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Pharmacological particulars
Pharmacotherapeutic group: antiparasitic products, ectoparasiticides, endectocides for systemic use (milbemycin combinations)
ATC vet code: QP54AB51
Pharmacodynamic properties
Lotilaner is an insecticide and acaricide of the isoxazoline family. It is a pure enantiomer that is active against adult ticks such as Dermacentor reticulatus, Ixodes hexagonus, I. ricinus, Rhipicephalus sanguineus, adult fleas such as Ctenocephalides felis and C. canis as well as Demodex canis mites.
Lotilaner is a potent inhibitor of gamma–aminobutyric acid (GABA)-gated chloride channels and to a lesser extent of glutamate-gated chloride ion channels of insects and ticks, resulting in rapid death of ticks and fleas. The activity of lotilaner has not been found to be affected by resistance to organochlorines (cyclodienes, e.g. dieldrin), phenylpyrazoles (e.g. fipronil), neonicotinoids (e.g. imidacloprid), formamidines (e.g. amitraz) and pyrethroids (e.g. cypermethrin).
For ticks, the onset of efficacy is within 48 hours of attachment for one month after product administration. Existing I. ricinus ticks present on the dog prior to administration are killed within 8 hours.
For fleas, the onset of efficacy is within 4 hours of being infested for one month after product administration. Fleas present on the dog prior to administration are killed within 6 hours.
The veterinary medicinal product kills existing and newly emerged flea infestations on dogs before the female can lay eggs. Therefore, the product breaks the flea life cycle and prevents environmental flea contamination in areas to which the dog has access.
Milbemycin oxime:
Milbemycin oxime is a systemically active macrocyclic lactone isolated from the fermentation of Streptomyces hygroscopicus var. aureolacrimosus. It contains two major factors, A3 and A4 (ratio of A3:A4 is 20:80). Milbemycin oxime is an antiparasitic endectocide with activity against mites, larval and adult stages of nematodes as well as larvae (L3/L4) of Dirofilaria immitis.
The activity of milbemycin oxime is related to its action on invertebrate neurotransmission. Milbemycin oxime, like avermectins and other milbemycins, increases nematode and insect membrane permeability to chloride ions via glutamate-gated chloride ion channels. This leads to hyperpolarisation of the neuromuscular membrane and flaccid paralysis and death of the parasite.
Pharmacokinetic particulars
Lotilaner is readily absorbed following oral administration and peak plasma concentration is reached within 3‒5 hours. Milbemycin A3 5-oxime and milbemycin A4 5-oxime are also rapidly absorbed following oral administration with a Tmax of approximately 2‒4 hours for each drug substance. Food enhances the absorption of both lotilaner and milbemycin oxime. The bioavailability of lotilaner is 75% and that of milbemycin (A3 and A4 5-oximes) is approximately 60%.
Lotilaner and milbemycin A3 and A4 5-oximes are extensively distributed in dogs where volume of distribution after intravenous administration is 3‒4 L/kg. Plasma protein binding is high for both lotilaner and milbemycin oxime (> 95%).
Metabolism and Excretion
Lotilaner is metabolized to a small extent into more hydrophilic compounds which are observed in faeces and urine.
The major route of elimination for lotilaner is biliary excretion, with renal excretion being the minor route of elimination (less than 10% of the dose). The terminal half-life is approximately 24 days. This long terminal half-life provides effective blood concentrations for the entire duration of the inter-dosing interval. With repeated monthly doses, slight accumulation is observed with steady state being reached after the fourth monthly dose.
The primary faecal and urinary metabolites of milbemycin oxime in dog were identified as glucuronide conjugates of milbemycin A3 or A4 5-oximes, dealkylated milbemycin A3 or A4 5-oximes, and hydroxylated milbemycin A4 5-oxime. Hydroxymilbemycin A4 5-oxime was detected only in plasma, but not in urine or faeces, suggesting predominant excretion of conjugated metabolites in the dog.
Milbemycin A4 5-oxime eliminates more slowly than milbemycin A3 5-oxime (clearance after intravenous administration was 47.0 and 106.8 mL/h/kg, respectively) resulting in exposure (AUC) to milbemycin A4 that is higher than to milbemycin A3 5-oxime. The mean elimination half-lives were 27 hours for A3 and 57 hours for A4. Excretion of milbemycin A3 and A4 5-oxime is primarily via faeces, and also to a lesser extent in the urine.