Afoxolaner

Afoxolaner (INN) is an insecticide and acaricide that belongs to the isoxazoline chemical compound group.
It acts as an antagonist at ligand-gated chloride channels, in particular those gated by the neurotransmitter gamma-aminobutyric acid (GABA-receptors). 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.
Marketing.
Afoxolaner is the active principle of the veterinary medicinal products NexGard (alone) and Nexgard Spectra (in combination with milbemycin oxime). 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. These products are administered orally and poisons fleas once they start feeding.
The marketing authorization was granted by the European Medicines Agency in February 2014, for NexGard and January 2015, for Nexgard Spectra, after only 14 and 12 months of quality, safety and efficacy assessment performed by the Committee for Medicinal Products for Veterinary Use (CVMP). Therefore, long-term effects are not known.
List of excipients.
In NexGard and NexGard Spectra:
Additionally in NexGard Spectra:
Safety.
Dosage.
Afoxolaner is recommended to be administered at a dose of 2.7–7 mg/kg dog's body weight.
Toxicity for mammals.
According to clinical studies performed prior marketing:
According to post-marketing safety experience:
Selectivity in insects over mammalians.
"In vivo" studies (repeat-dose toxicology in laboratory animals, target animal safety, field studies) provided by MERIAL, the company that produces afoxolaner-derivative medicines, did not show evidence of neurological or behavioural effects suggestive of GABA-mediated perturbations in mammals. The Committee for Medicinal Products for Veterinary Use (CVMP) therefore concluded that binding to dog, rat or human GABA receptors is expected to be low for afoxolaner.
Selectivity for insect over mammalian GABA-receptors has been demonstrated for other isoxazolines. The selectivity might be explained by the number of pharmacological differences that exist between GABA-gated chloride channels of insects and vertebrates.