Abstracts

Rationale: The development of new therapies for epilepsy is hindered by the limitations of efficiently and successfully translating results from animals to humans. Our research group is using dogs with naturally occurring epilepsy as a translational platform to evaluate the safety and efficacy of novel compounds and inform the design of canine and human trials. The objective of this study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of intravenous diazepam (DZP) and intravenous topiramate (TPM) in dogs with and without naturally-occurring epilepsy.Methods: Four dogs were used in this study. Each dog received an investigational formulation of TPM (10 mg/mL in Captisol®) as a single 10 mg/kg and 20 mg/kg intravenous dose infused over 5 minutes with a minimum washout period of 14 days. Blood samples were collected at scheduled times and plasma TPM concentrations were measured using a validated HPLC-MS method. Intracranial EEGs (iEEGs) from 16 channels were continuously recorded from which alpha and beta frequency amplitudes were determined and used as PD markers. As a positive control, intravenous DZP (0.5 mg/kg) was also studied. Compartmental PK and PD Emax models were evaluated to relate the drug concentration with changes in iEEG.Results: Both the TPM and DZP plasma concentrations were best fit by a two-compartment PK model. TPM clearance was ~4-fold greater and elimination half-life ~4-fold shorter in the dogs with naturally-occurring epilepsy that are on maintenance phenobarbital therapy compared with dogs not on co-medications. Both DZP and TPM dosing resulted in significantly greater beta phase frequency amplitude compared with the hour prior to dosing while the alpha phase frequency was reduced. For DZP, the PK/PD data were best fit by PK-linked, sigmoidal Emax PD model with rapid (within one minute) onset of action.Conclusions: From this work, we have shown that both BZD and TPM produce significant changes in the EEG and oscillatory activity in the brain. This effect is similar to what has been shown with benzodiazepines in humans with the largest effect at high frequency beta (18 - 30 Hz) range. This suggests that TPM may play a role in acute management of seizures and characterizing the PK and PD in dogs with naturally-occurring epilepsy can be used to further guide AED development.