Objective:

To develop a population pharmacokinetic model for mass drug administration-eligible populations receiving two ivermectin regimens in Kenya and characterize variability in drug exposure to inform dose selection for malaria vector control and deployment strategies.

Approach:

• Sampling Methods: Healthy adults receiving either a single 400 µg/kg ivermectin dose or 300 µg/kg on 3 consecutive days underwent venous plasma and dried blood spot sampling. Pharmacometric analyses compared the two regimens and evaluated whether dried blood spot sampling could serve as a practical alternative to plasma sampling in field trials.

Key Findings:

• Model-based simulations found that ivermectin concentrations remained above the estimated Anopheles gambiae LC50 for a median of 6.3 days after a single 400 µg/kg dose and 8.5 days after the 3-day 300 µg/kg regimen. Although the multidose regimen provided a longer period above the LC50, the gain largely reflected the 2 additional dosing days, and the regimen was sensitive to missed doses.
• Plasma and dried blood spot ivermectin concentrations were strongly correlated (R² = 0.93). After adjustment for hematocrit and protein binding, the mean percentage difference between the two sampling methods was 8.2%, supporting dried blood spot sampling as an alternative for field studies.

Interpretation:

Both ivermectin regimens produced exposure profiles that could provide a reasonable mosquito-killing window for mass drug administration. Although the 3-day regimen maintained concentrations above the estimated LC50 longer, a single 400 µg/kg dose may offer operational advantages by eliminating subsequent doses, while the 3-day regimen is sensitive to missed doses. The findings also support dried blood spot microsampling as a practical approach for pharmacokinetic assessment in field settings.

Limitations:

• The pharmacokinetic model was based on only 18 ivermectin-treated participants, limiting characterization of interindividual variability and the generalizability of model predictions.
• Only 3 of the 18 participants were women, limiting assessment of potential sex-based pharmacokinetic differences. In addition, sampling extended only to 168 hours for plasma and 96 hours for dried blood spots, restricting the timeframes supporting the exposure simulations.

Conclusion:

The pharmacometric analysis suggests that both a single 400 µg/kg ivermectin dose and 300 µg/kg administered for 3 consecutive days can maintain concentrations above the estimated A gambiae LC50 for several days. Although the multidose regimen produced a longer modeled duration above the LC50, a single-dose strategy may simplify implementation and improve adherence in mass drug administration campaigns. Dried blood spot microsampling also appears to be a viable alternative to plasma sampling for ivermectin pharmacokinetic studies in field settings.