Pharmacokinetics and Pharmacodynamic Modelling of Artemether-Lumefantrine in Paediatric Malaria Patients with Varying Nutritional Status in North West Nigeria: Implications for Optimal Dosing

Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for uncomplicated malaria in Nigeria, yet pharmacokinetic data in Nigerian paediatric populations, particularly those with varying degrees of malnutrition, are limited. Nutritional status profoundly influences drug absorption, distribution, metabolism, and excretion, potentially rendering standard weight-based dosing suboptimal in malnourished children. This study characterized the population pharmacokinetics and pharmacodynamics of artemether-lumefantrine in paediatric malaria patients with varying nutritional status in North West Nigeria, and developed optimized dosing recommendations using pharmacokinetic-pharmacodynamic modelling. A prospective clinical pharmacokinetic study was conducted in Kano and Zamfara States, enrolling 180 children aged six months to twelve years with confirmed uncomplicated malaria. Serial blood samples were collected for artemether, dihydroartemisinin, and lumefantrine plasma concentration quantification using validated high-performance liquid chromatography methods. Nutritional status was assessed by anthropometric Z-scores. Nonlinear mixed-effects population pharmacokinetic modelling was performed using NONMEM software. Malnutrition significantly reduced lumefantrine maximum plasma concentration and area under the curve by 34 percent and 29 percent respectively, mediated by reduced fat-assisted absorption and altered protein binding. Standard dosing achieved target pharmacodynamic exposure in only 61 percent of severely malnourished children. Pharmacokinetic-pharmacodynamic simulations support dose augmentation of approximately 30 percent in children with severe acute malnutrition. These findings have immediate clinical implications for artemether-lumefantrine dosing guidelines in malnourished paediatric malaria patients in northern Nigeria. Keywords: artemether-lumefantrine, pharmacokinetics, pharmacodynamic modelling, paediatric malaria, malnutrition