Development of a Physiologically Based Pharmacokinetic/Pharmacodynamic (PBPK/PD) Minipig Model for Simulation of Low Level Multiple Route CW Agent Exposure

摘要

A physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model was developed to simulate the concentration and effects of low-level chemical warfare agents (CWA) in the Goettingen minipig. The model code was written to account for absorption of CWAs from multiple sites (respiratory tract -- lower and upper, dermal, ocular) after vapor exposure. Literature references to minipig physiology were used for the majority of organ volumes and blood flows, while some parameter values were scaled from other species. Unique features of this PBPK/PD model structure were physiological compartments for the eyes, as a source of external CWA absorption and internally as a site of ChE binding, and skin as a dermal absorption pathway. One initial pharmacodynamic endpoint developed in this model was CWA inhibition of cholinesterases (AChE, BChE), with a particular focus on the dynamics of miosis. Preliminary assumptions were that pupil constriction (miosis) from external, systemic or combined delivery of CWA, could be predicted based on AChE inhibition at the ocular muscules. The PBPK/PD model was used to simulate AChE inhibition after inhalation of CWA and to predict potential pharmacodynamic effects at different tissue target sites. This preliminary model will provide a quantitative tool to predict the physiological consequences of low level, non-lethal exposure after CWA exposure.