Optimizing Lumefantrine Dosing for Young Children in High-Malaria-Burden Countries Using Pharmacokinetic-Pharmacodynamic Simulations.

Background: Artemether-lumefantrine is the most widely used treatment for uncomplicated malaria and it is dosed based on weight bands according to World Health Organization (WHO) guidelines. However, children are vulnerable to underdosing. Inadequate dosing can lead to treatment failure and drug resistance. Methods: Nutritional parameters for 372 363 children <5 years old in 25 high-malaria-burden countries were acquired from the Demographic and Health Surveys program. Prevalence of attaining day 7 lumefantrine concentrations ≥200 ng/mL and remaining reinfection free for 42 days were evaluated using a simulation-based approach with a population pharmacokinetic-pharmacodynamic model. Besides the WHO-recommended lumefantrine dosing regimen (twice daily for 3 days), we explored 3 adjusted regimens: extended (2 extra days of dosing), increased (1 extra 120-mg tablet per dose), and intensified (thrice daily for 3 days). We also explored an alternative method dosing malnourished children based on expected weight for age. Results: We estimated that 75% of children reached the 200 ng/mL lumefantrine threshold and 77% were malaria free for 42 days when using WHO treatment guidelines. By switching to the alternative dosing method, 5% more children achieved target lumefantrine levels; 22% more achieved the target using the alternative dosing and the extended regimen. With combined alternative plus extended dosing, 97% of children reached 200 ng/mL lumefantrine and 88% were malaria free for 42 days. Conclusions: This study highlights the inadequacies of weight-based lumefantrine dosing for young and underweight children and supports the need of clinical trials using extended dosing based on expected weight in malnourished children.