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

Abstract

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×, 3× or 5× the maximum exposure dose (6.3mg/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 6.3mg/kg (1×); Group 3: afoxolaner chews administered at a dosage of at least 18.9 mg/kg (3×); and Group 4: afoxolaner chews administered at a dosage of at least 31.5mg/kg (5×). 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 31.5mg/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 5× the maximum exposure dose in dogs as young as 8 weeks of age.

Safety evaluation of orally administered afoxolaner and milbemycin oxime in eight‐week‐old dogs

“…Safety testing in a study similar to the study described in this article showed that the formulation containing only afoxolaner was safe when administered to dogs between 8 and 24 weeks of age, six separate times at up to 5× the maximum exposure dose (Drag et al ., ). Milbemycin oxime at doses of 2.5, 7.5, and 12.5 mg/kg body weight was proven to be safe to dogs when administered for three consecutive days (Jung et al ., ).…”

Efficacy of Once-Monthly Doses of Oral Afoxolaner and Afoxolaner/Milbemycin Oxime in a Well-Controlled Study for the Treatment of Canine Generalized Demodicosis

“…An initial clinical assessment of afoxolaner activity against demodectic mange was done with bi-weekly treatments with NexGard at Days 0, 14 and then 28, a strategy based, in-part, on rapidly achieving a steady state of afoxolaner in the blood of the study animals [6]. This was considered to be safe because this schedule was performed in the NexGard and NexGard Spectra target animal safety studies conducted for its registration in the USA and Europe [7] [8]. In those studies, no adverse events related to the treatment were observed during the time that three doses were administered biweekly.…”

“…Afoxolaner is an isoxazoline administered monthly to protect dogs against fleas and ticks [NexGard ® (afoxolaner) and NexGard Spectra ® (afoxolaner/milbemycin oxime)] [6] [7] [8]. It is administered at the minimum therapeutic dose of 2.5 mg/kg.…”

The intravenous and oral pharmacokinetics of afoxolaner and milbemycin oxime when used as a combination chewable parasiticide for dogs

“…Afoxolaner administered in the palatable NexGard™ (Merial) soft chewable formulation has high bioavailability (73.9%) resulting in fast, consistent absorption and predictable pharmacokinetics (PK) (Letendre et al ., ). The NexGard margin of safety is high and treatment was demonstrated to be safe in puppies given multiple doses of up to 5 times the maximum exposure dose of 6.3 mg/kg (Drag et al ., ). Afoxolaner plasma concentrations are strongly correlated with the efficacy against both fleas and ticks (Letendre et al ., ).…”