Efficacy, safety, and tolerability of imepitoin in dogs with newly diagnosed epilepsy in a randomized controlled clinical study with long-term follow up

Abstract

BackgroundImepitoin is a novel antiepileptic drug for the treatment of canine idiopathic epilepsy. The present study was conducted to demonstrate superior antiepileptic activity of a high dose of 30 mg/kg BID over a low dose of 1 mg/kg BID of imepitoin during 12 weeks of treatment under double blind conditions in a field population of dogs with previously untreated epilepsy. In a consecutive 12 weeks open label follow up (phase 2), all animals received 30 mg/kg BID, to evaluate the persistence of the antiepileptic activity, and to evaluate the effect of a dose step up to 30 mg/kg in the former low-dose animals.ResultsA treatment with 30 mg/kg BID resulted in a significantly greater reduction in monthly seizure frequency relative to baseline data as compared to the 1 mg/kg dose. Both generalized and partial seizures but not cluster seizures were significantly less frequent in the high dose group. The antiepileptic activity was maintained during study phase 2 in the high dose group. An increase to 30 mg/kg BID in the low- dose animals resulted in a significant reduction in generalized and partial seizures, but not cluster seizures. At the end of study phase 2, 32.1 and 46.8 % of dogs of the former high and former low-dose groups respectively, remained free of generalized tonic-clonic seizures.Imepitoin was well tolerated. The frequency of dogs with any adverse drug reactions was higher in the 30 mg/kg BID dose (59 % vs. 41 %, p = 0.041), and the main target organ was the central nervous system (CNS). The occurrence of CNS related adverse reactions was transient and findings were mostly restricted to the first weeks of treatment. No hepatic enzyme increase and no other organ toxicity were observed.ConclusionThe administration of imepitoin twice daily at a dose of 30 mg/kg results in significant and persistent antiepileptic effects in patients with newly diagnosed epilepsy and generalized tonic-clonic seizures, as observed over a study period of up to 6 months. Imepitoin was well tolerated. Most CNS related adverse drug reactions were transient. Both the antiepileptic activity and the safety profile make the drug suitable for long-term clinical use.

Behavioral Changes Under Levetiracetam Treatment in Dogs

“…In the current study, 11% of the dogs were aggressive and 5% hyperactive after LEV treatment. The incidence of these two behavioral factors is comparable with other AEDs used in veterinary medicine (20,(38)(39)(40)(41)(42)(43)(44). A study in human medicine performed by White et al (14) showed that 38 of the 553 patients were forced to LEV discontinuation due to behavioral side effects.…”

“…Reported side effects for phenobarbital are aggression, restlessness and hyperactivity (20,(38)(39)(40). Imepitoin may also cause behavioral changes such as hyperactivity and aggression (41)(42)(43)(44). Moreover, potassium bromide is also reported to cause these two behavioral changes (10).…”

Long‐term efficacy of imepitoin in the treatment of naive dogs affected by idiopathic epilepsy

“…To date, according to EMA indications (based on the results of the study of Tipold and others 2015) and the results of a randomised, double-blind, controlled parallel group clinical field trial, there were no specific data to recommend using IMP monotherapy in the treatment of IE dogs affected by CS (Rundfeldt and others 2015). …”

2015 ACVIM Small Animal Consensus Statement on Seizure Management in Dogs

“…Several other trials have been performed in dogs including: (i) a randomized controlled blinded trial in which imepitoin was compared with a pseudoplacebo (ie, low dose of imepitoin); (ii) a randomized blinded trial in which imepitoin was compared with primidone; (iii) an exploratory trial comparing imepitoin with phenobarbital and primidone in newly diagnosed dogs with epilepsy; and, (iv) an exploratory trial comparing added imepitoin with added potassium bromide in dogs resistant to treatment with phenobarbital or primidone 31, 32, 35, 45, 46. Overall, >400 dogs were treated in these trials, and each study identified consistent anticonvulsant efficacy for imepitoin 45…”