Background

Drug repurposing offers a fast path to new antimalarial therapies. Both ivermectin and atovaquone have established safety profiles and known activity against Plasmodium species, but their combined effect on liver-stage parasites — particularly P. vivax hypnozoites — remains unexplored.

Hypothesis

Co-administration of ivermectin and atovaquone at sub-therapeutic doses will synergistically eliminate Plasmodium liver-stage hypnozoites by simultaneously disrupting parasite mitochondrial electron transport (atovaquone targeting cytochrome bc1) and chloride channel-dependent membrane potential (ivermectin targeting glutamate-gated chloride channels), leading to mitochondrial collapse at concentrations where neither drug alone is effective.

Rationale

• Atovaquone is a known inhibitor of the cytochrome bc1 complex (Complex III) in Plasmodium mitochondria, collapsing the mitochondrial membrane potential.
• Ivermectin activates glutamate-gated chloride channels, causing hyperpolarization. Recent evidence suggests it also disrupts mitochondrial function in parasites at low concentrations.
• Dual targeting of mitochondrial electron transport and ion homeostasis may produce synergistic killing, as the parasite cannot compensate for both insults simultaneously.
• This could address the critical unmet need of hypnozoite elimination without the hemolytic risk of primaquine in G6PD-deficient patients.

Testable predictions

1. In vitro liver-stage P. vivax assays will show a combination index (CI) < 0.5 at ED50 for the ivermectin + atovaquone pair
2. Mitochondrial membrane potential (JC-1 assay) in treated hepatocytes will decrease >80% vs. single-agent controls
3. The combination will show efficacy against primaquine-tolerant hypnozoite strains

Limitations

• Liver-stage P. vivax culture systems remain technically challenging
• Ivermectin CNS penetration and dosing constraints may limit achievable hepatic concentrations
• Synergy observed in vitro may not translate to in vivo pharmacokinetics