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In summary, this study shows that the pharmacokinetics of drugs can be investigated and modulated in an Ae. Ritonavir increased the lag phase of ivermectin by 11.4 h (CI 90%: 8.7–14.2 h) resulting in an increased exposure (+29%) and an enhanced mosquitocidal effect.
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By contrast, ketoconazole, ritonavir, and piperonyl butoxide were immediately excreted following first order elimination, whereas rifampicin accumulated over days in the mosquitoes. The kinetics of ivermectin were characterised by an initial lag phase of 18.5 h (CI 90%: 17.0–19.8 h) followed by a slow zero-order elimination rate of 5.5 pg/h (CI 90%: 5.1–5.9 pg/h). 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 (R 2: 0.99). Lastly, the drug effect of the treatments was examined. Primary pharmacokinetic parameters and extent of drug-drug interactions were calculated by pharmacometric modelling. Drug concentrations were quantified by LC-MS/MS at selected time points post-feeding. Female Aedes aegypti mosquitoes were fed with human blood containing either ivermectin alone or ivermectin in combination with ketoconazole, rifampicin, ritonavir, or piperonyl butoxide. 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.
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Mass drug administration of endectocides to humans and livestock is a promising complementary approach to current insecticide-based vector control measures. Mosquitoes are vectors of major diseases such as dengue fever and malaria.