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      Pharmacokinetics of a novel endectoparasiticide topical formulation for cats, combining esafoxolaner, eprinomectin and praziquantel Translated title: Pharmacocinétique d’une nouvelle formulation topique d’endectoparasiticide pour chats, combinant esafoxolaner, éprinomectine et praziquantel

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          Abstract

          Esafoxolaner, a purified enantiomer of afoxolaner with insecticidal and acaricidal properties, is combined with eprinomectin and praziquantel in NexGard ® Combo, a novel topical endectoparasiticide formulation for cats. The parasiticide potencies of topical esafoxolaner, eprinomectin and praziquantel, are based on transcutaneous absorption, systemic distribution, and exposure of respective target parasites. For each compound, the pharmacokinetic profile, non-interference, dose linearity/proportionality after one administration, and the accumulation and time to reach a steady state after repeated monthly administrations of the novel formulation, were investigated. After one topical application of NexGard ® Combo at the minimum recommended dose, the mean plasma concentration of esafoxolaner immediately reached (and remained at) a level supporting rapid onset and sustained efficacy against ectoparasites for at least 1 month. The mean C max, T max, T 1/2, and the topical bioavailability of esafoxolaner were 130 ng/mL, 7.1 days, 21.7 days and 47.2%, respectively, and the plasma profiles of eprinomectin and praziquantel supported their known endoparasiticide properties. No relevant interference between the three compounds was observed. Dose proportionality was demonstrated for the three compounds over a range of 0.5× to 2× the minimum recommended dose. Steady state after repeated monthly administrations was reached by the second dose for praziquantel and by the fifth dose for esafoxolaner and eprinomectin. Accumulation was limited and drug plasma concentrations were maintained within a safe level.

          Translated abstract

          L’esafoxolaner, un énantiomère purifié d’afoxolaner aux propriétés insecticides et acaricides, est combiné à l’éprinomectine et au praziquantel dans NexGard ® Combo, une nouvelle formulation endectoparasiticide topique pour chats. Les pouvoirs parasiticides de l’esafoxolaner topique, de l’éprinomectine et du praziquantel sont basés sur l’absorption transcutanée, la distribution systémique et l’exposition des parasites cibles respectifs. Pour chaque composé, le profil pharmacocinétique, la non-interférence, la linéarité/proportionnalité de dose après une administration, ainsi que l’accumulation et le temps nécessaire pour atteindre un état d’équilibre après des administrations mensuelles répétées de la nouvelle formulation, ont été étudiés. Après une application topique de NexGard ® Combo à la dose minimale recommandée, la concentration plasmatique moyenne d’esafoxolaner a immédiatement atteint et est restée à un niveau soutenant une apparition rapide et soutenue de l’efficacité contre les ectoparasites pendant au moins un mois. La C max moyenne, la T max, la T 1/2, et la biodisponibilité topique de l’esafoxolaner était respectivement de 130 ng/mL, 7,1 jours, 21,7 jours et 47,2 %, et les profils plasmatiques de l’éprinomectine et du praziquantel ont confirmé leurs propriétés endoparasiticides connues. Aucune interférence significative entre les trois composés n’a été observée. La proportionnalité de la dose a été démontrée pour les trois composés sur une plage de 0,5 × à 2 × la dose minimale recommandée. L’état d’équilibre après des administrations mensuelles répétées a été atteint par la deuxième dose de praziquantel et par la cinquième dose d’esafoxolaner et d’éprinomectine. L’accumulation était limitée et les concentrations plasmatiques du médicament étaient maintenues à un niveau sûr.

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          Most cited references 37

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          Discovery and mode of action of afoxolaner, a new isoxazoline parasiticide for dogs.

          Afoxolaner is an isoxazoline compound characterized by a good safety profile and extended effectiveness against fleas and ticks on dogs following a single oral administration. In vitro membrane feeding assay data and in vivo pharmacokinetic studies in dogs established an afoxolaner blood concentration of 0.1-0.2 μg/ml to be effective against both fleas (Ctenocephalides felis) and ticks (Dermacentor variabilis). Pharmacokinetic profiles in dogs following a 2.5mg/kg oral dosage demonstrated uniform and predictable afoxolaner plasma concentrations above threshold levels required for efficacy for more than one month. Dose ranging and a 5-month multi-dose experimental study in dogs, established that the 2.5mg/kg oral dosage was highly effective against fleas and ticks, and produced predictable and reproducible pharmacokinetics following repeated dosing. Mode of action studies showed that afoxolaner blocked native and expressed insect GABA-gated chloride channels with nanomolar potency. Afoxolaner has comparable potency between wild type channels and channels possessing the A302S (resistance-to-dieldrin) mutation. Lack of cyclodiene cross-resistance for afoxolaner was confirmed in comparative Drosophila toxicity studies, and it is concluded that afoxolaner blocked GABA-gated chloride channels via a site distinct from the cyclodienes. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.
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            Pet roundworms and hookworms: A continuing need for global worming

            Ascarids and ancylostomatids are the most important parasites affecting dogs and cats worldwide, in terms of diffusion and risk for animal and human health. Different misconceptions have led the general public and pet owners to minimize the importance of these intestinal worms. A low grade of interest is also registered among veterinary professions, although there is a significant merit in keeping our guard up against these parasites. This article reviews current knowledge of ascarids and ancylostomatids, with a special focus on pathogenicity, epidemiology and control methods in veterinary and human medicine.
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              The antiparasitic isoxazoline A1443 is a potent blocker of insect ligand-gated chloride channels.

              A structurally unique isoxazoline class compound, A1443, exhibits antiparasitic activity against cat fleas and dog ticks comparable to that of the commercial ectoparasiticide fipronil. This isoxazoline compound inhibits specific binding of the gamma-aminobutyric acid (GABA) receptor channel blocker [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB) to housefly-head membranes, with an IC(50) value of 455pM. In contrast, the IC(50) value in rat-brain membranes is>10muM. To study the mode of action of this isoxazoline, we utilized MdGBCl and MdGluCl cDNAs, which encode the subunits of housefly GABA- and glutamate-gated chloride channels, respectively. Two-electrode voltage clamp electrophysiology was used to confirm that A1443 blocks GABA- and glutamate-induced chloride currents in Xenopus oocytes expressing MdGBCl or MdGluCl channels, with IC(50) values of 5.32 and 79.9 nM, respectively. Blockade by A1443 was observed in A2'S-MdGBCl and S2'A-MdGluCl mutant channels at levels similar to those of the respective wild-types, and houseflies expressing A2'S-MdGBCl channels were as susceptible to A1443 as standard houseflies. These findings indicate that A1443 is a novel and specific blocker of insect ligand-gated chloride channels. Copyright 2009 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Parasite
                Parasite
                parasite
                Parasite
                EDP Sciences
                1252-607X
                1776-1042
                2021
                02 April 2021
                : 28
                : ( publisher-idID: parasite/2021/01 )
                Affiliations
                [1 ] Boehringer-Ingelheim Animal Health 29 avenue Tony Garnier 69007 Lyon France
                [2 ] Boehringer-Ingelheim Animal Health 631 Route 1 North Brunswick NJ 08902 USA
                Author notes
                Article
                parasite200070 10.1051/parasite/2021014
                10.1051/parasite/2021014
                8019567
                © V. Jacquot et al., published by EDP Sciences, 2021

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 5, Tables: 3, Equations: 0, References: 40, Pages: 10
                Categories
                Special Issue – NexGard ® Combo (esafoxolaner, eprinomectin, praziquantel): A new endectocide spot-on formulation for cats. Invited Editor: Frédéric Beugnet
                Research Article

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