The intravenous and oral pharmacokinetics of afoxolaner used as a monthly chewable antiparasitic for dogs

Abstract

The pharmacokinetics of afoxolaner in dogs was evaluated following either intravenous or after oral administration of NEXGARD(®), a soft chewable formulation. Afoxolaner is a member of one of the newest classes of antiparasitic agents, known as antiparasitic isoxazolines. The soft chewable formulation underwent rapid dissolution, and afoxolaner was absorbed quickly following oral administration of the minimum effective dose of 2.5mg/kg, with maximum plasma concentrations (Cmax) of 1,655 ± 332 ng/mL observed 2-6h (Tmax) after treatment. The terminal plasma half-life was 15.5 ± 7.8 days, and oral bioavailability was 73.9%. Plasma concentration-versus-time curves fit a 2-compartment model and increased proportionally with dose over the oral dose range of 1.0-4.0mg/kg, and over the oral dose range from 1.0 to 40 mg/kg. Following an intravenous dose of 1mg/kg, the volume of distribution (Vd) was 2.68 ± 0.55 L/kg, and the systemic clearance was 4.95 ± 1.20 mL/h/kg. Afoxolaner plasma protein binding was >99.9% in dogs. One major metabolite, formed following hydroxylation of afoxolaner, was identified in dog plasma, urine and bile. When afoxolaner is administered orally, there is a strong correlation between afoxolaner plasma concentration and efficacy with EC90 values of 23 ng/mL for Ctenocephalides felis and ≥ 100 ng/mL for Rhipicephalus sanguineus sensu lato and Dermacentor variabilis. The pharmacokinetic properties of afoxolaner are suited for a monthly administration product because the fast absorption and long terminal half-life support a rapid onset of action while ensuring month-long efficacy.

Afoxolaner against fleas: immediate efficacy and resultant mortality after short exposure on dogs

“…It induced the mortality of 97.6 to 100% of new infesting fleas after 6 h of exposure on dogs until Day 21. This property can be related to both the quick absorption and plasma peak [14], but also to the volume of blood ingested by the fleas. Afoxolaner is detected in plasma 20–30 min after oral administration and reaches its peak in 2–4 h. The frequency of flea bites is also a factor explaining the quick intoxication of fleas, which will ingest the insecticide present in the blood [25].…”

“…The cat flea, Ctenocephalides felis, is the main flea species infesting both dogs and cats [8, 14]. In addition to causing discomfort to pets and their owners, cat fleas are associated with several diseases.…”

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.…”

Assessment of the efficacy of orally administered afoxolaner against Rhipicephalus sanguineus sensu lato

“…This level of efficacy is similar to what has been published for topical formulations (Beugnet and Franc, 2012;Hunter et al, 2011;Kunkle et al, 2012). Afoxolaner is absorbed rapidly by the intestinal mucosa, and its plasma concentration peaks within 2-4 h after administration (Letendre et al, 2014), which ultimately results in a rapid uptake by the ticks. Further studies should be undertaken to assess the speed of kill on ticks after their attachment, knowing that ticks crawl on the skin of their host for a few hours before attaching.…”