Abstracts

Rationale: Rectal and nasal diazepam and nasal and manually-administered intramuscular (IM) midazolam (MDZ) are FDA-approved as out-of-hospital therapies for seizure emergencies in humans. While seizure clusters and status epilepticus are similar in human and dogs with respect to seizure semiology and pharmacotherapy response, out-of-hospital alternatives for pet owners are limited. We hypothesize that an IM MDZ product could be an easy to administer, safe, effective and affordable treatment for dogs and humans for these seizure emergencies. The aims of this study were to compare the pharmacokinetics (PK) and safety of MDZ following administration via IM and IV administration and to build a PK/pharmacodynamic (PD) model relating plasma MDZ concentrations to electroencephalographic (EEG) activity in dogs.

Methods: Two dogs were used for this study including one with epilepsy who was implanted with intracranial electrodes and treated with anti-seizure medications. Both dogs were given 2 single 0.1 and 0.3 mg/kg MDZ doses by manual IM administration and a 0.3 mg/kg intravenous dose separated by washout periods. Different needle sizes, 5/8 and 1in, and 23 and 27g were evaluated. The dogs also received a 0.3 mg/kg IM dose via an auto-injector (23g, 1in needle). Blood samples were obtained and plasma MDZ concentrations were measured by LC-MS/MS. EEG data were recorded and power in band features for each frequency were calculated. MDZ concentration-time data were analyzed by non-compartmental and compartmental PK methods. A PK-PD model was used to characterize the relationship between the MDZ concentrations and iEEG response parameters. Ataxia, sedation, and sleepiness were scored using a modified Glasgow coma scale; blood pressure, pulse, and respiratory rate measured; and the injection site examined.

Results: The IM MDZ injections were well tolerated with mild ataxia and sedation occurring at the times of high MDZ concentrations. IM administration resulted in rapid absorption (Tmax ~ 7-12 min) and a bioavailability of 0.62-0.91. Both Cmax and AUC increased proportionately with dose suggesting linear PK within the dose range studied. Needle size was not associated with significant differences in PK. The Cmax for the IM 0.1 and 0.3 mg/kg and IV 0.03 mg/kg doses ranged from 76-130, 284-377, and 612-693 ng/ml, respectively. MDZ concentrations were best fit by a first-order absorption, 2-compartment PK model. The relationship between MDZ concentrations and beta-phase iEEG activity was modeled using an indirect-link, Emax model. High drug concentrations following the IV bolus dose resulted in the most rapid onset of iEEG effect (0.167 min). Onset of changes in the iEEG beta phase power density following the auto-injection dose was more rapid (onset 0.67 min) than with manual injection (1.5 min) and corresponded with MDZ concentrations of ~50 ng/mL. The time to maximum effect occurred between 5 and 10 min.

Conclusions: IM midazolam plasma concentrations were dose dependent with maximal concentrations observed within 12 minutes. Onset of changes in iEEG beta phase power density occurred within minutes and was associated with MDZ concentrations of ~50 ng/mL.

Funding: Please list any funding that was received in support of this abstract.: Grant from MesaGreen Pharmaceuticals LLC.