Evaluation of the safety of spinosad and milbemycin 5-oxime orally administered to Collies with the MDR1 gene mutation

Abstract

Results indicated that oral administration of spinosad at 300 mg/kg alone or in combination with MBO at doses up to 10 mg/kg did not cause signs of AVM-MB toxicosis in AVM-MB-sensitive dogs with the MDR1 gene mutation.

Toxicology of Avermectins and Milbemycins (Macrocylic Lactones) and the Role of P-Glycoprotein in Dogs and Cats

“…59 A different study assessed the effects of co-administration of spinosad and milbemycin in collies with the ABCB1-1 Δmutation. 60 Up to 10 times the heartworm preventative dose of milbemycin along with spinosad at either 3 or 5 times the labeled therapeutic dose did not result in signs of milbemycin toxicosis. It is interesting to speculate whether milbemycin has a relatively poorer affinity for P-gp, as does moxidectin, 50 compared to ivermectin, which might explain the difference between the 2 studies.…”

Pharmacokinetic Interaction of the Antiparasitic Agents Ivermectin and Spinosad in Dogs

“…When spinosad was administered with ivermectin at its heartworm prevention dose, its safety has not been questioned on the basis of field experience. In a recent study, the safety of extra-label doses of the anthelmintic milbemycin oxime with concurrent spinosad treatment has also been confirmed (Sherman et al, 2010).…”

Evaluation of the biliary and brain distribution of technetium Tc 99m sestamibi in healthy dogs with the ABCB1 wildtype genotype before and after treatment with spinosad

“…Studies 30,36 conducted to investigate the safety of spinosad in clinically normal dogs and dogs with the ABCB1-1∆ mutation have been performed but have failed to directly address the concerns raised by the FDA. Studies 30,36 conducted to investigate the safety of spinosad in clinically normal dogs and dogs with the ABCB1-1∆ mutation have been performed but have failed to directly address the concerns raised by the FDA.…”

“…Studies 30,36 conducted to investigate the safety of spinosad in clinically normal dogs and dogs with the ABCB1-1∆ mutation have been performed but have failed to directly address the concerns raised by the FDA. It is interesting that none of the ivermectin-sensitive dogs with the ABCB1-1∆ mutation in that study 30 developed signs of avermectin toxicosis when treated with the 10 mg/kg dose of milbemycins; in another study, 37 all of the ivermectin-sensitive dogs (ABCB1 genotype unknown) developed mild transient signs of toxicosis after receiving a 10 mg/kg dose of milbemycin. Milbemycin is an avermectin similar to ivermectin and has toxic effects similar to those of ivermectin when administered at high, extralabel doses to dogs with the ABCB1-1∆ mutation.…”

“…5 However, dogs that have deficient P-glycoprotein function (intrinsic or extrinsic) markedly accumulate increased concentrations of ivermectin within their CNS tissues, which causes abnormal neurologic signs in dogs treated with extralabel doses of ivermectin. 30 Therefore, although spinosad is unlikely to be a substrate for P-glycoprotein, the role of spinosad as a potential inhibitor of P-glycoprotein has not been investigated. 28,29 Spinosad is marketed as an oral chewable product that is administered monthly for flea prevention in dogs.…”