Evaluation of in vitro drug-drug interactions of ivermectin and antimalarial compounds

BACKGROUND: Ivermectin is lethal to Anopheles mosquitoes and a novel approach to malaria transmission control. Ivermectin could be co-administered with antimalarial drugs in mass drug administration, seasonal malaria chemoprevention, or other chemoprevention approaches. Co-administration with antimalarial drugs may impact ivermectin metabolism and/or absorption, resulting in increased or decreased exposure to ivermectin. METHODS: To evaluate potential CYP-mediated drug-drug interactions (DDIs), ivermectin (1 µM) was incubated with pooled human liver microsomes, with and without the most commonly used antimalarial drugs at concentrations approximating twofold to tenfold the peak concentrations achieved following standard treatment. The antimalarial drugs investigated were dihydroartemisinin, piperaquine, chloroquine, artesunate, pyronaridine, mefloquine, artemether, lumefantrine, primaquine, atovaquone, proguanil, tafenoquine, sulfadoxine, pyrimethamine, and amodiaquine. Samples (50 µL) were collected at 0, 15, 30, 45, 60, 90, 120, and 150 min of incubation and ivermectin concentrations were measured using liquid chromatography-mass spectrometry. The metabolism rate of ivermectin was evaluated based on the normalized peak area (%) of ivermectin over a total of 150 min of incubation, applying linear regression to derive the rate of metabolism. Antimalarial compounds resulting in notable impact on the rate of ivermectin metabolism with a relative difference ≥ 50% and ≥ 25% were considered to have a substantial and partial effect on the in vitro metabolism of ivermectin, respectively. RESULTS: Compounds that had a substantial DDI effect on the in vitro metabolism of ivermectin included piperaquine (98%), mefloquine (91%), chloroquine (76%), proguanil (60%), and lumefantrine (51%). Compounds that a partial DDI effect on the in vitro metabolism of ivermectin included atovaquone (48%), artesunate (27%), and pyronaridine (25%). All other antimalarials evaluated showed an in vitro interaction of 8-23%. CONCLUSIONS: Several of the commonly used antimalarial drugs, are mostly or in part metabolized by CYP3A4 and showed a notable DDI effect on the in vitro metabolism of ivermectin. This could potentially lead to clinically important pharmacokinetic and pharmacodynamic DDIs if co-administered, and needs to be evaluated in prospective clinical trials.