Abstracts

Rationale: Barriers to developing new treatments for human status epilepticus (SE) include the inadequacy of experimental animal models. In contrast, naturally occurring canine epilepsy is similar to the human condition and can serve as a platform to translate drugs from rodents to humans. Our group has previously shown that both fosphenytoin and levetiracetam exhibit comparable efficacy in both dogs and humans for treatment of SE. We characterized the pharmacokinetics (PK) of a single intravenous (IV) dose of an investigational topiramate (TPM) formulation in dogs with epilepsy, and evaluated the pharmacodynamic effect of TPM on intracranial electroencephalographic (iEEG) features. A model based on PK results was used to determine a dosage regimen designed to attain a target concentration of 20-30 g/mL, which has been associated with efficacy in human super-refractory SE. Results: No adverse effects were observed. Topiramate concentration-time profiles were best fit by a two-compartment model. PB was associated with a 5.64-fold greater clearance and a ~4-fold shorter elimination half-life. One of five dogs provided interpretable iEEG data showing that TPM produced a significant increase in energy activity in frequencies >4 Hz across all 16 electrodes within 15 minutes of dosing. Intravenous DZP also increased energy in frequencies >4 Hz (most prominently in beta frequency), and significantly decreased delta frequency energy in most channels. Simulations suggested that dogs on an enzyme inducer would require 25 mg/kg, while dogs on non-inducing drugs would need 20 mg/kg to attain the target concentration at 30-minutes post-dose. Conclusions: This study shows that IV TPM has a relatively rapid onset of action, loading doses appear safe, and the presence of enzyme-inducing drugs necessitates a higher dose to attain targeted concentrations. These characteristics of IV TPM suggest that it would be a good candidate for further evaluation for treatment of seizure emergencies. Understanding TPM PK and iEEG effects in dogs will inform the design of future canine and human clinical trials. Funding: American Kennel Club Foundation Grant and NIH/NINDS R21-NS072166.