Project Scientist School of Medicine, University of California, Davis, Sacramento, CA, USA 95817, California
Rationale: When venous access is available, intravenous administration (IV) is the optimal route for delivery of an antiseizure treatment to abort an acute seizure. Allopregnanolone (brexanolone; 3α-hydroxy-5α-pregnan-20-one), an endogenous progesterone-derived neuroactive steroid that is positive allosteric modulator of GABAA receptors, is well recognized to have antiseizure activity in diverse animal seizure models. Low oral bioavailability limits its use as an oral treatment, but allopregnanolone is highly active when administered parenterally, including intramuscularly. The goal of this study was to evaluate the potential antiseizure activity of allopregnanalone when administered IV by bolus injection in mice and rats, and to correlate the activity with plasma levels as determined by LC-MS/MS. Methods: Allopregnanolone for IV administration was formulated in 6% sulfobutylether-β-cyclodextrin sodium salt (Captisol®) in 0.9% saline at a concentration of 1.5 mg/ml. Seizures were induced by IV infusion of PTZ at a rate of 5 mg/min in mice and 8 mg/min in rats. In each animal, the doses of IV PTZ causing myoclonic jerks and clonic and tonic seizures were determined. In a separate series of experiments, PTZ was administered intraperitoneally (IP) to rats at a dose of 80 mg/kg and the time to onset of myoclonic jerks and clonic and tonic seizures was recorded. Results: IV bolus administration of allopregnanolone at a dose of 1.5 mg/kg administered one minute before initiation of the PTZ infusion markedly increased the thresholds for all seizure signs in mice and rats. The effect on threshold diminished when the bolus pretreatment was administered at 30 minutes and was no longer evident at 60 minutes. The plasma concentration of allopregnanolone in mice at one minute after bolus dosing was 1500 ng/ml. IV bolus administration of allopregnanolone two minutes before PTZ IP at a dose of 0.5 mg/kg prolonged the onset of seizure signs in all animals compared to a vehicle-treated group; four of four allopregnanolone-treated animals survived at 30 minutes compared with one of four vehicle-treated animals. A 1 mg/kg IV bolus dose of allopregnanolone delayed the onset of the seizure signs further and four of four animals survived. Conclusions: We conclude that allopregnanolone is a potent, very rapidly acting antiseizure agents when administered IV. However, the antiseizure effects diminish quickly. To the extent that Cmax (rather than extended exposure) is the critical parameter for acute seizure termination, IV bolus administration of allopregnanolone has potential as a rapidly acting medical intervention for the treatment of seizures and status epilepticus. Funding: Please list any funding that was received in support of this abstract.: NINDS grant #1U54NS079202, DZ, MAR
