Canine status epilepticus treated with fosphenytoin: A proof of principle study

Abstract

Objectives There are a limited number of marketed intravenous antiepileptic drugs (AEDs) available for status epilepticus (SE). All were first developed for chronic therapy of epilepsy, not specifically for SE. Epilepsy and canine SE (CSE) occur naturally in dogs with prevalence, presentation, and percentage of refractory cases similar to human epilepsy. The objective of this study was to determine if CSE treated with fosphenytoin (FOS) results in a similar responder rate as for people. Methods A randomized clinical trial was performed for dogs with CSE. Dogs who presented during a seizure or had additional seizures after enrolling received an IV benzodiazepine (BZD) followed immediately by IV infusion of 15mg/kg phenytoin equivalent (PE) of fosphenytoin (FOS) or saline placebo (PBO). If seizures continued, additional AEDs were administered per the standard of care for veterinary patients. Total and unbound plasma phenytoin (PHT) concentrations were measured. Results Consent was obtained for fifty dogs with CSE. Thirty-one had additional motor seizures and were randomized to the study intervention (22 FOS and 9 PBO). There was a statistically significant difference in the 12 hour responder rate with 63% in the FOS group versus 22% in the placebo group (p=0.043) having no further seizures. The unbound PHT concentrations at 30 and 60 minutes were within the therapeutic concentrations for people (1–2 μg/mL) with the exception of one dog. There was mild vomiting in 36% of the FOS group (7/22) within 20 minutes of FOS administration and none of the placebo group (0/9) (p = 0.064). Significance This proof of concept study provides the first evidence that FOS is tolerated and effective in canine SE at PHT concentrations clinically relevant for human SE. Further, naturally occurring CSE can be utilized as a translational platform for future studies of novel SE compounds.

Status epilepticus in dogs and cats, part 2: treatment, monitoring, and prognosis

“…In a recent study of dogs with convulsive SE, 63% of dogs that received 15 mg/kg phenytoin equivalent of fosphenytoin had no further seizures, compared to 22% of dogs that received placebo. No hypotension was noted in this group, with vomiting being the only significant adverse effect …”

Intravenous Topiramate: Pharmacokinetics in Dogs with Naturally Occurring Epilepsy

“…Using pharmacokinetic data and simulations, we were able to predict phenytoin exposure from different fosphenytoin dosing strategies and determine the optimal dosing regimen to attain the same phenytoin concentrations that are considered therapeutic in human SE in dogs (11). We subsequently used that dosing regimen to attain the targeted phenytoin concentration in a randomized safety and efficacy clinical trial (31). Based on case reports of TPM oral suspensions used to treat refractory SE, our goal target concentration range was 20–30 μg/mL.…”

Use of IV fosphenytoin pharmacokinetics to determine the loading dose for a clinical trial of canine status epilepticus

“…Similarities between human and dog epilepsy, both in disease characteristics and therapeutic responses to current medications, suggest that CSE could be a valuable tool for studying the safety and efficacy of antiepileptic drugs prior to their use in humans. To validate the use of naturally occurring CSE as a translational platform to develop new therapies, we performed a randomized‐controlled trial of FOS in dogs to determine whether it had a response rate similar to that in humans …”

“…To validate the use of naturally occurring CSE as a translational platform to develop new therapies, we performed a randomized-controlled trial of FOS in dogs to determine whether it had a response rate similar to that in humans. 10 Epilepsia [companion manuscript to this submission]). A critical first step in designing the clinical trial in CSE was to determine dose to attain unbound PHT concentrations similar to those attained in treating in human status epilepticus.…”

“…In order to assess the performance of the PK model, we measured drug concentrations in plasma collected as part of the subsequent randomized-controlled trial. 10 As part of the randomized placebo-controlled study, blood samples were collected from all dogs enrolled in the clinical study 0.5, 1 and 1.5 h after the end of the infusion. Plasma was separated from blood and analyzed for PHT (total and unbound) concentrations as described later.…”