Selection of a Lead Long-Acting Formulation of Ivermectin to Target Major Malaria Vectors in Western Africa: Evaluation of Pharmacokinetics and Mosquitocidal Efficacy in Cattle under Laboratory Conditions.

BackgroundIvermectin, a semisynthetic endectocide from the avermectin family, has been used in mass drug administration (MDA) campaigns since the 1980s to control helminth infections. Its lethality to Anopheles mosquitoes after feeding on treated hosts offers a promising malaria control strategy, especially for outdoor transmission. However, existing oral formulations produce short-duration mosquitocidal blood concentrations, limiting epidemiological impact. The WHOs target product profile for endectocides calls for a hazard ratio >4 and sustained efficacy for at least one month. In this context, three long-acting injectable ivermectin formulations (LAIF) based on BEPO(R) depot technology were evaluated in cattle to evaluate the in vivo performance then to identify the most effective candidate. MethodsThe LAI candidates (mdc-STM-001, -002, and -003) were tested at 0.6 mg/kg, with mdc-STM- 003 also evaluated at 1.5 mg/kg. Each treatment group consisted of five calves, each receiving single sub-cutaneous injection. Plasma samples intensively collected over 130 days enabled non-compartmental pharmacokinetic analysis of ivermectin. Two mosquito strains: Anopheles coluzzii (VK5-pyrethroid-resistant) and Anopheles gambiae (KIS-Kisumu strain) were allowed to simultaneously blood-feed on treated animals from 2 to 126 days post-dose. Mosquito survival was monitored for 30 days. Mortality within 4 and 10 days post-feeding was emphasized, targeting the window before Plasmodium falciparum becomes transmissible. Efficacy was assessed via hazard ratios, cumulative mortality, lethal concentrations (LC) 50 and 90 values, and duration of effective coverage. ResultsAll formulations were well tolerated. mdc-STM-001 showed the most favorable pharmacokinetic profile with a controlled peak (Cmax= 34.5 {+/-} 12.7 ng/mL) and the lowest inter-individual variability (12%). mdc-STM-001 and -003 produced hazard ratios >4 and cumulative mortalities >50% for at least 60 days in both mosquito strains. Surviving mosquitoes had median lifespans below 10 days for at least 90 days post-injection. The 10- day LC50 for resistant mosquitoes (3.66 [2.69-4.97]) was maintained for [≥]126 days. mdc-STM- 001 provided 100% coverage at this threshold for [≥]2 months. Conclusionmdc-STM-001 is the lead candidate. A single injection allows killing >50% of biting mosquitoes before they become infectious, even in resistant populations, during at least 2 months. Given ivermectins established safety profile, its repurposing in LAIFs offers a promising strategy for malaria control. This approach directly targets two major challenges: outdoor transmission and rising insecticide resistance, and warrants further investigation.