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

Abstract

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 (Cmax) of diazepam after avizafone injection was higher than that obtained after injection of diazepam itself (231 vs. 148 ng·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 Cmax and AUC, but the time to Cmax 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 twocompartment 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 Cmax 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 Cmax.

Midazolam as an anticonvulsant antidote for organophosphate intoxication—A pharmacotherapeutic appraisal

“…The diazepam autoinjector for administration by caregivers in an outpatient setting for acute seizures is reported to cause injection site pain and hemorrhage . Avizafone, a water soluble prodrug of diazepam developed elsewhere, has better formulation features for an autoinjection delivery . It must be injected, however, at a higher molar dose than diazepam for seizure protection.…”

“…51 Avizafone, a water soluble prodrug of diazepam developed elsewhere, has better formulation features for an autoinjection delivery. [52][53][54] It must be injected, however, at a higher molar dose than diazepam for seizure protection. These limitations have prompted the search for alternative anticonvulsants to diazepam.…”

Chirally Pure Prodrugs and Their Converting Enzymes Lead to High Supersaturation and Rapid Transcellular Permeation of Benzodiazepines

“…The existence of such an enzyme is virtually certain, because AVF is known to be converted to DZP in humans. 24 Since acceptance of this manuscript, we have identified human aminopeptidase B, EC 3.4.11.6, as an enzyme that converts AVF to DZP.…”

Development of a simple and sensitive HPLC-MS/MS method for determination of diazepam in human plasma and its application to a bioequivalence study

“…[2] Previous studies have proposed several analytical methods using high-performance liquid chromatography (HPLC) with an ultraviolet (UV) [3,4] or mass spectrometry (MS) [5][6][7][8][9] detection to determine the concentrations of diazepam administered by various routes including nasal spray, rectal gel, intramuscular injection, and oral formulations. [10][11][12][13][14][15] However, these previously developed analytical methods have been associated with several limitations including inadequate sample preparation due to difficulty in removing impurities, [5] inadequate sensitivity (a lower limit of quantitation [LLOQ] up to 50 ng/mL), [6] labor-intensive sample preparation process, [7] the need for a relatively large volume of plasma (≥ 100 μL) for analysis, [8] and long retention times (≥ 8 min). [9] Therefore, a new bioanalytical method to quantitate diazepam has been needed to improve those limitations.…”