Evaluation of ivermectin as an antimalarial therapy against Plasmodium falciparum liver stage
The primary objective of this project is to assess the impact of ivermectin on liver-stage development of Plasmodium falciparum in primary human hepatocytes (PHHs).
The secondary objectives are:
- To determine if metabolism of ivermectin in PHHs is critical for ivermectin impact on liver-stage development of P. falciparum by using CYP3A4 inhibitors (e.g. ketoconazole, CYP3cide, SR-9186) to block ivermectin metabolism
- Characterize liver-stage efficacy against P. falciparum NF54 strain and artemisinin-resistant isolates in PHHs
- Characterize liver-stage efficacy of ivermectin in combination with antimalarial drugs in PHHs
- Characterize drug-drug interactions which alter ivermectin or antimalarial drug pharmacokinetics in PHHs
Malaria elimination prospects are threatened by artemisinin resistance in Plasmodium falciparum. Ivermectin mass drug administration (MDA) to humans has been proposed as a novel vector control measure to suppress transmission and potentially aid containment of drug-resistant parasites. Ivermectin has been shown to have liver-stage efficacy in Plasmodium berghei in vitro and in vivo models. However, a recent human clinical trial with a single prophylactic dose of ivermectin (400 µg/kg) failed to prevent blood-stage breakthrough of P. falciparum NF54 strain. However, ivermectin MDA strategies for malaria control currently propose three-day dosing of ivermectin along with antimalarial drug combinations such as dihydroartemisinin-piperaquine and sulfadoxine-pyrimethamine plus amodiaquine. Ivermectin concentrations are elevated substantially when co-administered with dihydroartemisinin-piperaquine. Thus, it is relevant to assess the impact of ivermectin on liver stage development with different isolates of P. falciparum with and without combinations of antimalarial drugs. Additionally, it is not known if ivermectin metabolism is required for liver-stage efficacy. Here we propose to use a primary human hepatocyte model to evaluate the effect of ivermectin on P. falciparum liver-stage development. Ivermectin will be used in combination with CYP3A4 inhibitors to assess the impact metabolism on liver-stage efficacy. Ivermectin will also be screened with a panel of antimalarial drugs to determine if co-administration inhibits or enhances potential liver-stage efficacy. Additionally, we will measure ivermectin and antimalarial drug levels in hepatocyte media to assess for drug-drug interactions which may enhance liver-stage, blood-stage, and mosquito-lethal efficacy to determine which drug combinations may be optimal for evaluation in future clinical trials.
- Primary outcome: Inhibition of liver-stage P. falciparum schizont development at various ivermectin concentrations, with and without CYP3A4 inhibitors, and antimalarial drugs.
- Secondary outcomes: Ivermectin and antimalarial drug area under the concentration curve (AUC) with and without antimalarial drugs; metabolic activity as measured by elimination rate of the parent drug and formation rate of the metabolites.