Monepantel is ananthelmintic approved for use in sheep and cattle to control gastrointestinalnematodes. It belongs to a new class of anthelmintics called aminoacetonitrile derivatives (AAD).[2][3][4] It is marketed byElanco asZolvix (United Kingdom) as a single active, orZolvix Plus (New Zealand, Australia) in combination with the macrocyclic lactoneabamectin.
Aminoacetonitrile derivatives were originally discovered by scientists working atNovartis to have high potency againstin vitro parasite models.[2] Compounds were further validated in rodent parasite models following oral and subcutaneous administration. A lead compound AAD 1566 was isolated that eliminated pathogenic nematodes at doses of 2.5 mg/kg in sheep and 5.0 mg/kg in cattle and was named monepantel.[4] The structure and anthelmintic activity of monepantel were first described in patent WO2005/44784.[5]
It was first registered in 2009 for use in sheep in New Zealand to control adult and immature L4 stages of all major GI nematodes.
Studies using a molecular genetic approach inC. elegans indicated that AADs worked via ligand-gated ion channels.[2] Further research identified the DEG-3 subfamily of nicotinic acetylcholine receptors as the likely putative target of monepantel.[6] Rufeneret al published in 2009 that MPTL-1 was the likely binding site of monepantel inHaemonchus contortus.[7] The DEG-3 subfamily is absent in mammals and this might explain the minimal toxicity of monepantel. It has been shown the AADs and monepantel in particular potentiate DEG-3/Des-2 receptors ofH. contortus acting as an agonist of the nicotinic acetylcholine receptor producing spastic paralysis and death of the nematode.[7] Interestingly, only the (S)-enantiomer was found to be active against gastrointestinal nematodes.[4]
After administration to either sheep or cattle, monepantel is rapidly converted to its major metabolite monepantel sulfone, which also has similar levels of efficacy against gastrointestinal nematodes compared to the parent compound.[3][8]
Data on the pharmacokinetics of monepantel in sheep following intravenous and oral dosing have been published.[3] The sulfone metabolite was rapidly formed and predominated after four hours regardless of the route of administration. Following oral dosing of sheep with 3 mg/kg of monepantel the Tmax, Cmax and AUC of monepantel were 16 h, 17.9 ng/mL and 671 ng.h/mL, while for the sulfone metabolite they were 24 h, 94.3 ng/mL and 11125 ng.h/mL.
After oral treatment of dairy cattle, monepantel and monepantel sulfone are found in the plasma and milk.[8] Monepantel is rapidly converted to the major metabolite monepantel sulfone which is then found in much higher concentration and lasts much longer in tissues than the parent compound. In one study in calves dosed orally with 2.5 mg/kg of monepantel the Tmax was 8 hours, Cmax 21.5 ng/mL and AUC 2174 ng.h/mL, while the major metabolite monepantel sulfone had a Tmax of 41.3 hours, Cmax of 96.8 ng/mL and AUC of 10242 ng.h.mL.[9] In dairy cows given monepantel orally the major metabolite observed in plasma and milk was monepantel sulfone.[8] Monepantel was detected for up to 33 hours in milk and the sulfone metabolite up to 177 hours. The milk concentrations of the sulfone metabolite were substantially higher than the plasma with the AUC being nearly 7 fold higher in milk than plasma. There was no significant change in the pharmacokinetics with the addition ofoxfendazole.
In sheep, monepantel is considered to have a good safety profile. Weaned lambs treated with 1x, 3x and 5x doses every 21 days for 8 occasions were found to be unaffected with no adverse events noted.[11] Between control lambs and treated lambs there were no significant differences in body weight, organ weight, blood chemistry and haematology and coagulation detected.
Due to having a different mode of action and molecular target than other anthelmintics, monepantel will generally kill nematodes resistant to the other major classes of anthelmintics. However, within a few years of monepantel's release on the market, anthelmintic resistance was reported in several countries including Australia,[12] New Zealand,[13] Uruguay,[14] Brazil,[15] the Netherlands[16] and the United Kingdom.[17] These reports have shown a number of species were resistant to monepantel, includingHaemonchus contortus,Teladorsagia circumcincta,Trichostrongylus colubriformis, andOesophagostomum.
^Sales, Narelle; Love, Stephen (2016-09-15). "Resistance of Haemonchus sp. to monepantel and reduced efficacy of a derquantel / abamectin combination confirmed in sheep in NSW, Australia".Veterinary Parasitology.228:193–196.doi:10.1016/j.vetpar.2016.08.016.ISSN1873-2550.PMID27692326.
^Scott, I.; Pomroy, W. E.; Kenyon, P. R.; Smith, G.; Adlington, B.; Moss, A. (2013-11-15). "Lack of efficacy of monepantel against Teladorsagia circumcincta and Trichostrongylus colubriformis".Veterinary Parasitology.198 (1–2):166–171.doi:10.1016/j.vetpar.2013.07.037.ISSN1873-2550.PMID23953148.
^Cintra, M. C. R.; Teixeira, V. N.; Nascimento, L. V.; Sotomaior, C. S. (2016-01-30). "Lack of efficacy of monepantel against Trichostrongylus colubriformis in sheep in Brazil".Veterinary Parasitology.216:4–6.doi:10.1016/j.vetpar.2015.11.013.ISSN1873-2550.PMID26801587.
