Pharmacodynamic properties
Imepitoin is a centrally acting substance with anxiolytic and antiepileptic properties which crosses the blood brain barrier without involvement of active transport or active clearance, resulting in immediate equilibrium between plasma and brain. Here it acts as a low affinity partial agonist of the benzodiazepine receptor.
The anxiolytic effect of imepitoin is mediated via the GABAA receptor. Imepitoin also inhibits seizures via potentiation of the GABAA receptor-mediated inhibitory effects on the neurons and in addition, imepitoin has a weak calcium channel blocking effect which may contribute to its anticonvulsive properties.
Clinical trials in epilepsy
In a European field trial that compared the efficacy of imepitoin to phenobarbital in 226 dogs with newly diagnosed idiopathic epilepsy, 45% of cases from the imepitoin group and 20% from the phenobarbital group were excluded from the efficacy analysis for reasons that included failure to respond to treatment. In the remaining dogs (64 dogs for Pexion and 88 dogs for phenobarbital), the following clinical results were observed: Mean frequency of generalised seizures was reduced from 2.3 seizures per month in the imepitoin group and from 2.4 seizures per month in the phenobarbital group to 1.1 seizures per month in both groups after 20 weeks of treatment. The difference between imepitoin and phenobarbital groups in the seizure frequency per month after treatment (adjusted for baseline difference) was 0.004, 95% CI [-0.928, 0.935]. During the evaluation phase of 12 weeks, the proportion of generalised seizure-free dogs was 47% (30 dogs) in the imepitoin group and 58% (51 dogs) in the phenobarbital group.
The safety of both treatments was evaluated in the full analysis data set (or safety data set, i.e. 116 animals in the imepitoin group and 110 animals in the phenobarbital group). Increasing doses of phenobarbital were associated with increasing levels of the liver enzymes ALT, AP, AST, GGT, and GLDH. In comparison, none of the five enzymes increased with increasing doses of imepitoin. A slight increase in creatinine values compared to baseline was observed in the imepitoin-treated dogs. However, the upper limit of the confidence interval for creatinine remained within the reference range at all visits. Additionally, fewer adverse events were noted for polyuria (10% vs 19% of dogs), polydipsia (14% vs 23%) and marked sedation (14% vs 25 %) when comparing imepitoin to phenobarbital. Please refer to section 4.6 of the SPC for further details of adverse reactions.
In a US field trial that compared the efficacy of imepitoin at a fixed dose of 30 mg/kg twice daily to a placebo in 151 dogs with idiopathic epilepsy during a treatment period of 84 days, the proportion of generalized seizure-free dogs was 21% (21 dogs out of 99; 95 % CI [0.131; 0.293]) in the imepitoin group and 8% (4 dogs out of 52; 95% CI [0.004; 0.149]) in the placebo group. 25% of dogs did not respond to the treatment with imepitoin (same or increased frequency of seizures).
Clinical trial in noise phobia
In a placebo-controlled field trial with a treatment duration of 3 days, the efficacy of imepitoin was investigated in dogs diagnosed with noise phobia during the traditional New Year’s Eve fireworks. For the efficacy analysis, 226 dogs (104 imepitoin, 122 placebo) were eligible (at least one dose of medication & data for evaluation of co-primary endpoints), and the following results were observed for the two co-primary endpoints:
1. Owner assessed overall effect of study treatment (based on signs during a noise event and a comparison to signs during a previous noise event(s) without treatment: The cumulative odds of a good or excellent effect were significantly greater in the imepitoin group compared with the placebo group (Odds Ratio = 4.689; p < 0.0001, 95% CI [2.79;7.89]).
2. Owner-reported measure of their dog’s anxiety symptoms (based on Lincoln Sound Sensitivity Scale) during a noise event: The sum scores showed a statistically significant treatment effect favouring imepitoin with a difference in anxiety score between imepitoin and placebo of -6.1; p < 0.0001, 95% CI [-8.6;-3.6].
Pharmacokinetic particulars
Absorption Pharmacokinetic studies indicate that imepitoin is well absorbed (> 92 %) after oral administration and that no pronounced first pass effect occurs. After oral administration of imepitoin tablets at 30 mg/kg without food, peak blood concentrations are attained rapidly with a Tmax of around 2 hours, a Cmax of about 18 µg/ml. Co-administration of imepitoin tablets with food, reduces the total AUC by 30% but produces no significant change in Tmax and Cmax. Gender-specific differences do not occur.
Distribution Dose linearity occurs over the therapeutic dose range of imepitoin. Imepitoin has a relatively high volume of distribution (579 to 1548 ml/kg). The in-vivo plasma protein binding of imepitoin in dogs is low (60 to 70%). No interaction with highly protein bound compounds is therefore expected. No accumulation of imepitoin in plasma occurs after repeated administration, once steady state is reached.
Metabolism Imepitoin is extensively metabolised prior to elimination. Metabolite profiles in urine and faeces revealed four major inactive metabolites which are formed by oxidative modification.
Elimination Imepitoin is rapidly cleared from blood (Cl = 260 to 568 ml/hours/kg) with an elimination half-life of approximately 1.5 to 2 hours. The majority of imepitoin and its metabolites are excreted via the faecal route rather than the urinary route so that no major change in pharmacokinetics and no accumulation is expected in renally impaired dogs.