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 concentrati...

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Bibliographic Details
Published in:Veterinary parasitology 2014-04, Vol.201 (3-4), p.179-189
Main Authors: Shoop, Wesley L., Hartline, Eric J., Gould, Brandon R., Waddell, Molly E., McDowell, Richard G., Kinney, John B., Lahm, George P., Long, Jeffrey K., Xu, Ming, Wagerle, Ty, Jones, Gail S., Dietrich, Robert F., Cordova, Daniel, Schroeder, Mark E., Rhoades, Daniel F., Benner, Eric A., Confalone, Pat N.
Format: Article
Language:English
Subjects:
Afoxolaner
Animals
Antiparasitic Agents - blood
Antiparasitic Agents - pharmacokinetics
Antiparasitic Agents - pharmacology
Antiparasitic Agents - therapeutic use
Chloride Channels - metabolism
Cockroaches - drug effects
Ctenocephalides felis
Dermacentor variabilis
Dog Diseases - drug therapy
Dog Diseases - physiopathology
Dogs
Drosophila
Drosophila melanogaster - drug effects
Ectoparasiticide
Electrophysiological Phenomena - drug effects
Female
Flea Infestations - drug therapy
Flea Infestations - prevention & control
Flea Infestations - veterinary
Fleas
Isoxazoles - blood
Isoxazoles - pharmacokinetics
Isoxazoles - pharmacology
Isoxazoles - therapeutic use
Isoxazoline
Ixodidae
Male
Naphthalenes - blood
Naphthalenes - pharmacokinetics
Naphthalenes - pharmacology
Naphthalenes - therapeutic use
Oocytes - drug effects
Protein Binding - drug effects
Random Allocation
Siphonaptera - drug effects
Tick Infestations - drug therapy
Tick Infestations - prevention & control
Tick Infestations - veterinary
Ticks
Ticks - drug effects
Xenopus laevis
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Summary: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 0.1–0.2μg/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.
ISSN:0304-4017
1873-2550
DOI:10.1016/j.vetpar.2014.02.020