It acts as an antagonist at GABA-receptors (those gated by the neurotransmitter gamma-aminobutyric acid) and other ligand-gated chloride channels. Isoxazolines, among the chloride channel modulators, bind to a distinct and unique target site within the insect GABA-gated chloride channels, thereby blocking pre-and post-synaptic transfer of chloride ions across cell membranes. Prolonged afoxolaner-induced hyperexcitation results in uncontrolled activity of the central nervous system and death of insects and acarines.[3][6][7]
Safety
Toxicity for mammals
According to clinical studies performed prior to marketing:
The oral toxicity profile of afoxolaner consists of a diuretic effect (rats only), effects secondary to a reduction in food consumption (rats and rabbits only) and occasional vomiting and/or diarrhea (dogs, 120 and 200 mg/kg bodyweight (bw)) following high oral doses. No treatment-related effects on vomiting or diarrhea were noted following oral doses of up to 31.5 mg/kg bw in the pivotal target animal safety study, nor in the EU field trial.[8]
(in combination with milbemycin oxime): vomiting, diarrhea, lethargy, anorexia, and pruritus were observed in 0.2 to 1% of 10,000 animals treated and were generally self-limiting and of short duration,[6]
(in combination with milbemycin oxime): erythema and neurological signs (convulsions, ataxia and muscle tremors) have been reported in less than 0.1% of 10,000 animals treated, including isolated reports,[6]
The US Food and Drug Administration FDA reports[10] that some drugs in this class (isoxazolines), including afoxolaner, can have adverse neurologic effects on some dogs, such as muscle tremors, ataxia, and convulsions.
Extralabel use of afoxolaner in a pet pig has been described without any adverse effects.[11] Experimental use in commercial pigs also did not result in any adverse effects.[12]
Selectivity for insect over mammalian GABA-receptors has been demonstrated for other isoxazolines.[13] The selectivity might be explained by the number of pharmacological differences that exist between GABA-gated chloride channels of insects and vertebrates.[14]
Legal status
The marketing authorization was granted by the European Medicines Agency in February 2014, for Nexgard,[3][8] and in January 2015, for Nexgard Spectra.[7][15]
Brand names
Afoxolaner is the active ingredient of the veterinary medicinal products Nexgard,[3] Frontpro, and Nexgard Spectra (in combination with milbemycin oxime).[7][16][17][18] They are indicated for the treatment and prevention of flea infestations, and the treatment and control of tick infestations in dogs and puppies (8 weeks of age and older, weighing 4 pounds (~1.8 kilograms) of body weight or greater) for one month.[19]
^Casida JE (April 2015). "Golden age of RyR and GABA-R diamide and isoxazoline insecticides: common genesis, serendipity, surprises, selectivity, and safety". Chemical Research in Toxicology. 28 (4): 560–566. doi:10.1021/tx500520w. PMID25688713.
