Gastroplus™ software

These simple models based on the assumption of a single intestinal compartment have been refined to the advanced compartmental absorption and transport model that allows transit and differential expression of enzymes and transporters down the length of the gastrointestinal tract including pH, fluid, and blood flow differences [3]. The ACAT model is based on a series of integrated differential equations and has been implemented in the commercial software Gastroplus (see Chapter 17). 

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... 

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. 

The CAT model was further modified to include pH-dependent solubility, dis-solution/precipitation, absorption in the stomach or colon, first-pass metabolism in gut or liver, and degradation in the lumen. Physiological and biochemical factors such as changes in absorption surface area, transporter, and efflux protein densities have also been incorporated. This advanced version of CAT, called ACAT [176], has been formulated in a commercially available simulation software product under the trademark name GastroPlus . A set of differential equations, which is solved by numerical integration, is used to describe the various drug processes of ACAT as depicted in Figure 6.4. 

More recent PBPK software packages such as SIMCYP [www.simcyp.com], PK-Sim [www.pk-sim.com], GastroPlus [www.simulations-plus.com], and Cloe PK [www.cyprotex.com] offer similar bioavailability estimation. It is clear that these approaches require more data input than just molecular structure as in QSAR models. 

As one part of our software validation, we tested the accuracy of GastroPlus simulation of fraction absorbed. Starting from two-dimensional structures, ADMET Predictor was used to generate the molecular descriptors and estimates of log P,... 

Figure 2. Estimation of DCS class based on the GastroPlus software of SimulationPlus. Based on the dimensionless Dose, Absorption and Dissolution Numbers, drugs can be defined as DCS Class 1 (A), 11 (B), 111 (C) and IV (D) based solely on structural information. The program gives predicted values for solubility, pKa and effective human intestinal permeability in order to suggest a fraction absorbed into the portal vein. (See color insert after Index.)...

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