PBPK-PD model

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to delineate and characterize the relationships between (1) the external/exposure concentration and target tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen et al. 1987 Andersen and Krishnan 1994). These models are biologically and mechanistically based and can be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from route to route, between species, and between subpopulations within a species. The biological basis of... 

No data were located regarding PBPK/PD modeling to explain the biological basis for the dose-response relationship in humans or animals after exposure to diisopropyl methylphosphonate. 

Medinsky MA. 1995. The application of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling to understanding the mechanism of action of hazardous substances. Toxicol Lett 79 185-191. 

In a PBPK/PD model based closely on the Corley model, Reitz et al. (1990) described a pharmacodynamic end point (cytotoxicity) in the livers of chloroform-exposed animals produced by phosgene, the reactive metabolite of chloroform. 

Is a relevant PBPK/PD model or studies on joint toxic action available for mixture of components of concern ... 

Often PK/PD models are developed using classic PK models to describe plasma concentrations, which is often appropriate when P K samples are obtained during the PD assay so that plasma concentrations are most accurately simulated. A PBPK/PD model may be particularly useful when P K data are not available for a given PD assay, when a PD effect is not related to free plasma concentrations but instead is related to the free concentration in a target tissue, orwhena PK/PD model must be extrapolated to humans. 

No PBPK/PD models were identified for HDI in the open literature. 

Absorption, Distribution, Metabolism, and Excretion. There is an obvious data need to determine the pharmacokinetic and toxicokinetic behavior of HDl in both humans and laboratory animals. Determination of blood levels of inhaled, ingested and dermally absorbed HDl would be difficult, given the very short half-life in biological matrices (Berode et al. 1991) and the rate at which HDl binds to proteins in the blood. Although some information is known about the metabolism of HDl in humans inhaling a known quantity of HDl (Brorson et al. 1990), the rate at which absorption occurs, where the majority of the metabolism of HDl occurs (in the water in the mucous layer of the bronchi as opposed to the blood or the kidney), and the distribution patterns and toxic effects of the metabolite (if any) are not well described. Information in these areas of toxicokinetics and toxicodynamics could also be useful in developing a PBPK/PD model for HDl. Research should focus on the respiratory and dermal routes of exposure. 

Polybrominated Diphenyl Ethers. No PBPK/PD models were located for PBDEs. 

Stern, A.H., M. Gochfeld, C. Weisel, and J. Burger. 2001. Mercury and methylmercury exposure in the New Jersey pregnant population. Arch Environ Health. 56(1) 4-10. Timchalk, C., R.J. Nolan, A.L. Mendrala, D.A. Dittenber, K.A. Brzak, and J.L. Mattsson. 2002. A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for the organophosphate insecticide chlorpyrifos in rats and humans. Toxicol. Sci 66(1) 34-53. 

Lohitnavy M, Lu Y, Lohitnavy O, Chubb LS, Hirono S, Yang RSH. 2008. A possible role of multidrug resistance-associated protein 2 (Mrp2) in hepatic excretion of PCB126, an environmental contaminant PBPK/PD modeling. Toxicol Sci 104 27-39. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to delineate and characterize the relationships between the extemal/exposure concentration and target tissue dose of... 

FIGURE 51.1. PBPK-PD model schematic of sarin in Hartley guinea pig. This model structure allows for the simulation of experimental studies with dosing hy intravenous or subcutaneous dosing, and inhalation exposure. This model design was after Gearhart et al. (1990) and was adapted to simulate the pharmacokinetics and pharmacodynamics of sarin in the guinea pig. 

The overall performance of the PBPK-PD model in predicting both the concentration of regenerated GB and the inhibition of RBC AChE was very successfiil for both the subcutaneous and inhalation routes of exposure, at these doses. Previously published studies showing the significant... 

A previously developed PBPK-PD model for the CWNA surrogate DFP was parameterized to simulate the concentration and effects of low-level chemical warfare agents (CWAs) in the guinea pig after exposure by inhalation and subcutaneous injection. The model code was written to account for absorption of CWAs from multiple sites (respiratory tract - lower and upper, dermal, ocular) after... 

Physiologically based phannacokinetic/pharmacodynamic (PBPK/PD) modeling has proven useful in many areas of toxicology and therapeutics. This quantitative, mechanism-based approach has allowed limited experimental in vivo and in vitro data to be quantitatively integrated with physiological data so as to facilitate predictions of the behavior of organisms under different exposure conditions. Specifically, it has been used for ... 

The content of this chapter is not inclusive, in the sense of taking one through the complete development and validation of a complex PBPK/PD model, which would describe the kinetics of each component, together with the pharmacodynamic interactions between selected NAs and countermeasures. Rather, this chapter briefly describes some examples of progress made in quantitative modeling and explores how specific countermeasures interfere in this NA-induced cascade of events, and how such quantitative approaches could be used to develop improved treatment regimens. 

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