Physiologically-based modeling

FUN tool is a new integrated software based on a multimedia model, physiologically based pharmacokinetic (PBPK) models and associated databases. The tool is a dynamic integrated model and is capable of assessing the human exposure to chemical substances via multiple exposure pathways and the potential health risks (Fig. 9) [70]. 2-FUN tool has been developed in the framework of the European project called 2-FUN (Full-chain and UNcertainty Approaches for Assessing Health Risks in FUture ENvironmental Scenarios www.2-fun.org). 

Figure 5.5 Flowchart showing various human risk assessment options for chemical mixtures based on component data. PBPK model = Physiologically Based Pharmacokinetic model. 

PBPK model Physiologically based pharmacokinetic model. Physiologically based compartmental model used to characterize pharmacokinetic behavior of a chemical. Available data on blood flow rates, and metabolic and other processes, which the chemical undergoes within each compartment are used to construct a mass-balance framework for the PBPK model. 

Physiologic model-physiologically based pharmacokinetic model (PB/PK) A physiologically based model for Gl transit and absorption in humans is presented. The model can be used to study the dependency of the fraction dose absorbed (Fabs) of both neutral and ionizable compounds on the two main physico-chemical input parameters [the intestinal permeability coefficient (Pint) and the solubility in the intestinal fluids (Sint)] as well as the physiological parameters, such as the gastric emptying time and the intestinal transit time. For permeability-limited compounds, the model produces the established sigmoidal dependence between Fabs and Pnt. In case of solubility-limited absorption, the model enables calculation of the critical mass-solubility ratio, which defines the onset of nonlinearity in the response of fraction absorbed to dose. In addition, an analytical equation to calculate the intestinal permeability coefficient based on the compound s membrane affinity and MW was used successfully in combination with the PB-PK model to predict the human fraction dose absorbed of compounds with permeability-limited absorption. Cross-validation demonstrated a root-mean-square prediction error of 7% for passively absorbed compounds. 

Absorption, distribution, biotransformation, and excretion of chemical compounds have been discussed as separate phenomena. In reality all these processes occur simultaneously, and are integrated processes, i.e., they all affect each other. In order to understand the movements of chemicals in the body, and for the delineation of the duration of action of a chemical m the organism, it is important to be able to quantify these toxicokinetic phases. For this purpose various models are used, of which the most widely utilized are the one-compartment, two-compartment, and various physiologically based pharmacokinetic models. These models resemble models used in ventilation engineering to characterize air exchange. 

Physiologically based toxicokinetic models are nowadays used increasingly for toxicological risk assessment. These models are based on human physiology, and thus take into consideration the actual toxicokinetic processes more accurately than the one- or two-compartment models. In these models, all of the relevant information regarding absorption, distribution, biotransformarion, and elimination of a compound is utilized. The principles of physiologically based pharmaco/ toxicokinetic models are depicted in Fig. 5.41a and h. The... 

Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models... 

Note This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 

Andersen ME, Kirshnan K. 1994. Relating in vitro to in vivo exposures with physiologically based tissue dosimetry and tissue response models. In Salem H,ed. Animal test alternatives Refinement, reduction, replacement. New York, NY Marcel Dekker, Inc., 9-25. 

Krishnan K, Andersen ME, Clewell H 3rd, et al. 1994. Physiologically based pharmacokinetic modeling of chemical mixtures. In Yang R, ed. Toxicology of chemical mixtures. New York, NY Academic Press, 399-437. 

Leung H-W. 1993. Physiologically-based pharmacokinetic modelling. In Ballentine B, Marro T, Turner P, eds. General and applied toxicology. New York, NY Stockton Press, 153-164. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent chemical or metabolite in an animal system. There are two types of pharmacokinetic models data-based and physiologically-based. A data-based model divides the animal system into a series of compartments which, in general, do not represent real, identifiable anatomic regions of the body whereby the physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically-based dose-response model which quantitatively describes the relationship between target tissue dose and toxic end points. These models advance the importance of physiologically based models in that they clearly describe the biological effect (response) produced by the system following exposure to an exogenous substance. 

Physiologically Based Phamiacokinetic (PBPK) Model—Comprised of a series of compartments representing organs or tissue groups with realistic weights and blood flows. These models require a variety of physiological information tissue volumes, blood flow rates to tissues, cardiac output, alveolar ventilation rates and, possibly membrane permeabilities. The models also utilize biochemical information such as air/blood partition coefficients, and metabolic parameters. PBPK models are also called biologically based tissue dosimetry models. 

KrishnanK, Andersen ME. 1994. Physiologically-based pharmacokinetic modeling in toxicology. In Wallace Hayes, ed. Principles and methods of toxicology. 3rd edition. New York, NY Raven Press, Ltd. 

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. 

Notice Approaches for the Application of Physiologically-Based Pharmacokinetic (PBPK) Models and Supporting Data in Risk Assessment E-Docket ID No. ORD-2005-0022. Fed Reg July 28, 2005 70 (144) 43692-43693. 

Nestorov lA, Aarons LJ, Rowland M. Physiologically based pharmacokinetic modeling of a homologous series of barbiturates in the rat a sensitivity analysis. / Pharmacokinet Biopharm 1997 25 413-47. 

What are called physiologically based pharmacokinetic (PBPK) and pharmacodynamic (PBPD) models are more mechanistically complex and often include more compartments, more parameters, and more detailed expressions of rates and fluxes and contain more mechanistic representation. This type of model is reviewed in more detail in Section 22.5. Here, we merely classify such models and note several characteristics. PBPK models have more parameters, are more mechanistic, can exploit a wider range of data, often represent the whole body, and can be used both to describe and interpolate as well as to predict and extrapolate. Complexity of such models ranges from moderate to high. They typically contain 10 or more compartments, and can range to hundreds. The increase in the number of flux relationships between compartments and the related parameters is often more than proportional to compartment count. 

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