Comparative Toxicokinetics of MMB4 DMS in Rats, Rabbits, Dogs, and Monkeys Following Single and Repeated Intramuscular Administration

Abstract

1,1'-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] (MMB4) dimethanesulfonate (DMS) is a bisquaternary pyridinium aldoxime that reactivates acetylcholinesterase inhibited by organophosphorus nerve agent. Time courses of MMB4 concentrations in plasma were characterized following 7-day repeated intramuscular (IM) administrations of MMB4 DMS to male and female Sprague-Dawley rats, New Zealand White rabbits, beagle dogs (single dose only), and rhesus monkeys at drug dose levels used in earlier toxicology studies. In general, there were no significant differences in MMB4 toxicokinetic (TK) parameters between males and females for all the species tested in these studies. After a single IM administration to rats, rabbits, dogs, and monkeys, MMB4 DMS was rapidly absorbed, resulting in average T max values ranging from 5 to 30 minutes. Although C max values did not increase dose proportionally, the overall exposure to MMB4 in these preclinical species, as indicated by area under the curve (AUC) extrapolated to the infinity (AUC∞) values, increased in an approximately dose-proportional manner. The MMB4 DMS was extensively absorbed into the systemic circulation after IM administration as demonstrated by greater than 80% absolute bioavailability values for rats, rabbits, and dogs. Repeated administrations of MMB4 DMS for 7 days did not overtly alter TK parameters for MMB4 in rats, rabbits, and monkeys (150 and 300 mg/kg/d dose groups only). However, C max and AUC values decreased in monkeys given 450 and 600 mg/kg IM doses of MMB4 DMS following repeated administrations for 7 days. Based on the TK results obtained from the current study and published investigations, it was found that the apparent volume of distribution and clearance values were similar among various preclinical species, except for the rat.

Behavioral, Pharmacokinetic, and Cardiovascular Evaluation of Candidate Oximes in African Green Monkeys

“…18 The highest dose (116 mmol/kg or 55.5 mg/kg) of MMB-4 DMS tested in this study had an elimination half-life of 60.85 minutes, similar to values reported in rhesus monkeys. 19 Interestingly, apparent volumes of distribution (L/kg) and apparent clearances (ml/h/kg) appear to be conserved across species, with the exception of rats, as noted by Hong et al 19 The current study evaluated the cardiovascular effects of MMB-4 and 2 other fielded oximes, HI-6 and 2-PAM. There were minimal to no significant effects of lower doses of the oximes, so only the highest doses (116 mmol/kg for HI-6 and MMB-4 salts and 447 mmol/kg for 2-PAM Cl) are presented in the results.…”

“…18 The highest dose (116 µmol/kg or 55.5 mg/kg) of MMB-4 DMS tested in this study had an elimination half-life of 60.85 minutes, similar to values reported in rhesus monkeys. 19 Interestingly, apparent volumes of distribution (L/kg) and apparent clearances (ml/h/kg) appear to be conserved across species, with the exception of rats, as noted by Hong et al 19…”

“…Test compounds (!95% purity) were synthesized at the Walter Reed Army Institute of Research and included MMB-4 2Cl (MW ¼ 329. 19 22), and HI-6 DMS (MW ¼ 448.47). The doses of oximes in this study were chosen based on the currently fielded treatments.…”

“…Pharmacokinetic Parameter Estimates Determined for Both MMB-4 Dichloride (2Cl) and Dimethanesulphonate (DMS) salts(19, 58, and 116 mmol/kg) Following Intramuscular Administration To African Green Monkeys (n ¼ 8-9). a…”

MMB4 DMS Nanoparticle Suspension Formulation With Enhanced Stability for the Treatment of Nerve Agent Intoxication

“…The EFs maintain the favorable PK properties of comparable aqueous solutions, such as rapid absorption and high bioavailability. 11…”