Safety, pharmacokinetics, and mosquito-lethal effects of ivermectin in combination with dihydroartemisinin-piperaquine and primaquine in healthy adult Thai subjects.
Kobylinski KC., Jittamala P., Hanboonkunupakarn B., Pukrittayakamee S., Pantuwatana K., Phasomkusolsil S., Davidson SA., Winterberg M., Hoglund RM., Mukaka M., van der Pluijm RW., Dondorp A., Day NPJ., White NJ., Tarning J.
Mass administration of antimalarial drugs and ivermectin are being considered as potential accelerators of malaria elimination. The safety, tolerability, pharmacokinetics and mosquito-lethal effects of combinations of ivermectin, dihydroartemisinin-piperaquine, and primaquine were evaluated. Co-administration of ivermectin and dihydroartemisinin-piperaquine, resulted in increased ivermectin concentrations with corresponding increases in mosquito-lethal effect across all subjects. Exposure to piperaquine was also increased when co-administered with ivermectin, but electrocardiograph QT-interval prolongation was not increased. One subject had transiently impaired liver function. Ivermectin mosquito-lethal effect was greater than predicted previously against the major Southeast Asian malaria vectors. Both Anopheles dirus and Anopheles minimus mosquito mortality was increased substantially (20-fold and 35-fold increase, respectively) when feeding on volunteer blood after ivermectin administration compared to in vitro ivermectin-spiked blood. This suggests the presence of ivermectin metabolites that impart mosquito-lethal effects. Further studies of this combined approach to accelerate malaria elimination are warranted.