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

Abstract

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.

Evidence for Personal Protective Measures to Reduce Human Contact With Blacklegged Ticks and for Environmentally Based Control Methods to Suppress Host-Seeking Blacklegged Ticks and Reduce Infection with Lyme Disease Spirochetes in Tick Vectors and Rodent Reservoirs

“…However, this general approach merits further study with alternative compounds acting as tick development inhibitors or systemic acaricides. For example, afoxolaner and fluralaner—recently described compounds belonging to a group of systemic insecticides and acaricides termed isoxazolines (Gassel et al 2014, Shoop et al 2014)—were demonstrated to disrupt feeding of I. scapularis adults on orally treated dogs for at least 4 wk (Mitchell et al 2014, Williams et al 2015). Such compounds could prove useful as systemic acaricides offered via oral baits in rodent bait boxes to reduce infestation by I. scapularis immatures on rodent reservoirs.…”

Novel GABA receptor pesticide targets

“…Several types of evidence establish that isoxazolines [57][58][59][60][61][62][63][64][65][66] and meta-diamides (including mDA-7 [24,67] and BPB-1 [68]) are NCAs but at a different high affinity site(s) than those for compounds acting at the NCA-IA, NCA-IB and AVE targets ( …”

“…A 2012 compilation considering the chronology and numbers for introduction of the current insecticides gave the GABA-R targeting compounds as only 1.7% of the total with half of them introduced by 1955 [81]. Newly introduced GABAergic insecticides are flu and afoxolaner used for flea and tick control on cats and dogs [58,[62][63][64][65]. There are also important crop pests highly sensitive to NCA-IIs [24,60,82] indicating possible expanded use on optimization.…”

The ability of an oral formulation of afoxolaner to block the transmission of Babesia canis by Dermacentor reticulatus ticks to dogs

“…The present study describes the results of an experimental study to assess the efficacy of afoxolaner , a new insecticide-acaricide administered orally in a soft chewable formulation (Nexgard®, Merial), against D. reticulatus infected with Babesia canis in dogs. Afoxolaner belongs to a new class of insecticides-acaricides, the isoxazoline [22], acting systemically through oral formulation [23]. Afoxolaner is highly bound to plasmatic proteins and it is ingested by the hematophagous arthropods during their blood meal.…”