Imepitoin as novel treatment option for canine idiopathic epilepsy: pharmacokinetics, distribution, and metabolism in dogs

Rundfeldt, Chris; Gasparic, Antje; Właź, Piotr

doi:10.1111/jvp.12117

Cited by 22 publications

(25 citation statements)

References 30 publications

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“…Imepitoin is a partial agonist at the benzodiazepine recognition site of the γ-amino butyric acid (GABA A ) receptor that was developed as an antiepileptic (antiseizure) drug (AED) for canine idiopathic epilepsy [6–9]. Since its introduction in 2013, imepitoin has become one of the two AEDs with the highest level of evidence for efficacy for the treatment of generalized tonic-clonic seizures, with an improved safety profile compared to phenobarbital [10, 11].…”

Section: Introductionmentioning

confidence: 99%

Clinical evaluation of a combination therapy of imepitoin with phenobarbital in dogs with refractory idiopathic epilepsy

Neßler

Rundfeldt²,

Löscher³

et al. 2016

BMC Vet Res

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BackgroundImepitoin was tested as a combination treatment with phenobarbital in an open-label mono-centre cohort study in dogs with drug-resistant epilepsy. Diagnosis of idiopathic epilepsy was based on clinical findings, magnetic resonance imaging and cerebrospinal fluid analysis. Three cohorts were treated. In cohort A, dogs not responding to phenobarbital with or without established add-on treatment of potassium bromide or levetiracetam were treated add-on with imepitoin, starting at 10 mg/kg BID, with titration allowed to 30 mg/kg BID. In cohort B, the only difference to cohort A was that the starting dose of imepitoin was reduced to 5 mg/kg BID. In cohort C, animals not responding to imepitoin at >20 mg/kg BID were treated with phenobarbital add-on starting at 0.5 mg/kg BID.ResultsThe add-on treatment resulted in a reduction in monthly seizure frequency (MSF) in all three cohorts. A reduction of ≥50% was obtained in 36-42% of all animals, without significant difference between cohorts. The lower starting dose of 5 mg/kg BID imepitoin was better tolerated, and an up-titration to on average of 15 mg/kg BID was sufficient in cohort A and B. In cohort C, a mean add-on dose of 1.5 mg/kg BID phenobarbital was sufficient to achieve a clinically meaningful effect. Six dogs developed a clinically meaningful increase in MSF of ≥ 50%, mostly in cohort A. Neither imepitoin nor phenobarbital add-on treatment was capable of suppressing cluster seizure activity, making cluster seizure activity an important predictor for drug-resistance.ConclusionA combination treatment of imepitoin and phenobarbital is a useful treatment option for a subpopulation of dogs with drug-resistant epilepsy, a low starting dose with 5 mg/kg BID is recommended.

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Section: Introductionmentioning

confidence: 99%

Clinical evaluation of a combination therapy of imepitoin with phenobarbital in dogs with refractory idiopathic epilepsy

Neßler

Rundfeldt²,

Löscher³

et al. 2016

BMC Vet Res

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“…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…”

Section: Which Drug Should Be Used First?mentioning

confidence: 99%

2015 ACVIM Small Animal Consensus Statement on Seizure Management in Dogs

Podell

Volk

Berendt

et al. 2016

Veterinary Internal Medicne

131

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This report represents a scientific and working clinical consensus statement on seizure management in dogs based on current literature and clinical expertise. The goal was to establish guidelines for a predetermined, concise, and logical sequential approach to chronic seizure management starting with seizure identification and diagnosis (not included in this report), reviewing decision‐making, treatment strategies, focusing on issues related to chronic antiepileptic drug treatment response and monitoring, and guidelines to enhance patient response and quality of life. Ultimately, we hope to provide a foundation for ongoing and future clinical epilepsy research in veterinary medicine.

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“…Partial activation of the GABA receptors by imepitoin has been demonstrated to have pronounced anti-seizure activity and anxiolytic activity in rodent models, with a high tolerability [14]. The anxiolytic effects of imepitoin have been demonstrated in the rat in three experimental paradigms, the Vogel conflict test, the elevated plus maze and the light-dark box [15].…”

Section: Introductionmentioning

confidence: 99%

“…The anxiolytic effects of imepitoin have yet to be demonstrated in detail in the dog; however, anecdotal evidence from the first clinical studies of imepitoin indicated that owners perceived that their dog’s epilepsy-related behavioural changes had improved during imepitoin treatment, an effect not previously seen with other anti-epileptic drugs (AEDs) such as phenobarbital [21]. Imepitoin has potential benefits over existing anxiolytics with a fast onset of action ~2–3 h post oral dosing [14, 22], compared to around 3–5 weeks for SSRIs and TCAs [23]. To date, the only behavioural effect of imepitoin that has been reported is hyperactivity [18], which may be expected as paradoxical excitement can occur in dogs treated with benzodiazepines (e.g.…”

Section: Introductionmentioning

confidence: 99%

Investigating the potential of the anti-epileptic drug imepitoin as a treatment for co-morbid anxiety in dogs with idiopathic epilepsy

2017

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BackgroundBehavioural changes associated with idiopathic epilepsy (IE) have been identified in dogs, with fear and anxiety-related problems seen in both drug-naïve dogs and dogs treated with anti-epileptic drugs (AEDs). Treating anxiety-related behaviour in dogs with IE may be challenging, as seizures are a contraindication for many conventional anxiolytic drugs. In addition, many dogs with IE are already treated with AEDs to reduce their seizure frequency, which may have negative effects if used in polytherapy. Imepitoin is low-affinity partial agonist at the benzodiazepine (BDZ) site of the GABAA receptor, and has been demonstrated to have both anticonvulsant and anxiolytic effects in laboratory rodents. Imepitoin has been developed for the treatment of IE in dogs, with demonstrated anticonvulsant effects and high tolerability and safety. To date, imepitoin’s potential to reduce anxiety in dogs with IE has not been investigated. An online survey was conducted to investigate the effect of imepitoin on fear and anxiety-related behaviours in dogs with IE. Eighty-five valid responses were received from owners of dogs with IE currently treated with imepitoin. Anxiety-related behaviour was quantified before and during imepitoin treatment using a validated questionnaire tool (C-BARQ).ResultsNo differences were observed in the five fear/anxiety-related measures between the two time periods (before vs. during treatment) for dog directed fear, stranger directed fear, non-social fear, pain sensitivity and separation related behaviour. A median 45% reduction in seizure frequency/month was observed following imepitoin treatment; however, imepitoin did not appear effective in reducing seizure frequency in a minority of cases. Polyphagia was the most common chronic side effect, and more side effects were reported in polytherapy cases.ConclusionsImepitoin does not appear to improve anxiety-related behaviour in dogs with IE treated with this medication for its anti-epileptic effects. Investigating the effects of imepitoin upon the behaviour of dogs with recognised behavioural anxiety-related problems (e.g. specific fears and phobias, separation related behaviours), in both healthy dogs and dogs with epilepsy is required to further explore any potential anxiolytic effects of this medication.

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Imepitoin as novel treatment option for canine idiopathic epilepsy: pharmacokinetics, distribution, and metabolism in dogs

Cited by 22 publications

References 30 publications

Clinical evaluation of a combination therapy of imepitoin with phenobarbital in dogs with refractory idiopathic epilepsy

Clinical evaluation of a combination therapy of imepitoin with phenobarbital in dogs with refractory idiopathic epilepsy

2015 ACVIM Small Animal Consensus Statement on Seizure Management in Dogs

Investigating the potential of the anti-epileptic drug imepitoin as a treatment for co-morbid anxiety in dogs with idiopathic epilepsy

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