TY - JOUR
T1 - Safety, Pharmacokinetics, and Mosquito-Lethal Effects of Ivermectin in Combination With Dihydroartemisinin-Piperaquine and Primaquine in Healthy Adult Thai Subjects
AU - Kobylinski, Kevin C.
AU - Jittamala, Podjanee
AU - Hanboonkunupakarn, Borimas
AU - Pukrittayakamee, Sasithon
AU - Pantuwatana, Kanchana
AU - Phasomkusolsil, Siriporn
AU - Davidson, Silas A.
AU - Winterberg, Markus
AU - Hoglund, Richard M.
AU - Mukaka, Mavuto
AU - van der Pluijm, Rob W.
AU - Dondorp, Arjen
AU - Day, Nicholas P. J.
AU - White, Nicholas J.
AU - Tarning, Joel
PY - 2020/5/1
Y1 - 2020/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85077397164&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/cpt.1716
DO - https://doi.org/10.1002/cpt.1716
M3 - Article
C2 - 31697848
SN - 0009-9236
VL - 107
SP - 1221
EP - 1230
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 5
ER -