Intravenous and Intramuscular Allopregnanolone for Early Treatment of Status Epilepticus: Pharmacokinetics, Pharmacodynamics, and Safety in Dogs

Abstract

Allopregnanolone (ALLO) is a neurosteroid that modulates synaptic and extrasynaptic GABA A receptors. We hypothesize that ALLO may be useful as first-line treatment for status epilepticus (SE). Our objectives were to 1) characterize ALLO pharmacokineticspharmacodynamics following intravenous (IV) and intramuscular (IM) administration and 2) compare IV and IM ALLO safety and tolerability. Three healthy dogs and two with a history of epilepsy were used. Single ALLO IV doses ranging from 1-6 mg/kg were infused over 5 min or injected IM. Blood samples, vital signs, and sedation assessment were collected up to 8 hours post-dose. Intracranial EEG (iEEG) was continuously recorded in one dog. IV ALLO exhibited dose-proportional increases in exposure, which were associated with an increase in absolute power spectral density in all iEEG frequency bands. This relationship was best described by an indirect link PK-PD model where concentration-response was described by a sigmoidal Emax equation. Adverse events included site injection pain with higher IM volumes and ataxia and sedation associated with higher doses. IM administration exhibited incomplete absorption and volume-dependent bioavailability. Robust iEEG changes following IM administration were not observed. Based on PK/PD simulations, a 2 mg/kg dose infused over 5 minutes is predicted to achieve plasma concentrations above the EC 50 , but below those associated with heavy sedation. This study demonstrates that ALLO is safe and well tolerated when administered at 1-4 mg/kg IV and up to 2 mg/kg IM. The rapid onset of effect following IV infusion suggests that ALLO may be useful in the early treatment of SE.

Tolerability and pharmacokinetics of intravenous allopregnanolone with and without midazolam pretreatment in two healthy dogs

“…We obtained estimated Cmax values in the range of 1500-3000 ng/mL, validating our modeling. The Cmax value predicted by simulation in the earlier study 22 for a 1 mg/kg dose (~1000 ng/ml) is below the range obtained in the present study, likely because the dose was infused over 5 min rather than as a rapid bolus injection as was done here.…”

“…Therefore, we evaluated the cardiopulmonary safety of intravenous ALLO delivered alone or shortly after intravenous MDZ in two dogs. The dose of ALLO (1 mg/kg) was selected based on a two‐compartment model using results from a prior study in dogs 22 . We intended to target a C max value of approximately 2000 ng/ml because peak plasma concentrations of ALLO of approximately 600–2000 ng/ml can effectively terminate benzodiazepine‐refractory SE in rodent models 17,23 .…”

Dogs as a Natural Animal Model of Epilepsy

“…Recently, Vuu et al ( 387 ) reported the pharmacokinetics, pharmacodynamics, and safety of a new cyclodextrin-based i.v. formulation of allopregnanolone in healthy and epileptic dogs to develop this formulation for early treatment of SE.…”

“…In the dog study, the rapid onset of effect of allopregnanolone after i.v. infusion suggested that this drug may be useful in the early treatment of SE ( 387 ). Overall, these various studies establish the dog as a viable clinical model of human SE.…”

“…Numerous other groups have used healthy or epileptic dogs for pharmacokinetic studies, including recent studies on i.v. fosphenytoin ( 382 , 395 ), topiramate ( 383 ), and allopregnanolone ( 387 ). Such studies are important to further characterize species differences in drug pharmacokinetics and provide a basis for rational therapy of canine epilepsy or SE.…”