Kevin C. KobylinskiPodjanee JittamalaBorimas HanboonkunupakarnSasithon PukrittayakameeKanchana PantuwatanaSiriporn PhasomkusolsilSilas A. DavidsonMarkus WinterbergRichard M. HoglundMavuto MukakaRob W. van der PluijmArjen DondorpNicholas P.J. DayNicholas J. WhiteJoel TarningArmed Forces Research Institute of Medical Sciences, ThailandWalter Reed Army Institute of ResearchMahidol UniversityNuffield Department of Clinical MedicineRoyal Institute of Thailand2020-01-272020-01-272019-01-01Clinical Pharmacology and Therapeutics. (2019)15326535000992362-s2.0-85077397164https://repository.li.mahidol.ac.th/handle/20.500.14594/52374© 2019 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics. 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.Mahidol UniversityMedicinePharmacology, Toxicology and PharmaceuticsArticleSCOPUS10.1002/cpt.1716