Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 225, Issue 6, Pages 1062-1069Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiaa287
Keywords
Plasmodium vivax; artefenomel; OZ439; Malaria; Volunteer infection studies; IBSM; transmission
Categories
Funding
- Medicines for Malaria Venture
- US Aid
- Bill and Melinda Gates Foundation
- UK Department for International Development
- Norwegian Agency for Development Cooperation
- Irish Aid
- Newcrest Mining
- Australian Aid
- Swiss Agency for Development and Co-operation
- Wellcome Trust
- National Health and Medical Research Council of Australia
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This study evaluated the antimalarial activity of artefenomel, a new drug candidate, against P. vivax malaria. The results showed that artefenomel effectively cleared parasites after oral administration, but recrudescence occurred in some participants. The minimum inhibitory concentration and parasiticidal concentration were estimated, and a single 300-mg dose showed a high efficacy in clearing parasites. Gametocytemia was observed in all participants and cleared after dosing. Overall, the findings support further clinical development of artefenomel as a treatment for P. vivax malaria.
Background Interventions that effectively target Plasmodium vivax are critical for the future control and elimination of malaria. We conducted a P. vivax volunteer infection study to characterize the antimalarial activity of artefenomel, a new drug candidate. Methods Eight healthy, malaria-naive participants were intravenously inoculated with blood-stage P. vivax and subsequently received a single oral 200-mg dose of artefenomel. Blood samples were collected to monitor the development and clearance of parasitemia, and plasma artefenomel concentration. Mosquito feeding assays were conducted before artefenomel dosing to investigate parasite transmissibility. Results Initial parasite clearance occurred in all participants after artefenomel administration (log(10) parasite reduction ratio over 48 hours, 1.67; parasite clearance half-life, 8.67 hours). Recrudescence occurred in 7 participants 11-14 days after dosing. A minimum inhibitory concentration of 0.62 ng/mL and minimum parasiticidal concentration that achieves 90% of maximum effect of 0.83 ng/mL were estimated, and a single 300-mg dose was predicted to clear 10(9) parasites per milliliter with 95% certainty. Gametocytemia developed in all participants and was cleared 4-8 days after dosing. At peak gametocytemia, 75% of participants were infectious to mosquitoes. Conclusions The in vivo antimalarial activity of artefenomel supports its further clinical development as a treatment for P. vivax malaria.
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