CHAPTER 8: Modeling Organophosphorus Chemical Warfare Nerve Agents: A Physiologically Based Pharmacokinetic–Pharmacodynamic (PBPK-PD) Model of VX

In order to improve the risk estimates for VX exposures, the pharmacodynamics and, consequently, the pharmacokinetics must be better understood. Physiologically based pharmacokinetic–pharmacodynamic (PBPK-PD) models have proven to be useful analytical tools for this task. To date, relatively few PBPK models have been developed to describe the pharmacokinetics and pharmacodynamics of chemical warfare nerve agents. The model described in this chapter is a PBPK-PD model for VX exposure based upon previous PBPK-PD models with the goal of developing a multispecies and multi-route model. The current model simulates exposure in guinea pigs via the intravenous, subcutaneous or dermal route and predicts the pharmacokinetics of VX in the blood and various tissues as well as the pharmacodynamics through the incorporation of B-esterase inhibition. Datasets used for model development and validation include doses via the intravenous, subcutaneous and dermal routes that ranged from 0.1 to 2 lethal doses, 50% (LD₅₀). In general, the simulations are quite good with predictions within 2 standard deviations for most of the data points. Sensitivity analyses were also conducted for all three dose routes. While sensitivity coefficients for the intravenous route are more varied, those for the subcutaneous and dermal routes are primarily less than or equal to 2 in absolute value.