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 pharmacokinetics-pharmacodynamics 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 EC₅₀, 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.

Significance Statement The characterization of the pharmacokinetics and pharmacodynamics of allopregnanolone is essential in order to design clinical studies evaluating its effectiveness as an early treatment for status epilepticus in dogs and people. We have proposed a target dose/therapeutic range for a clinical trial in canine status epilepticus.