a compartmental disposition model fitted to the mean observed intravenous data. 

II. Product Summaries Simulations Plus develops simulation and predictive modeling software for in silico compound screening and for preclinical and clinical drug development in the area of Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET). The available applications include GastroPlus, ADMET Predictor, ADMET Modeler, DDDPlus, and MembranePlus. 

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