title: Intravenous Topiramate: Pharmacokinetics in Dogs with Naturally Occurring Epilepsy.
abstract: BACKGROUND
  Barriers to developing treatments for human status epilepticus 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 research from rodents to humans. The objectives of this study were to characterize the pharmacokinetics of an intravenous (IV) dose of topiramate (TPM) in dogs with epilepsy and evaluate its effect on intracranial electroencephalographic (iEEG) features.
  
  
  METHODS
  Five dogs with naturally occurring epilepsy were used for this study. Three were getting at least one antiseizure drug as maintenance therapy including phenobarbital (PB). Four (ID 1-4) were used for the 10 mg/kg IV TPM + PO TPM study, and three (ID 3-5) were used for the 20 mg/kg IV TPM study. IV TPM was infused over 5 min at both doses. The animals were observed for vomiting, diarrhea, ataxia, and lethargy. Blood samples were collected at scheduled pre- and post-dose times. Plasma concentrations were measured using a validated high-performance liquid chromatography-mass spectrometry method. Non-compartmental and population compartmental modeling were performed (Phoenix WinNonLin and NLME) using plasma concentrations from all dogs in the study. iEEG was acquired in one dog. The difference between averaged iEEG energy levels at 15 min pre- and post-dose was assessed using a Kruskal-Wallis test.
  
  
  RESULTS
  No adverse events were noted. TPM concentration-time profiles were best fit by a two compartment model. PB co-administration was associated with a 5.6-fold greater clearance and a ~4-fold shorter elimination half-life. iEEG data showed that TPM produced a significant energy increase at frequencies >4 Hz across all 16 electrodes within 15 min of dosing. 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 (20-30 μg/mL) at 30 min post-dose.
  
  
  CONCLUSIONS
  This study shows that IV TPM has a relatively rapid onset of action, loading doses appear safe, and the presence of PB necessitates a higher dose to attain targeted concentrations. Consequently, it is a good candidate for further evaluation for treatment of seizure emergencies in dogs and people.
authors.affiliation: Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN, USA; Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Vuu
authors.affiliation: Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN, USA; Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Coles
authors.affiliation: Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN, USA; College of Science and Engineering, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Maglalang
authors.affiliation: Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA; UMP MINCEP Epilepsy Care, Minneapolis, MN, USA.
authors.forename: Ilo E
authors.initials: IE
authors.lastname: Leppik
authors.affiliation: Mayo Clinic , Rochester, MN , USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Worrell
authors.affiliation: Mayo Clinic , Rochester, MN , USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Crepeau
authors.affiliation: Center for Orphan Drug Research, University of Minnesota , Minneapolis, MN , USA.
authors.forename: Usha
authors.initials: U
authors.lastname: Mishra
authors.affiliation: Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN, USA; Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Cloyd
authors.affiliation: College of Veterinary Medicine, University of Minnesota , Saint Paul, MN , USA.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Patterson
keywords: ASD; dog; epilepsy; seizures; topiramate; translational