There were an estimated 263 million cases of malaria worldwide, leading to 597,000 deaths, in 2023. Children under the age of five accounted for 74% of all malaria-related deaths. Artemisinin-based combination therapy (ACT) is the first-line therapy for uncomplicated falciparum malaria, but artemisinin resistance in Asia and now sub-Saharan Africa is threatening our ability to control and eliminate malaria. Triple-ACTs have emerged as a viable alternative treatment to combat declining ACT efficacy due to drug-resistant malaria. In this study, we developed and evaluated an optimal fixed-dose regimen of artemether-lumefantrine-amodiaquine through population pharmacokinetic modeling and simulation. Three published population-based pharmacometric models and two large cohorts of observed adult subjects and pediatric malaria patients were used to simulate pharmacokinetic profiles of different dosing strategies. Based on simulated total exposure and peak concentrations, an optimal dose regimen was developed resulting in an extension of the current 4 weight bands to a total of 5 weight bands to generate equivalent exposures in all body weight groups and minimize the fluctuation in exposure between patients. The proposed drug-to-drug ratio of artemether-lumefantrine-amodiaquine (20:120:40 mg) was kept constant throughout the dosing bands in order to simplify manufacturing, implementation, and further development of a fixed-dose co-formulated product.

Key words: malaria, resistance, dose-optimisation, triple combination therapy, pharmacokinetics, pharmacometrics