Milbemycin oxime: mechanism of action, pharmacokinetics and safety

General Description

Milbemycin oxime is a broad-spectrum parasiticide used in combination with afoxolaner to effectively treat internal and external parasites in dogs. It works by binding to specific sites on parasite cells, increasing the release of inhibitory neurotransmitter GABA and preventing nerve signal transmission. This leads to neuro-paralysis and eventual death of the parasites. Milbemycin oxime has rapid absorption, reaching peak plasma concentration in 1-2 hours, and a half-life of 1.6 days. It distributes widely in the body and is efficiently eliminated. Safety studies have shown that afoxolaner/milbemycin oxime chewables are well-tolerated, with no significant adverse effects observed. Overall, milbemycin oxime's mechanism of action and favorable pharmacokinetics contribute to its efficacy and safety in controlling parasitic infestations in dogs.

Figure 1. Tablets of milbemycin oxime

Mechanism of action

Milbemycin oxime is a broad-spectrum parasiticide that exhibits excellent efficacy against both internal and external parasites, particularly nematodes and arthropods. Its mechanism of action involves binding to specific high-affinity sites on the target parasite cells, which affects the permeability of the cell membrane to chloride ions (Cl-). This, in turn, leads to an increase in the release of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the nerve cells of nematodes and the muscle cells of arthropods. By opening glutamate-gated chloride channels, milbemycin oxime enhances the permeability of the nerve membrane to chloride ions, thereby preventing the transmission of nerve signals. This ultimately results in neuro-paralysis, causing the muscle cells to lose their ability to contract, leading to the death of the parasites. Milbemycin oxime's unique mechanism of action, coupled with its broad-spectrum activity, makes it a valuable tool in the control and prevention of parasitic infestations in both animals and humans. Its ability to effectively target and eliminate various parasites contributes to its widespread use in veterinary medicine for the treatment of internal and external parasites in animals. ¹

Pharmacokinetics

The pharmacokinetic characteristics of milbemycin oxime were evaluated in dogs following oral administration of NexGard Spectra®, a fixed combination chewable formulation with afoxolaner. The absorption of milbemycin oxime was rapid, providing the minimum effective dose of 0.5 mg/kg. The time to reach maximum plasma concentration (tmax) for milbemycin oxime was 1-2 hours. The terminal plasma half-life (t1/2) was determined to be 1.6 ± 0.4 days, and the oral bioavailability was 80.5% for milbemycin oxime A3 and 65.1% for milbemycin oxime A4. The volume of distribution (Vd) for milbemycin oxime A3 and A4 was approximately 2.7 L/kg, indicating widespread distribution throughout the body. The systemic clearance (Cls) for milbemycin oxime A3 and A4 was 75 ± 22 and 41 ± 12 mL/h/kg, respectively, suggesting efficient elimination from the body. The pharmacokinetic profile of milbemycin oxime, when combined with afoxolaner, supports its rapid onset and sustained efficacy against external parasites. Additionally, milbemycin oxime is known for its activity against internal parasites. Overall, these findings highlight the favorable pharmacokinetic characteristics of milbemycin oxime in supporting its therapeutic effects in dogs. ²

Safety

The safety of milbemycin oxime, in combination with afoxolaner, was assessed in accordance with regulatory requirements in a study involving 8-week-old Beagle dogs. The dogs were administered the combination orally in a soft chewable formulation at doses equivalent to 1×, 3×, or 5× the maximum exposure dose. The study lasted for 126 days, during which the dogs underwent regular physical examinations, clinical pathology analysis, and blood collections for assessing plasma concentrations of afoxolaner and milbemycin oxime. The results of the study demonstrated that the administration of afoxolaner/milbemycin oxime did not cause any treatment-related changes in growth, physical variables, clinical pathology variables, or histological examination of tissues. No clinically significant health abnormalities or signs of sensitivity to milbemycin oxime were observed. Occasional instances of vomiting and diarrhea were observed across all groups, including the control group. Based on these findings, it was concluded that afoxolaner/milbemycin oxime soft chewables are safe for repeated administration at doses up to 5× the maximum exposure dose in dogs as young as 8 weeks of age. The study provides evidence of the safety profile of milbemycin oxime, a macrocyclic lactone, when used in combination with afoxolaner. ³

Reference

1. Di Cesare A, Morelli S, Morganti G, et al. Efficacy of milbemycin oxime/afoxolaner chewable tablets (NEXGARD SPECTRA®) against Capillaria aerophila and Capillaria boehmi in naturally infected dogs. Parasit Vectors, 2021, 14(1):143.

2. Letendre L, Harriman J, Drag M, Mullins A, Malinski T, Rehbein S. The intravenous and oral pharmacokinetics of afoxolaner and milbemycin oxime when used as a combination chewable parasiticide for dogs. J Vet Pharmacol Ther, 2017, 40(1):35-43.

3. Drag M, Saik J, Harriman J, Letendre L, Yoon S, Larsen D. Safety evaluation of orally administered afoxolaner and milbemycin oxime in eight-week-old dogs. J Vet Pharmacol Ther, 2017, 40(5):447-453.