Evaluation of Imepitoin + Phenobarbital Therapy in Dogs with Refractory Epilepsy

A study recently published in BMC Veterinary Research reported safety and efficacy results of imepitoin + phenobarbital combination therapy in dogs with refractory idiopathic epilepsy.

Idiopathic epilepsy is chronic and spontaneous. For 20% to 40% of dogs with this condition, one antiepileptic drug (AED) may not be enough to achieve sufficient seizure control.

Imepitoin was originally developed to treat canine idiopathic epilepsy; it has also demonstrated treatment effectiveness for generalized tonic—clonic seizures in dogs. Although imepitoin is not currently approved for combination therapy with other AEDs, it has shown clinical efficacy when combined with phenobarbital. Importantly, imepitoin’s safety profile is favorable to that of phenobarbital.

From 2013 to 2015, the study authors evaluated the safety and efficacy of imepitoin + phenobarbital in 34 client-owned dogs with refractory idiopathic epilepsy. The dogs were grouped into three cohorts:

• Cohort A (n = 16): Refractory to phenobarbital ± potassium bromide or levetiracetam; add-on imepitoin (10 mg/kg BID, titrated up to 30 mg/kg BID)
• Cohort B (n­ = 11): Refractory as for cohort A; add-on imepitoin (5 mg/kg BID, titrated up to 30 mg/kg BID)
• Cohort C (n = 7): Refractory to imepitoin or levetiracetam; add-on phenobarbital (0.5 mg/kg BID, titrated up to 6 mg/kg BID)

The authors evaluated all dogs for safety and efficacy; a subpopulation of dogs completing all add-on treatments (n=19) was analyzed separately.

Australian shepherds and border collies, which are prone to severe seizures, accounted for nearly one-third of the 19 breeds represented in the study. At baseline, seizure activity was most severe in cohort A, reflected by the cohort’s highest monthly seizure frequency (MSF), longest duration of epilepsy, and highest percentage of dogs on a second permanent AED.

In the full population, no dogs became seizure free with add-on treatment. However, over one-third of dogs achieved clinically meaningful MSF reduction (>50%), with several dogs in cohorts A and B achieving 75% or higher MSF reduction. MSF reduction was statistically significant in cohort B. Interestingly, MSF increased by 50% or more for several dogs in cohorts A and B. Cluster seizure activity was not significantly affected by add-on treatment.

For all cohorts, MSF reductions were more pronounced in the completer population than in the full population. Cluster seizure activity for completers decreased in cohorts A and B and increased in cohort C; these findings were not statistically significant.

Mean daily doses of add-on imepitoin were markedly lower for the completer dogs than for those that discontinued treatment, indicating poorer seizure control in the early terminators. Mean daily doses of add-on phenobarbital varied little between completers and early terminators. In cohorts A and B, imepitoin add-on treatment did not significantly affect plasma phenobarbital or potassium bromide levels, which remained within therapeutic range; phenobarbital also remained within therapeutic range in cohort C.

Dogs experienced adverse drug reactions (ADRs) at baseline and during add-on treatment, with ataxia being a common ADR. The number of ADRs increased after add-on treatment initiation, then decreased as the study progressed. Cohort A had the highest ADR frequency, reflecting this cohort’s high treatment intensity. Five dogs, all within cohort A, were euthanized due to poor quality of life.

The study’s findings indicate that imepitoin + phenobarbital combination therapy is safe in dogs with refractory idiopathic epilepsy. In addition, the effectiveness of low-dose, add-on phenobarbital may make this treatment combination preferable to high-dose phenobarbital monotherapy. The authors advised interpreting the study’s efficacy results with caution, though, given the lack of randomization and a control group.

Dr. Pendergrass received her doctorate in veterinary medicine from the Virginia-Maryland College of Veterinary Medicine. Following veterinary school, she completed a postdoctoral fellowship at Emory University’s Yerkes National Primate Research Center. Dr. Pendergrass is the founder and owner of JPen Communications, LLC.