Allopregnanolone (ALLO) is a neurosteroid that modulates synaptic and extrasynaptic GABAA 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 (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 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.
|Original language||English (US)|
|Number of pages||10|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Feb 1 2022|
Bibliographical noteFunding Information:
The authors would like to acknowledge the American Epilepsy Society Predoctoral Fellowship, American Foundation of Pharmaceutical Education Pre-Doctoral Fellowship, American Kennel Club Foundation, National Institutes of Health/National Institute of Neurologic Disorders and Stroke (NIH/NINDS), and MacMillan Epilepsy Innovation Fund who funded this research. The authors also acknowledge and thank Andrea Eckert for her care of the animals and sample collection.
This work was supported by the American Epilepsy Society Predoctoral Fellowship, American Foundation of Pharmaceutical Education Pre-Doctoral Fellowship, American Kennel Club Foundation [Grant 02133], National Institutes of Health/National Institute of Neurological Disorders and Stroke [Grant R21-NS072166], and MacMillan Epilepsy Innovation Fund.
Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.