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

Allopregnanolone (ALLO) is a neurosteroid that modulates synaptic and extrasynaptic GABA_A receptors. We hypothesize that ALLO may be useful as first-line treatment of status epilepticus (SE). Our objectives were to (1) characterize ALLO pharmacokinetics-pharmacodynamics PK-PD after 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 minutes or injected IM. Blood samples, vital signs, and sedation assessment were collected up to 8 hours postdose. 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 maximum response (E_max) 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 after 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 after IV infusion suggests that ALLO may be useful in the early treatment of SE.