ACAT models

The ACAT model is loosely based on the work of Amidon and Yu who found that seven equal transit time compartments are required to represent the observed cumulative frequency distribution for small intestine transit times [4], Their original compartmental absorption and transit (CAT) model was able to explain the oral plasma concentration profiles of atenolol [21]. 

Mechanistic Simulation (ACAT models) in Early Discovery... 

Fig. 18.3. ACAT model schematic. The diagram includes the consideration of six states (unreleased, undissolved, dissolved, degraded, metabolized, and absorbed), 18 compartments [nine gastrointestinal (stomach, seven small intestine, and colon) and nine...

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. 

Table 18.2 lists 30 of the molecules used in this study that are known to be substrates for active transport or active efflux. The mechanistic ACAT model was modified to accommodate saturable uptake and saturable efflux using standard Michaelis-Menten equations. It was assumed that enzymes responsible for active uptake of drug molecules from the lumen and active efflux from the enterocytes to the lumen were homogeneously dispersed within each luminal compartment and each corresponding enterocyte compartment, respectively. Equation (5) is the overall mass balance for drug in the enterocyte compartment lining the intestinal wall. 

In spite of its limitations, the ACAT model combined with modeling of saturable processes has become a powerful tool in the study of oral absorption and pharmacokinetics. To our knowledge, it is the only tool that can translate in vitro data from early drug discovery experiments all the way to plasma concentration profiles and nonlinear dose-relationship predictions. As more experimental data become available, we believe that the model will become more comprehensive and its predictive capabilities will be further enhanced. 

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]. 

Figure 10.2 Schematic diagram of the advanced compartmental absorption and transit (ACAT) model [18].

Figure 6.4 Schematic of the ACAT model. Reprinted from [176] with permission from Elsevier.

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). 

We have developed a two-step procedure for the in silico screening of compound libraries based on biopharmaceutical property estimation linked to a mechanistic simulation of GI absorption. The first step involves biopharmaceutical property estimation by application of machine learning procedures to empirical data modeled with a set of molecular descriptors derived from 2D and 3D molecular structures. In silico methods were used to estimate such biopharmaceutical properties as effective human jejunal permeability, cell culture permeability, aqueous solubility, and molecular diffusivity. In the second step, differential equations for the advanced compartmental absorption and transit model were numerically integrated to determine the rate, extent, and approximate GI location of drug liberation (for controlled release), dissolution, and absorption. Figure 17.3 shows the schematic diagram of the ACAT model in which each one of the arrows represents an ordinary differential equation (ODE). 

The form of the ACAT model implemented in GastroPlus describes the release, dissolution, luminal degradation (if any), metabolism, and absorption/exsorption of... 

Simulated HIA% (GastroPlus ACAT model) Figure 17.5 Correlation of experimental and simulated percentage absorbed. Percentage absorbed is defined as the percentage of the dose that crosses the apical membrane of the intestine. Percentage absorbed was simulated using the ACAT model as described in the text. 

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