Pharmacokinetics and Pharmacodynamics of Standard Nerve Agent Medical Countermeasures in G öttingen Minipigs

Toxicol Lett. 2024 May 2:S0378-4274(24)00084-5. doi: 10.1016/j.toxlet.2024.04.014. Online ahead of print.ABSTRACTAnimal research continues to serve a critical role in the testing and development of medical countermeasures. The Göttingen minipig, developed for laboratory research, may provide many benefits for addressing research questions within chemical defense. Targeted development of the Göttingen minipig model could reduce reliance upon non-human primates, and improve study design, statistical power, and throughput to advance medical countermeasures for regulatory approval and fielding. In this vein, we completed foundational pharmacokinetics and physiological safety studies of intramuscularly administered atropine sulfate, pralidoxime chloride (2-PAM), and diazepam across a broad range of doses (1 to 6 autoinjector equivalent) using adult male Göttingen minipigs (n=11; n=4-8/study) surgically implanted with vascular access ports and telemetric devices to monitor cardiovascular, respiratory, arterial pressure, and temperature signals. Pharmacokinetic data were orderly and the concentration maximum mirrored available human data at comparably scaled doses clearly for atropine, moderately for 2-PAM, and poorly for diazepam. Time to peak concentration approximated 2, 7, and 20minutes for atropine, 2-PAM, and diazepam, respectively, and the elimination half-life of these drugs approximated 2hr (atropine), 3hr (2-PAM), and 8hr (diazepam). Atropine sulfate dose-dependently in...
Source: Toxicology Letters - Category: Toxicology Authors: Source Type: research