Safety, Pharmacokinetics, and Mosquito-Lethal Effects of Ivermectin in Combination With Dihydroartemisinin-Piperaquine and Primaquine in Healthy Adult Thai Subjects

Clin Pharmacol Ther. 2020 May;107(5):1221-1230. doi: 10.1002/cpt.1716. Epub 2019 Dec 27.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Anopheles / drug effects
  • Antimalarials / administration & dosage
  • Antimalarials / adverse effects
  • Antimalarials / pharmacokinetics
  • Artemisinins / administration & dosage*
  • Artemisinins / adverse effects
  • Artemisinins / pharmacokinetics
  • Drug Interactions
  • Drug Therapy, Combination
  • Female
  • Humans
  • Insecticides / administration & dosage
  • Insecticides / adverse effects
  • Insecticides / pharmacokinetics
  • Ivermectin / administration & dosage*
  • Ivermectin / adverse effects
  • Ivermectin / pharmacokinetics
  • Malaria / prevention & control
  • Male
  • Middle Aged
  • Primaquine / administration & dosage*
  • Primaquine / adverse effects
  • Primaquine / pharmacokinetics
  • Quinolines / administration & dosage*
  • Quinolines / adverse effects
  • Quinolines / pharmacokinetics
  • Thailand
  • Young Adult

Substances

  • Antimalarials
  • Artemisinins
  • Insecticides
  • Quinolines
  • artenimol
  • Ivermectin
  • piperaquine
  • Primaquine