Pharmacokinetic analysis of pralidoxime after its intramuscular injection alone or in combination with atropine‐avizafone in healthy volunteers

Abstract

BACKGROUND AND PURPOSETreatment of organophosphate poisoning with pralidoxime needs to be improved. Here we have studied the pharmacokinetics of pralidoxime after its intramuscular injection alone or in combination with avizafone and atropine using an auto-injector device. EXPERIMENTAL APPROACHThe study was conducted in an open, randomized, single-dose, two-way, cross-over design. At each period, each subject received either intramuscular injections of pralidoxime (700 mg), or two injections of the combination: pralidoxime (350 mg), atropine (2 mg), avizafone (20 mg). Pralidoxime concentrations were quantified using a validated LC/MS-MS method. Two approaches were used to analyse these data: (i) a non-compartmental approach; and (ii) a compartmental modelling approach. KEY RESULTSThe injection of pralidoxime combination with atropine and avizafone provided a higher pralidoxime maximal concentration than that obtained after the injection of pralidoxime alone (out of bioequivalence range), while pralidoxime AUC values were equivalent. Pralidoxime concentrations reached their maximal value earlier after the injection of the combination. According to Akaike and to goodness of fit criteria, the best model describing the pharmacokinetics of pralidoxime was a two-compartment with a zero-order absorption model. When avizafone and atropine were injected with pralidoxime, the best model describing pralidoxime pharmacokinetics becomes a two-compartment with a first-order absorption model. CONCLUSIONS AND IMPLICATIONSThe two approaches, non-compartmental and compartmental, showed that the administration of avizafone and atropine with pralidoxime results in a faster absorption into the general circulation and higher maximal concentrations, compared with the administration of pralidoxime alone.

Pharmacokinetics of Lidocaine Hydrochloride Administered with or without Adrenaline for the Paravertebral Brachial Plexus Block in Dogs

“…Although these investigators found that the goodness-of-fit of this alternative model was lower than their original model, other authors have found it useful to fit the i.m. absorption kinetics of several other aqueous drug products such as trovafloxacin [30], pralidoxime [31], or recombinant human luteinizing hormone [32]. Another possible modification is to use two asynchronous inverse-gaussian absorption processes, a strategy that successfully quantified the effect of adrenaline on the uptake of ropivacaine in a thoracic paravertebral or a femoral nerve block [25,26].…”

Pharmacokinetics of Dexamethasone and Nefopam Administered Alone or in Combination Using a Newly Developed Prefilled Multi-Drug Injector in Rats

“…Clearance (CL) was estimated by dividing the administered dosage by AUC 0- ∞ . AUC and C max of DXM and nefopam administered alone or in combination were log-transformed and compared using a confidence interval (CI) approach [13]. The nonparametric test (Wilcoxon test) was used for statistical evaluation of t max of the two treatments.…”

“…An important consideration when combination therapies are used is the potential for drug-drug interactions [12,13]. Preclinical pharmacokinetic studies are needed in order to maximize both efficacy and safety in clinical trials of combination therapies for TBI [14].…”

Quantification of pralidoxime (2‐PAM) in urine by ion pair chromatography‐diode array detection: application to in vivo samples from minipig

“…[23,24] But most frequently ion pair chromatography (IPC) coupled to electrochemical detection (ECD), [25,26] radio detection (RD), [27] and UV detection [14,28,29] has been applied. [30] Although more modern RPC-tandem mass spectrometric (RPC-MS/MS) methods provide better sensitivity and selectivity, [23,24] UV-detection appears to be sufficient for the quantification of high micromolar 2-PAM concentrations present in plasma and urine samples. [30] Although more modern RPC-tandem mass spectrometric (RPC-MS/MS) methods provide better sensitivity and selectivity, [23,24] UV-detection appears to be sufficient for the quantification of high micromolar 2-PAM concentrations present in plasma and urine samples.…”

“…For a detailed overview, see the review on 2-PAM quantification in this issue. [12][13][14]20,[23][24][25][26][27] In general, reports of quantitative urine analysis are quite rare, covering only 2-PAM concentrations in rats by IMAC-UV [19] and IPC-RD [27] and in humans by CZE-UV. [12][13][14]20,[23][24][25][26][27] In general, reports of quantitative urine analysis are quite rare, covering only 2-PAM concentrations in rats by IMAC-UV [19] and IPC-RD [27] and in humans by CZE-UV.…”