Safety, Pharmacokinetics, and Mosquito‐Lethal Effects of Ivermectin in Combination With Dihydroartemisinin‐Piperaquine and Primaquine in Healthy Adult Thai Subjects
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. Coadmi...
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| Published in | Clinical pharmacology and therapeutics Vol. 107; no. 5; pp. 1221 - 1230 |
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| Main Authors | , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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United States
01.05.2020
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| 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. |
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| AbstractList | 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. |
| Author | Davidson, Silas A. Kobylinski, Kevin C. White, Nicholas J. Hoglund, Richard M. Pukrittayakamee, Sasithon Winterberg, Markus Pluijm, Rob W. Pantuwatana, Kanchana Hanboonkunupakarn, Borimas Jittamala, Podjanee Dondorp, Arjen Mukaka, Mavuto Day, Nicholas P.J. Phasomkusolsil, Siriporn Tarning, Joel |
| Author_xml | – sequence: 1 givenname: Kevin C. surname: Kobylinski fullname: Kobylinski, Kevin C. email: kobylinskikevin@yahoo.com organization: Walter Reed Army Institute of Research – sequence: 2 givenname: Podjanee surname: Jittamala fullname: Jittamala, Podjanee organization: Mahidol University – sequence: 3 givenname: Borimas surname: Hanboonkunupakarn fullname: Hanboonkunupakarn, Borimas organization: Mahidol University – sequence: 4 givenname: Sasithon surname: Pukrittayakamee fullname: Pukrittayakamee, Sasithon organization: Dusit – sequence: 5 givenname: Kanchana surname: Pantuwatana fullname: Pantuwatana, Kanchana organization: Armed Forces Research Institute of Medical Sciences – sequence: 6 givenname: Siriporn surname: Phasomkusolsil fullname: Phasomkusolsil, Siriporn organization: Armed Forces Research Institute of Medical Sciences – sequence: 7 givenname: Silas A. surname: Davidson fullname: Davidson, Silas A. organization: Walter Reed Army Institute of Research – sequence: 8 givenname: Markus surname: Winterberg fullname: Winterberg, Markus organization: University of Oxford – sequence: 9 givenname: Richard M. surname: Hoglund fullname: Hoglund, Richard M. organization: University of Oxford – sequence: 10 givenname: Mavuto surname: Mukaka fullname: Mukaka, Mavuto organization: University of Oxford – sequence: 11 givenname: Rob W. surname: Pluijm fullname: Pluijm, Rob W. organization: University of Oxford – sequence: 12 givenname: Arjen surname: Dondorp fullname: Dondorp, Arjen organization: University of Oxford – sequence: 13 givenname: Nicholas P.J. surname: Day fullname: Day, Nicholas P.J. organization: University of Oxford – sequence: 14 givenname: Nicholas J. surname: White fullname: White, Nicholas J. organization: University of Oxford – sequence: 15 givenname: Joel surname: Tarning fullname: Tarning, Joel organization: University of Oxford |
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| SubjectTerms | 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 |
| Title | Safety, Pharmacokinetics, and Mosquito‐Lethal Effects of Ivermectin in Combination With Dihydroartemisinin‐Piperaquine and Primaquine in Healthy Adult Thai Subjects |
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