The pharmacokinetics and drug-drug interactions of ivermectin in Aedes aegypti mosquitoes

Abstract

Mosquitoes are vectors of major diseases such as dengue fever and malaria. Mass drug administration of endectocides to humans and livestock is a promising complementary approach to current insecticide-based vector control measures. The aim of this study was to establish an insect model for pharmacokinetic and drug-drug interaction studies to develop sustainable endectocides for vector control. Female Aedes aegypti mosquitoes were fed with human blood containing either ivermectin alone or ivermectin in combination with ketoconazole, rifampicin, ritonavir, or piperonyl butoxide. Drug concentrations were quantified by LC-MS/MS at selected time points post-feeding. Primary pharmacokinetic parameters and extent of drug-drug interactions were calculated by pharmacometric modelling. Lastly, the drug effect of the treatments was examined. The mosquitoes could be dosed with a high precision (%CV: ≤13.4%) over a range of 0.01–1 μg/ml ivermectin without showing saturation (R2: 0.99). The kinetics of ivermectin were characterised by an initial lag phase of 18.5 h (CI90%: 17.0–19.8 h) followed by a slow zero-order elimination rate of 5.5 pg/h (CI90%: 5.1–5.9 pg/h). By contrast, ketoconazole, ritonavir, and piperonyl butoxide were immediately excreted following first order elimination, whereas rifampicin accumulated over days in the mosquitoes. Ritonavir increased the lag phase of ivermectin by 11.4 h (CI90%: 8.7–14.2 h) resulting in an increased exposure (+29%) and an enhanced mosquitocidal effect. In summary, this study shows that the pharmacokinetics of drugs can be investigated and modulated in an Ae. aegypti animal model. This may help in the development of novel vector-control interventions and further our understanding of toxicology in arthropods.

Next Generation Neuropeptide Y Receptor Small Molecule Agonists Inhibit Mosquito Biting Behavior

“…More recent work has established novel models for pharmacokinetic assays in mosquitoes by delivering ivermectin and cytochrome P450 modulators in blood, using liquid chromatography with tandem mass spectrometry (LC-MS/MS) to quantify clearance rates after feeding, and modeling primary pharmacokinetic parameters and drug/drug interactions. Ivermectin clearance kinetics differ between mosquitoes compared to mammals, and individual P450 modulators were eliminated with differing kinetics in mosquitoes (Duthaler et al, 2021). However, detection remains a limiting factor.…”

Next-generation neuropeptide Y receptor small-molecule agonists inhibit mosquito-biting behavior

“…More recent work has established novel models for pharmacokinetic assays in mosquitoes by delivering ivermectin and cytochrome P450 modulators in blood, using liquid chromatography with tandem mass spectrometry (LC–MS/MS) to quantify clearance rates after feeding and modeling primary pharmacokinetic parameters and drug/drug interactions. Ivermectin clearance kinetics differ between mosquitoes and mammals, and individual P450 modulators were eliminated with differing kinetics in mosquitoes [ 41 ]. However, detection remains a limiting factor.…”

Pharmacokinetics of ivermectin metabolites and their activity against Anopheles stephensi mosquitoes

“…The same conclusion was drawn by Hugnet et al, since ketoconazole did not decrease M1 levels in dogs but significantly increased exposure to ivermectin [ 53 ]. On the contrary, ketoconazole did not alter the PK of ivermectin in invertebrates, most likely because it is rapidly excreted by Aedes aegypti mosquitoes [ 16 ]. Finally, the CYP activity in rats was increased by administering either rifampicin or phenobarbital daily for 1 week, but still the disposition kinetics was only modified for ivermectin—and not the investigated metabolites [ 55 ].…”

“…Exposure to ivermectin concentrations in the low ng/mL range decreases the survival and fertility of mosquitoes. The concentration that kills 50% of mosquitoes (LC 50 ) within 7-days ranges from 3 to 55 ng/mL in Anopheles spp., and 178–187 ng/mL in Aedes aegypti [ 16 – 19 ].…”