The overall goal of this project is to advance the understanding of the pharmacology of ivermectin and to enhance the treatment of malaria.
The specific objectives are to:
- identify and characterize ivermectin metabolite production in vitro and in vivo,
- determine which metabolites impart mosquito-lethal effect in the major Greater Mekong Subregion Anopheles vectors,
- assess parent compound and metabolite activity and pharmacokinetics to characterize the duration of mosquito-lethal effects of oral ivermectin in a detailed clinical trial, and
- investigate whether ivermectin alters drug sensitivity in artemisinin-resistant P. falciparum field isolates.
Rationale and Abstract
Ivermectin is lethal to Anopheles mosquitoes at concentrations safe to administer to people during mass drug administrations. However, mosquito survival from field MDA, laboratory, and clinical trial assays, and pharmacokinetic results do not always correlate with laboratory assays with ivermectin compound under predicting mosquito-lethal effect observed in field MDAs and clinical trials. This suggests that there may be ivermectin metabolites with a mosquito-lethal effect that extend the window of efficacy beyond that predicted by parent compound pharmacokinetics.