Pharmacokinetic/pharmacodynamic PBPK/PD modelling

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. 

Physiologically based pharmacokinetic/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 to facilitate predictions of the behavior of organisms under different exposure conditions. Specifically, it has been used for ... 

Modeling Organophosphortis Chemical Watfare Nerve Agents A Physiologically Based Pharmacokinetic-Pharmacodynamic (PBPK-PD) Model ofVX... 

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. 

Timchalk, C., Kousba, A., Poet, T. (2002a). Monte Carlo analysis of the human chlorpyrifos-oxonase (PONl) polymorphism using a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model. Toxicol. Lett. 135 51. 

Timchalk C, Nolan RJ, Mendrala AL, Dittenber DA, Brzak KA, Mattsson JL (2002) A physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) model for the organophos-phate insecticide chlorpyrifos in rats and humans. Toxicol Sci 66 34—53... 

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. 

Many types of modeling techniques are available in the discovery phase of drug development, from structure activity relationships (SAR) to physiology based pharmacokinetics (PBPK) and pharmacokinetics-/pharmacodynamics (PK/PD) to help choosing some of the lead compounds. Some tests that are carried out by discovery include techniques related to structure determination, metabolism, and permeability NMR, MS/MS, elemental analysis, PAMPA, CACO-2, and in vitro metabolic stability. Although they are important as a part of physicochemical molecular characterization under the biopharmaceutics umbrella, they will not be discussed here. The reader can find relevant information in numerous monographs [9,10]. 

Model refinement and validation for both the chltnpyrifos and the diazinon PBPK/PD models wa.s accomplished by conducting a scries of in vivo pharmacokinetic and pharmacodynamic studies in the rat and by evaluating the capability of the model to accurately simulate in vivo data published in the literature. The experimental details are fully described in Timchalk et ai (2002b) and Poet et at. (2004). In brief, these studies involved an acute oral exposure to chlorpyrifos or diazinon and the blood time course of the parent compounds and metabolites was determined, as well as the time course for the cholinesterase inhibition in several tissues. Representative results and model simulations are presented in Fig. 12 and 13 for the pharmacokinetic and pharmacodynamic response in rats following comparable oral doses (50 and 100 mg/kg) of chlorpyrifos and diazinon, respectively, The overall response was fairly comparable for these two insecticides, and the models reasonably simulated both dosimetry and the dose-dependent cholinesterase inhibition. These results arc very consistent with a fairly rapid oral absorption for both insecticides and subsequent metabolism and distribution of the active oxon metabolites. Figure 14 illustrates the capability of the diazinon PBPK/PD model to simulate rodent dosimetry data from the open literature and the capability of the model to accommodate alternative exposure routes (Poet et ai, 2004). In these examples, the time course of diazinon in plasma and cholinesterase inhibition in tissues (i.e.. blood,... 

As stated, a number of PBPK/PD models have been developed for individual nerve agents (sarin, VX, soman, and cyclosarin) in multiple species. Chapter 58 in the current volume discusses tiie development of such models. Standalone PBPK or compartmental models have also been developed that describe the pharmacokinetics of certain countermeasures, such as diazepam (Igari et al., 1983 Gueorguieva et al., 2004) and oximes (Stemler et al., 1990 Sterner et al., 2013). However, to date, few models for specific countermeasures have been harmonized and linked to NA PBPK/PD models to be able to quantitatively describe their pharmacokinetic and pharmacodynamic interactions. This is partly due to the fact that most PBPK/ PD models developed for NAs and other OPs focus on the inhibition of ChEs as the critical endpoint. The lack of a mathematical description of the disruption of other complex biochemical pathways presents a problem for linking these NA models to those of many countermeasures. For example, the conventional NA countermeasures, atropine and diazepam, as well as many novel countermeasures, do not directly impact ChE kinetics because they act at sites distinct from the active site of the esterases, such as muscarinic, GABA, or NMDARs (Figure 69.2). 

Relatively few PBPK models have been developed to describe the pharmacokinetics and pharmacodynamics of chemical warfare nerve agents. Maxwell et aV developed a PBPK-PD model for GD in the rat, describing the inhibition of AChE and carboxylesterase (CaE) in blood and tissues with mass balance equations based on parameters for blood flow, tissue volumes, GD metabolism and tissue/plasma partition coefficients. The resulting model gives accurate predictions of AChE activity in the blood and seven different tissues following intramuscular dosing with 90 pg GD kg bodyweight (BW), and was able to reproduce dose-response AChE inhibition from 10 to 100% in the brain. 

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

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