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Safety, Pharmacokinetics, and Mosquito‐Lethal Effects of Ivermectin in Combination With Dihydroartemisinin‐Piperaquine and Primaquine in Healthy Adult Thai Subjects
Author(s) -
Kobylinski Kevin C.,
Jittamala Podjanee,
Hanboonkunupakarn Borimas,
Pukrittayakamee Sasithon,
Pantuwatana Kanchana,
Phasomkusolsil Siriporn,
Davidson Silas A.,
Winterberg Markus,
Hoglund Richard M.,
Mukaka Mavuto,
Pluijm Rob W.,
Dondorp Arjen,
Day Nicholas P.J.,
White Nicholas J.,
Tarning Joel
Publication year - 2020
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1716
Subject(s) - ivermectin , dihydroartemisinin , primaquine , piperaquine , pharmacology , malaria , pharmacokinetics , medicine , anopheles gambiae , biology , artemisinin , plasmodium falciparum , immunology , veterinary medicine , chloroquine
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. Coadministration 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 coadministered 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 with 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.