Pharmacotherapeutic group: Ectoparasiticides for topical use, ATCvet code: QP53AX65 (fipronil, combination).
Fipronil is an insecticide and acaricide belonging to the phenylpyrazole family. Fipronil and its metabolite fipronil sulfone act at ligand-gated chloride channels, in particular those gated by the neurotransmitter gamma-aminobutyric acid (GABA) as well as desensitising (D) and non-desensitising (N) channels gated by glutamate (Glu, unique invertebrate ligand-gated chloride channels), thereby blocking pre- and post-synaptic transfer of chloride ions across cell membranes. This results in uncontrolled activity of the central nervous system and death of arthropods.
Permethrin belongs to the Type I class of pyrethroids, which are acaricides and insecticides with repellent activity. Pyrethroids affect the voltage-gated sodium channels in vertebrates and non-vertebrates. Pyrethroids are so-called “open channel blockers” affecting the sodium channel by slowing both the activation and the inactivation properties, thus leading to hyper-excitability and death of the parasite. Permethrin in the product provides repellent activity (anti-feeding activity) against sandflies (> 80% for 4 weeks), mosquitoes and ticks.
In one experimental study, the product had a faster onset on flea adulticidal activity than fipronil alone at 7 and 14 days after treatment administration.
Speed of kill
The product kills new infesting fleas (C. canis, C. felis) within 6 hours from 2 days after treatment and for a full month. C. felis fleas already present on dogs when the treatment is applied are killed in 24 hours. Speed of kill against pre-existing C. canis has not been evaluated.
The product kills new infesting ticks (R. sanguineus and I. ricinus) within 6 hours from 2 days after treatment and for a full month. Ticks (R. sanguineus, I. ricinus, D. reticulatus) already present on dogs when the treatment is applied are killed in 48 hours.
In one experimental study, the product was shown to indirectly reduce the risk of transmission of Babesia canis from infected Dermacentor reticulatus ticks from 7 days after application up to 4 weeks, thereby reducing the risk of canine babesiosis in treated dogs in this study.
In one experimental study, the product was shown to indirectly reduce the risk of transmission of Ehrlichia canis from infected Rhipicephalus sanguineus ticks, from 7 days after application up to 4 weeks, thereby reducing the risk of ehrlichiosis in treated dogs in this study.
However, the effectiveness of the product at reducing the transmission of infectious agents following natural exposure under field conditions has not been investigated.
The pharmacokinetic profiles of fipronil and permethrin in combination were studied after topical application in dogs by measuring plasma and hair concentrations for 58 days following treatment. Both permethrin and fipronil, together with its major metabolite, fipronil sulfone, are well distributed on the haircoat of a dog during the first day after application. The concentrations of fipronil, fipronil sulfone and permethrin in the hair coat decrease with time and are detectable for at least 58 days after dosing.
Fipronil and permethrin act topically upon contact with external parasites and the low systemic absorption of fipronil and permethrin is not relevant for the clinical efficacy.
The spot-on application resulted in negligible systemic absorption of permethrin with sporadic measureable concentrations of cis-permethrin between 11.4 ng/mL and 33.9 ng/mL observed 5 to 48 hours following treatment.
Mean maximum plasma concentrations (Cmax) of 30.1 ± 10.3 ng/ml fipronil and 58.5 ± 20.7 ng/ml of fipronil sulfone were observed between Day 2 and 5 (Tmax) following application. Fipronil plasma concentrations then decline with a mean terminal half-life of 4.8 ± 1.4 days.