Mosquitocidal efficacy and pharmacokinetics of single-dose ivermectin versus three-day dose regimen for malaria vector control in comparison with albendazole and no treatment: an open-label randomized controlled trial

Objectives
When malaria vectors consume ivermectin in a blood meal, their survival probability decreases, potentially reducing malaria transmission during mass drug administrations (MDA). However, questions remain regarding the optimal dosing. This study aimed at comparing the mosquitocidal effect and pharmacokinetics of two dose regimens of ivermectin for malaria vector control.

Design
We conducted an open-label randomized control trial in Kenya staggered in blocks with sequential intervention groups and parallel controls. Participants were randomly assigned (2:1:1:1) using computer random sequence generation, unstratified, with one block of six pharmacokinetic only participants (single-dose ivermectin) and six blocks of four participants (3:1 intervention vs control), to receive single-dose ivermectin (400 mcg/kg, n=12), three daily doses (three-day regimen 300 mcg/kg, n=6), albendazole (400 mg, n=6), or no treatment (negative control, n=6). Our primary outcome was Anopheles gambiae survival (time-to-event (days)) post blood feeding up to 10-days after drug administration. We also evaluated pharmacokinetics (Cmax, AUC, Tmax, Thalf) up to 7 days post treatment.

Results
A total of 36 healthy volunteers aged 21-32 years were recruited into the study and followed up to completion with 2 participants not attending visit on day 28. All drug regimens were well tolerated. Both regimens showed significant mosquitocidal effect in the first 7 days. At 10-days post treatment single dose presented superior longevity of effect (aHR(adjusted hazard ratio)=3.91; 95% CI=1.93- 7.93; p<0.001) compared to triple dose (aHR=1.79; 95% CI=0.88-3.62; p=0.0.11). Albendazole had overall no mosquitocidal effect.

Conclusions
It is unclear why a single dose led to increased bio-efficacy compared to triple dose. We recommend trials investigating ivermectin MDA for malaria control to consider single-dose ivermectin. A single-dose regimen is also expected to present additional operational advantages compared to a three-day regimen leading to improved programmatic suitability.