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. 2017 Jul 7;16(1):280.
doi: 10.1186/s12936-017-1923-8.

Ivermectin susceptibility and sporontocidal effect in Greater Mekong Subregion Anopheles

Kevin C Kobylinski  1   2 , Ratawan Ubalee  3 , Alongkot Ponlawat  3 , Chanyapat Nitatsukprasert  3 , Siriporn Phasomkulsolsil  3 , Thanaporn Wattanakul  4 , Joel Tarning  4   5 , Kesara Na-Bangchang  6 , Patrick W McCardle  3   7 , Silas A Davidson  3   7 , Jason H Richardson  3   7   8
Affiliations

Ivermectin susceptibility and sporontocidal effect in Greater Mekong Subregion Anopheles

Kevin C Kobylinski et al. Malar J. .

Abstract

Background: Novel vector control methods that can directly target outdoor malaria transmission are urgently needed in the Greater Mekong Subregion (GMS) to accelerate malaria elimination and artemisinin resistance containment efforts. Ivermectin mass drug administration (MDA) to humans has been shown to effectively kill wild Anopheles and suppress malaria transmission in West Africa. Preliminary laboratory investigations were performed to determine ivermectin susceptibility and sporontocidal effect in GMS Anopheles malaria vectors coupled with pharmacokinetic models of ivermectin at escalating doses.

Methods: A population-based pharmacokinetic model of ivermectin was developed using pre-existing data from a clinical trial conducted in Thai volunteers at the 200 µg/kg dose. To assess ivermectin susceptibility, various concentrations of ivermectin compound were mixed in human blood meals and blood-fed to Anopheles dirus, Anopheles minimus, Anopheles sawadwongporni, and Anopheles campestris. Mosquito survival was monitored daily for 7 days and a non-linear mixed effects model with probit analyses was used to calculate concentrations of ivermectin that killed 50% (LC50) of mosquitoes for each species. Blood samples were collected from Plasmodium vivax positive patients and offered to mosquitoes with or without ivermectin at the ivermectin LC25 or LC5 for An. dirus and An. minimus.

Results: The GMS Anopheles displayed a range of susceptibility to ivermectin with species listed from most to least susceptible being An. minimus (LC50 = 16.3 ng/ml) > An. campestris (LC50 = 26.4 ng/ml) = An. sawadwongporni (LC50 = 26.9 ng/ml) > An. dirus (LC50 = 55.6 ng/ml). Mosquito survivorship results, the pharmacokinetic model, and extensive safety data indicated that ivermectin 400 µg/kg is the ideal minimal dose for MDA in the GMS for malaria parasite transmission control. Ivermectin compound was sporontocidal to P. vivax in both An. dirus and An. minimus at the LC25 and LC5 concentrations.

Conclusions: Ivermectin is lethal to dominant GMS Anopheles malaria vectors and inhibits sporogony of P. vivax at safe human relevant concentrations. The data suggest that ivermectin MDA has potential in the GMS as a vector and transmission blocking control tool to aid malaria elimination efforts.

Keywords: Anopheles; Greater Mekong Sub-region; Ivermectin; Plasmodium.

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Figures

Fig. 1
Fig. 1
Experimental design for determining the effect of ivermectin against Plasmodium vivax in Anopheles dirus. Each timeline depicts when ivermectin (red arrow), control (blue arrow), and P. vivax (green) blood meals were offered to mosquitoes and when dissections (orange triangle) occurred
Fig. 2
Fig. 2
Visual predictive check of final population pharmacokinetic model of ivermectin in healthy volunteers. Open circles represent observed concentrations; solid and dashed lines represent the 5th, 50th, and 95th percentiles of the observed data; shaded areas represent the 95% confidence intervals of the simulated 5th, 50th and 95th percentiles (n = 2000)
Fig. 3
Fig. 3
Simulation population mean pharmacokinetic profiles of ivermectin at single oral doses of 200, 400 and 800 µg/kg, based on final population pharmacokinetic model
Fig. 4
Fig. 4
Anopheles survival post ingestion of ivermectin compound by day. Boxed legends represent the concentrations of ivermectin imbibed by each species. Not all concentrations included in the lethal concentration analyses are displayed here. Each line represents 1–6 replicates with standard error
Fig. 5
Fig. 5
Plasmodium vivax oocyst prevalence (a) and intensity (b) in Anopheles dirus when ivermectin co-ingested with parasites. Plasmodium vivax oocyst prevalence (a) and intensity (b) in An. dirus when ivermectin LC25 (38.1 ng/ml) and LC5 (22.1 ng/ml) co-ingested with parasites at DPI 0. Oocyst prevalence was significantly reduced at the LC25 and LC5 concentrations as determined by the Fishers Exact test. Oocyst intensity was significantly reduced at the LC25 and LC5 concentrations as determined by the by the Mann–Whitney U test. Prevalence error bars represent standard error
Fig. 6
Fig. 6
Plasmodium vivax oocyst prevalence (a) and intensity (b) in Anopheles minimus when ivermectin co-ingested with parasites. Plasmodium vivax oocyst prevalence (a) and intensity (b) in An. minimus when ivermectin LC25 (11.3 ng/ml) and LC5 (6.7 ng/ml) co-ingested with parasites at DPI 0. Oocyst prevalence was significantly reduced at the LC25 and LC5 concentrations as determined by the Fishers Exact test. Oocyst intensity was significantly reduced at the LC5 but not the LC25 concentration as determined by the by the Mann–Whitney U test. Prevalence error bars represent standard error
Fig. 7
Fig. 7
Plasmodium vivax infection prevalence in Anopheles dirus when ivermectin ingested at DPI −3, 6, and 9. Plasmodium vivax infection prevalence in An. dirus when ivermectin LC5 (22.1 ng/ml) ingested at DPI −3 and LC25 (38.1 ng/ml) ingested at DPI 6 and 9. Oocyst prevalence was not significantly reduced at the DPI −3, 6, or 9 time points as determined by the Fishers Exact test. Prevalence error bars represent standard error
Fig. 8
Fig. 8
Survivorship of Anopheles dirus when ivermectin ingested with and without Plasmodium vivax. Survivorship of An. dirus when ivermectin LC25 (38.1 ng/ml) ingested with and without P. vivax. Survivorship between mosquito treatment groups was not significantly different as determined by the Mantel–Cox method
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