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

摘要

The pharmacokinetics of afoxolaner in dogs was evaluated following either intravenous or after oral administration of NEXGARD((R)), 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 2.5 mg/kg, with maximum plasma concentrations (C-max) of 1655 +/- 332 ng/mL observed 2-6 h (T-max) 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 1.0-4.0 mg/kg, and over the oral dose range from 1.0 to 40 mg/kg. Following an intravenous dose of 1 mg/kg, the volume of distribution (V-d) 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 fells 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