Physiologically based pharmacokinetic extrapolation

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. 

Clewell HJ III, Andersen ME. 1985. Risk assessment extrapolations using physiologically-based pharmacokinetic modeling. Toxicol Ind Health 1 111-131. 

If physiologically based pharmacokinetic (PBPK) models cannot be used, interspecies extrapolation is best undertaken by means of scaling according to basal metabolic rate, see Section 5.3.2.3. A second aspect, interspecies variability, should be considered in cases where a higher than average level of safety (achieved by consideration of a higher percentile of the substances) is desired. 

Once a chemical is in systemic circulation, the next concern is how rapidly it is cleared from the body. Under the assumption of steady-state exposure, the clearance rate drives the steady-state concentration in the blood and other tissues, which in turn will help determine what types of specific molecular activity can be expected. Chemicals are processed through the liver, where a variety of biotransformation reactions occur, for instance, making the chemical more water soluble or tagging it for active transport. The chemical can then be actively or passively partitioned for excretion based largely on the physicochemical properties of the parent compound and the resulting metabolites. Whole animal pharmacokinetic studies can be carried out to determine partitioning, metabolic fate, and routes and extent of excretion, but these studies are extremely laborious and expensive, and are often difficult to extrapolate to humans. To complement these studies, and in some cases to replace them, physiologically based pharmacokinetic (PBPK) models can be constructed [32, 33]. These are typically compartment-based models that are parameterized for particular... 

Another model, which is increasingly being used, is the physiologically based pharmacokinetic model. This uses data on the absorption, distribution, metabolism, tissue sequestration, kinetics, elimination, and mechanism to determine the target dose used for the extrapolation, but it requires extensive data. 

Johanson. G. Filser, J.G. (1993) A physiologically based pharmacokinetic model for butadiene and its metabolite butadiene monoxide in rat and mouse and its significance for risk extrapolation. Arch. Toxicol., 61, 151-163... 

The explanation of the pharmacokinetics or toxicokinetics involved in absorption, distribution, and elimination processes is a highly specialized branch of toxicology, and is beyond the scope of this chapter. However, here we introduce a few basic concepts that are related to the several transport rate processes that we described earlier in this chapter. Toxicokinetics is an extension of pharmacokinetics in that these studies are conducted at higher doses than pharmacokinetic studies and the principles of pharmacokinetics are applied to xenobiotics. In addition these studies are essential to provide information on the fate of the xenobiotic following exposure by a define route. This information is essential if one is to adequately interpret the dose-response relationship in the risk assessment process. In recent years these toxicokinetic data from laboratory animals have started to be utilized in physiologically based pharmacokinetic (PBPK) models to help extrapolations to low-dose exposures in humans. The ultimate aim in all of these analyses is to provide an estimate of tissue concentrations at the target site associated with the toxicity. 

REITZ, R., MCDOUGAL, J.N., HIMMELSTEIN, M.W., NOLAN, R.J. and SCHUMANN, A.M. (1988). Physiologically-based pharmacokinetic modeling with methylchloroform Implications for interspecies, high dose/low dose, and dose-route extrapolations, Toxicol. Appl. Pharmacol. 95, 185-192. 

Exposures of newborns to PAHs depend on pharmacokinetic processes operating in the mother, and transfer through breast milk. Since it is difficult to characterize these pathways in humans, physiologically based pharmacokinetic (PBPK) and pharmacodynamic (PD) models need to be developed using appropriate animal models, and incorporating key parameters such as dose, exposure duration, and developmental stage (Dorman et al, 2001). Thus, development of PBPK and PBPD models for PAHs is an immediate need that will help in not only characterizing the dose-response relationship, but also extrapolation of results from animal studies to humans. 

Currently, the growing trend is to make use of physiologically-based pharmacokinetic models to study the behavior of drugs in animals and extrapolate the data to humans. In this context, computers will be of immense help in developing predictive models that might assist in the scale-up of animal data to humans and predicting the concentration of drugs in human body fluids. 

Kedderis, GM. In vitro to in vivo extrapolation of metabolic rate constants for physiologically based pharmacokinetic models. In JC Lipscomb and EV Ohanian, editors Toxicokinetics and Risk Assessment. Informa Healthcare Publishers, New York, 2007. 

Recent physiologically based pharmacokinetic models have tried to address 2-butoxyethanol metabolism and disposition in an effort to derive animal-to-human extrapolations (Medinsky et al. 1993 Shyr et al. 

Eventually, the toxicokinetic data, together with the distribution data, are very useful for the validation of physiologically based pharmacokinetic modeling (PBPK). " These models are needed because the experiments that were discussed in this chapter can never be performed in humans, whereas extrapolation of the results obtained in these animal experiments to man is stiU the ultimate goal of these investigations. 

Present-day risk assessment methodologies have an increasing emphasis on physiologically based pharmacokinetics (PBPK) or toxicokinetic models and mode of action (MOA). Snch models have been developed to predict exposure levels in target tissues for a large number of agents. PBPK models are especially useful in the risk assessment context because they allow data to be extrapolated across species, dose levels, and routes of exposure. 

Clewell, H. J. I., and Andersen, M. E. (1987). Dose, species and route extrapolation using physiologically-based pharmacokinetic models. Drinking Water and Health 8, 159-182. 

Doerge, D. R., Young, J. F., Chen, J. J., Dinovi, M. J., and Henry, S. H. (2008). Using dietary exposure and physiologically based pharmacokinetic/pharmacodynamic modeling in human risk extrapolations for acrylamide toxicity. J Agric Food Chem 56, 6031-6038. 

Figure 2. A suggested approach utilizing physiologically based pharmacokinetics and computer technology for the extrapolation and prediction of various situations in toxicology.

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