Abstracts

Rationale: Allopregnanolone (ALLO) is a neurosteroid that positively modulates synaptic and extrasynaptic GABA_A receptors. Given its physico-chemical and pharmacological properties, we hypothesize that ALLO may be useful as a first-line treatment for both human and canine status epilepticus (SE).  Our objectives were: 1) compare the pharmacokinetics (PK) of intramuscular (IM) and intravenous (IV) ALLO including estimation of IM bioavailability, 2) assess the IM and IV adverse effects, and 3) simulate dosing regimens that would provide at least 50% seizure protection for a minimum of 15 minutes following the start of an IV infusion or immediately after an IM injection. Methods: Our subjects included healthy dogs (n=3) and those with spontaneous epilepsy (n=2, 1 on phenobarbital [PB]). One 2 mg/kg dose was administered IM, and single ALLO doses ranging from 1-4 mg/kg were infused IV over 5 minutes. For each dog, there was at least a 1 week washout period between study days. To better understand the effect of PB on ALLO PK, repeated studies were done in 2 healthy dogs after receiving PB (2 mg/kg orally twice daily) for at least 15 days. Serial blood samples were collected up to 6 hrs post-dose. Plasma ALLO concentrations were measured by a UPLC-MS/MS system. Non-compartmental and compartmental PK analyses were performed. Results: Concentration-time profiles were best fit by a two-compartment model (IV t_1/2: alpha:1.6-3.1 min, beta:13-38 min; IM t_1/2 alpha: 1.9 min, beta: 158 min). There were no adverse events, including injection site reactions, following the 2 mg/kg IM dose. IM bioavailability was estimated to be 55%. There was a IV dose-dependent increase in ataxia and sedation. At 4 mg/kg IV, dogs were immobile and briefly unarousable for 1-3 minutes, but with stable vital signs. Peak effects occurred 3 minutes into the infusion, with a return to baseline within 20 minutes. The dog on chronic PB had greater sedation at 2 mg/kg IV, which correlated with lower clearance and volume of distribution. Simulations show that an 8 mg/kg IM dose can attain and sustain concentrations associated with 50+% seizure protection in mice for 40 minutes, while a 2.5 mg/kg IV dose can attain those concentrations for approximately 15 minutes. Conclusions: In conclusion, IM ALLO PK differs from its PK following IV administration with the former exhibiting a longer beta t_1/2, and intermediate bioavailability. IV ALLO exhibited a rapid central nervous system effect. IM and IV doses up to 2 mg/kg were well-tolerated in dogs on or off chronic PB. Dogs on chronic PB may require a different ALLO dosing regimen due to a drug interaction. Our results support further evaluation of ALLO for SE in dogs and humans. Funding: American Epilepsy Society Pre-Doctoral Fellowship, American Foundation of Pharmaceutical Education Pre-Doctoral Fellowship