Nerve agents pharmacodynamic

Physiologically Based Pharmacokinetic/ Pharmacodynamic Modeling of Countermeasures to Nerve Agents... 

K.C., Population pharmacokinetics and pharmacodynamics of pyridostigmine hro-mide for prophylaxis against nerve agents in humans, J. Clin. Pharmacol., 38, 227, 1998. 

Marino, M. T., Schuster, B, G, Brueckoer, R. R, Lin, E., Kaminskis, A and Lasseter, K, C. (1998). Ftopulation pharmacokinetics and pharmacodynamics of pyridostigmine bromide for prophylaxis against nerve agents in humans. J. Clin. Pharmacol. 38,227-235. 

PHYSIOLOGICALLY BASED PHARMACOKINETIC/PHARMACODYNAMIC MODELING OF COUNTERMEASURES TO NERVE AGENTS... 

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). 

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

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. 

R. E. Sweeney and D. M. Maxwell, A physiologically based pharmacoki-netic/pharmacodynamic model with stoichiometric scavenger for predictions of nerve agent concentration and cholinesterase inhibition in tissues and blood of guinea pig, 2008 Bioscience Review, Hunt Valley, MD, 2008. 

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