Safety of Credelio Quattro in MDR1 mutant Collie dogs

Abstract

BACKGROUND: Multidrug resistance-1 (MDR1) mutant dogs have diminished or lack P-glycoprotein (Pgp) expression at the blood-brain barrier and are therefore more susceptible to neurotoxicity caused by macrocyclic lactones and other Pgp substrates due to increased drug penetration into the brain. Therefore, the safety of products containing macrocyclic lactones are required to be evaluated in this sensitive population. Credelio Quattro (lotilaner, moxidectin, praziquantel, and pyrantel chewable tablets) is a novel endectocide for monthly oral administration in dogs. As moxidectin is a macrocyclic lactone, Credelio Quattro was administered to homozygous MDR1 mutant Collie dogs to evaluate the safety of the product. METHODS: The study employed a completely randomized and blinded design, where dogs were allocated to one of four treatment groups. A total of 32 dogs were divided into 4 groups (placebo control, 1×, 2×, or 5×, the maximum recommended labeled dose of Credelio Quattro) each consisting of 8 dogs. Treatment was administered on 3 consecutive occasions, 28 days apart. Dogs were evaluated pre-dose and through 72-h post-treatment using the avermectin sensitive (AVS) categories of seizures or convulsions, ataxia, depression, mydriasis, muscle tremors, and salivation/drooling/vomiting. The assessment of safety was based on AVS scores, general health observations, body weight, and physical examinations. RESULTS: Credelio Quattro was well tolerated with no serious adverse events. There were no incidents of seizures or convulsions, ataxia, mydriasis, or muscle tremors observed. Salivation/drooling/vomiting was the most frequent observation, occurring in all groups, and most frequently in the 5× group. Vomiting is a dose-dependent effect observed for Credelio Quattro in healthy dogs and is therefore unlikely to represent a neurological effect in MDR1 dogs. Depression was observed in one dog in each of the 0×, 2×, and 5× groups. This was likely a spurious result versus true toxicity, as the sign was subtle and occurred singularly including at 0×. For all AVS signs, the events were transient, and dogs recovered without any intervention. CONCLUSIONS: Credelio Quattro was well tolerated and is safe in MDR1 mutant dogs up to 5× the maximum recommended dose following three consecutive monthly administrations.