Bioavailability of diazepam after intramuscular injection of its water-soluble prodrug alone or with atropine-pralidoxime in healthy volunteers

Background and purpose: The aim of this study was to assess the relative bioavailability of diazepam after administration of diazepam itself or as a water-soluble prodrug, avizafone, in humans. Experimental approach: The study was conducted in an open, randomized, single-dose, three-way, cross-over design. Each subject received intramuscular injections of avizafone (20 mg), diazepam (11.3 mg) or avizafone (20 mg) combined with atropine (2 mg) and pralidoxime (350 mg) using a bi-compartmental auto-injector (AIBC). Plasma concentrations of diazepam were quantified using a validated LC/MS-MS assay, and were analysed by both a non-compartmental approach and by compartmental modelling. Key results: The maximum concentration (C-max) of diazepam after avizafone injection was higher than that obtained after injection of diazepam itself (231 vs. 148 ng center dot mL(-1)), while area under the curve (AUC) values were equal. Diazepam concentrations reached their maximal value faster after injection of avizafone. Injection of avizafone with atropine-pralidoxime (AIBC) had no effect on diazepam C-max and AUC, but the time to C-max was increased, relative to avizafone injected alone. According to the Akaike criterion, the pharmacokinetics of diazepam after injection as a prodrug was best described as a two-compartment with zero-order absorption model. When atropine and pralidoxime were injected with avizafone, the best pharmacokinetic model was a two-compartment with a first-order absorption model. Conclusion and implications: Diazepam had a faster entry to the general circulation and achieved higher C-max after injection of prodrug than after the parent drug. Administration of avizafone in combination with atropine and pralidoxime by AIBC had no significant effect on diazepam AUC and C-max.