Compartmental absorption and transit models

The compartmental absorption and transit model was developed based on the transit model. The assumptions for the CAT model include the following. 

Figure 10 The fraction of dose absorbed as a function of the effective human permeability. (---) Compartmental absorption and transit model (Eqs. (59) or (60)) (—) single-...

Refinement and expansion of these steady-state mass balance approaches has led to the development of dynamic models which allow for estimation of the fraction absorbed as a function of time and can therefore be used to predict the rate of dmg absorption [37], These compartmental absorption and transit models (CAT) models have subsequently been used to predict pharmacokinetic profiles of drugs on the basis of in vitro dissolution and permeability characteristics and drug transit times in the intestine [38],... 

Yu LX and Amidon GL (1999) A Compartmental Absorption and Transit Model for Estimating Oral Drug Absorption. Int J Pharm 186 pp 119-125. 

Yu LX, Amidon GL (1999) A compartmental absorption and transit model for estimating oral drug absorption. Int. J. Pharm. 186 119-125. 

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). 

ACAT Advanced compartmental absorption and transit model... 

Caco-2 Adenocarcinoma cell line derived from human colon CAT Compartmental absorption and transit model... 

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). 

Figure 17.3 Schematic diagram of the advanced compartmental absorption and transit model as implemented in CastroPlus.

The models presented above will allow the adequate description of most drug absorption profiles however, on occasion more complex models are needed. These would include the saturable time-constraint absorption model with a storage compartment (67), an extended compartmental absorption and transit model for... 

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). 

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]. 

The basis for all CAT models is the fundamental understanding of the transit flow of drugs in the gastrointestinal tract. Yu et al. [61] compiled published human intestinal transit flow data from more than 400 subjects, and their work showed the human mean small intestinal transit time to be 199 min. and that seven compartments were optimal in describing the small intestinal transit process using a compartmental approach. In a later work, Yu et al. [58] showed that between 1 and 14 compartments were needed to optimally describe the individual small intestine transit times in six subjects but in agreement with the earlier study, the mean number of compartments was found to be seven. This compartmental transit model was further developed into a compartmental absorption and transit (CAT) model ([60], [63]). The assumptions made for this CAT model was that no absorption occurs in the stomach or in the colon and that dissolution is instantaneous. Yu et al. [59] extended the CAT model... 

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]. 

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). 

A series of rate constants (k, h ) are currently used in physiologically based models to describe the transfer of a dose to the stomach and then its distribution to the various regions of the small intestine. This compartmental approach was used by Timchalk et al. (2002) to predict the ADMET (absorption, distribution, metabolism, elimination, and toxicity) of chlorpyrifos in rats and humans. Zhang et al. (2007) chose a compartmental transit and absorption GI model for carbofuran. The model incorporated the majority of the GI, including colon, duodenum, lower small intestine, and stomach lumen (food flow, L h , and volumes, L) and walls (volume, percent). Yu et al. (1996) developed one of the first compartmental absorption and transit (CAT) models that were described by a set of differential... 

A special case in dissolution-limited bioavailability occurs when the assumption of sink condition in vivo fails that is, the drug concentration in the intestine is dose to the saturation solubility. Class IV compounds, according to BCS, are most prone to this situation due to the combination of low solubility and low permeability, although the same could also happen for class II compounds, depending primarily on the ratio between dose and solubility. Non-sink conditions in vivo lead to less than proportional increases of bioavailability for increased doses. This is illustrated in Fig. 21.8, where the fraction of drug absorbed has been simulated by use of an compartmental absorption and intestinal transit model [35] for different doses and for different permeabilities of a low-solubility, aprotic compound. 

More sophisticated approaches to predict the extent of oral absorption of drugs use mathematical models based on the known physiology and utilizing simple physicochemical measurements as input. The GastroPlus [4] program is a commercial tool that utilizes an advanced compartmental and transit model, based on the work of Amidon and Yu [5], and allows what-if questions to be posed to enable pharmaceutical optimization (see Chapter 17). For instance, the impact of morphology, formulation, and/or particle size changes, and sensitivity analysis to include errors in parameters on the prediction, can be considered. 

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