The novel antiepileptic drug imepitoin compares favourably to other GABA-mimetic drugs in a seizure threshold model in mice and dogs

Abstract

Recently, the imidazolinone derivative imepitoin has been approved for treatment of canine epilepsy. Imepitoin acts as a low-affinity partial agonist at the benzodiazepine (BZD) site of the GABA_A receptor and is the first compound with such mechanism that has been developed as an antiepileptic drug (AED). This mechanism offers several advantages compared to full agonists, including less severe adverse effects and a lack of tolerance and dependence liability, which has been demonstrated in rodents, dogs, and nonhuman primates. In clinical trials in epileptic dogs, imepitoin was shown to be an effective and safe AED. Recently, seizures in dogs have been proposed as a translational platform for human therapeutic trials on new epilepsy treatments. In the present study, we compared the anticonvulsant efficacy of imepitoin, phenobarbital and the high-affinity partial BZD agonist abecarnil in the timed i.v. pentylenetetrazole (PTZ) seizure threshold test in dogs and, for comparison, in mice. Furthermore, adverse effects of treatments were compared in both species. All drugs dose-dependently increased the PTZ threshold in both species, but anticonvulsant efficacy was higher in dogs than mice. At the doses selected for this study, imepitoin was slightly less potent than phenobarbital in increasing seizure threshold, but markedly more tolerable in both species. Effective doses of imepitoin in the PTZ seizure model were in the same range as those suppressing spontaneous recurrent seizures in epileptic dogs. The study demonstrates that low-affinity partial agonists at the benzodiazepine site of the GABA_A receptor, such as imepitoin, offer advantages as a new category of AEDs.

Introduction

The dog is an important large animal model in various fields of biomedical research and fills a crucial step in the translation of basic research to new treatment regimens [1], [2], [3], [4], [5]. Recently, naturally occurring canine epilepsy has been proposed as a translational platform for human therapeutic trials on new epilepsy treatments [6], [7], [8], [9]. This idea is not new; it has been proposed by us almost 30 years ago [10], [11]. The prevalence and phenomenology of naturally occurring canine epilepsy are very similar to human epilepsy [11], [12], [13], [14], [15], [16]. Epilepsy is the most common chronic neurological disease in dogs, affecting about 0.6–1% of the dog population [11], [13], [16]. However, clinical trials on new antiepileptic drugs (AEDs) in epileptic dogs are as laborious and time-consuming as clinical trials in human patients, necessitating randomized trial designs in which the new drug is compared with either placebo or a standard comparator [17], [18].

One critical decision for all clinical trials is selection of appropriate doses, which has a large impact on the success of drug development programmes [19]. This is also true for clinical trials in dogs with epilepsy, so that a seizure model in dogs would be a valuable tool for pharmaceutical dose selection [20]. Several canine seizure models have been described and used for drug testing, including induction of seizures in healthy dogs by maximal electroshock [20], [21], [22], [23], microinjection of kainate into the amygdala [24], or, most commonly, systemic administration of pentylenetetrazole (PTZ) [21], [25], [26], [27], [28], [29]. We started to use timed intravenous (i.v.) PTZ infusion for determining seizure threshold in dogs in 1982 [30]. Since then, this model has been used by us to study the relationship between GABA and seizure threshold [30], [31], to determine the liability of benzodiazepine (BZD) receptor ligands to induce tolerance and physical dependence during chronic treatment [32], [33], and to determine the anticonvulsant efficacy of BZD receptor ligands such as diazepam (DZP), clonazepam (CLZ), abecarnil and imepitoin [29], [32] or derivatives of the AED valproate (VPA) [34].

For the novel AED imepitoin [35], which acts as a low-affinity partial agonist at the BZD site of the GABA_A receptor [36], the timed i.v. PTZ seizure threshold test was used for dose selection for subsequent clinical trials in dogs with epilepsy [29]. Imepitoin (Pexion^®) has recently been approved in Europe for treatment of epilepsy in dogs. The only other drug that is approved for monotherapy of canine epilepsy in Europe is phenobarbital (PB), which has been used as an AED for more than 100 years [37]; however, its use in the treatment of human epilepsy has declined because of substantial tolerability issues. In epileptic dogs, imepitoin exerts a similar antiepileptic efficacy as PB, but its tolerability is much higher [29], [35]. The aim of the present study was to compare the anticonvulsant activity of imepitoin and PB in the timed i.v. PTZ seizure threshold test in dogs. Furthermore, the two compounds were compared in the same test in mice to determine whether mice correctly predict efficacy in dogs. In order to allow comparisons between drugs and species, we determined threshold increasing doses (TID) for 20% and 50% increase by dose–effect curves as previously suggested for comparison of drug effects in this model in mice [38], [39]. The high-affinity partial BZD receptor agonist abecarnil [40] was included in the experiments for comparison.