Safety evaluation of orally administered afoxolaner in 8-week-old dogs

The safety profile of afoxolaner, a new isoxazoline molecule, was evaluated following the regulatory requirements when administered six times orally in a soft chewable formulation at a dose of at least 1 x, 3 x or 5 x the maximum exposure dose (6.3 mg/kg) in 8-week-old Beagle dogs. Thirty-two healthy puppies (16 males and 16 females) were enrolled and allocated randomly to one of four treatment groups. Treatments were administered at three, one-month dose intervals (Days 0,28 and 56) followed by three, 2-week dose intervals (Days 84,98 and 112). The study ended at Day 126. The groups were: Group 1: non-treated control; Group 2: afoxolaner chews administered at a dosage of at least 6.3 mg/kg (1 x); Group 3: afoxolaner chews administered at a dosage of at least 18.9 mg/kg (3 x); and Group 4: afoxolaner chews administered at a dosage of at least 31.5 mg/kg (5 x). All dogs were examined for general health twice a day beginning on at least Day-14. Physical examinations, and blood collections for clinical pathology analysis and afoxolaner plasma concentrations, were performed throughout the study. On Day 126, 2 weeks following the last treatment, all dogs were humanely euthanized prior to the conduction of a full necropsy with tissue collection. No afoxolaner-related changes were observed in growth, physical variables, clinical pathology variables, or tissues examined histologically. No clinically or statistically significant health abnormalities related to the administration of afoxolaner were observed. Vomiting and diarrhea were observed sporadically across all groups including the controls. The kinetics of afoxolaner plasma concentrations was linear following 6 doses of 6.3, 18.9 and 31.5 mg/kg and dose proportionality was demonstrated. There were no statistical differences (p < 0.05) between samples taken on Days 55 and 83 when compared to Day 27. Based upon the results of this study, afoxolaner was shown to be safe when administered repeatedly in a soft chewable formulation at up to 5x the maximum exposure dose in dogs as young as 8 weeks of age. (c) 2014 The Authors. Published by Elsevier B.V.