Population Pharmacokinetics and Pharmacodynamics of Pyridostigmine Bromide for Prophylaxis against Nerve Agents in Humans

Abstract

This study was conducted to determine the pharmacokinetics and pharmacodynamics of pyridostigmine given as 30 mg of pyridostigmine bromide every 8 hours in healthy subjects. Plasma pyridostigmine concentration and red blood cell acetylcholinesterase activity were measured in blood samples collected during a 3-week period. Population analysis was performed using standard pharmacokinetic and pharmacodynamic models with the nonlinear mixed-effect modeling software (NONMEM). The pharmacokinetic model that best fit the pyridostigmine plasma levels was a two-compartment open model with first-order absorption, a lag time, and first-order elimination from the central compartment. The pharmacodynamic model that best fit red blood cell acetylcholinesterase activity was an inhibitory Emax model with an effect compartment linked to the central compartment. The results showed that the pharmacokinetics of pyridostigmine bromide are both gender and weight dependent. The pharmacodynamic effect does not lag significantly from the plasma concentration and returns to near normal within 8 hours. With the present dosage regimen of 30 mg every 8 hours, 30% of individuals may not have red blood cell acetylcholinesterase inhibition > 10% at the time of the trough.

Effect of acetylcholinesterase inhibition with pyridostigmine on cardiac parasympathetic function in sedentary adults and trained athletes

“…A sex-based difference in pretreatment parasympathetic tone could make female athletes more susceptible to a ceiling effect that attenuates the pharmacological response to pyridostigmine. Alternatively, small sex-based differences in pyridostigmine pharmacokinetics could have contributed to our findings (39). The reduced response to pyridostigmine in female athletes cannot account for the overall differences between the two study cohorts, since our sedentary group tended to have more women than the trained athlete group.…”

“…Physical training is unlikely to alter renal excretion of pyridostigmine (48), but other effects of training, including reduced fat mass, increased basal metabolic rate, and longer duration of exercise testing in the study protocol, may have altered other aspects of pyridostigmine metabolism and thereby contributed to our findings. Moreover, individual differences in pyridostigmine pharmacokinetics related to age, sex, body habitus, or genetic factors are potential confounders that should be assessed in future studies (5,27,37,39). Resting autonomic tone was not formally evaluated by pharmacological blockade with atropine in either cohort.…”

“…Pyridostigmine is an Food and Drug Administration-approved acetylcholinesterase inhibitor used for the treatment of myasthenia gravis. In healthy subjects, peak plasma levels and peak cholinesterase inhibition (15-20%) occur 90 -150 min after oral dosing with minimal variation in drug levels and degree of cholinesterase inhibition during this time period (3,39,44). The study protocol is shown schematically in Fig.…”

Prophylaxis Against Nerve Agent Intoxications

“…Recommended dose of pyridostigmine (pyridostigmine bromide 29,30 ) as prophylactic antidote is 30 mg every 8 h. At this recommended dose, pyridostigmine did not show the side effects in the animal efficacy studies conducted in several species in a number of countries. Also, the evidence of pyridostigmine pretreatment strongly enhancing post-exposure antidote therapy for soman poisoning 31,32 was found.…”

Protective Effect of Reversible Cholinesterase Inhibitors (Tacrine, Pyridostigmine) and EqBuChE against VX Poisoning and Brain Acetylcholinesterase Inhibition in Rats

“…Only data with atropine provided as a supplement to other (reactivation) experiments have been published (22)(23)(24). Moreover, these doses represent doses close to the doses planned for human use (14,28).…”