The effects of body size and gender on the population pharmacokinetics of artesunate and 1 its active metabolite dihydroartemisinin in pediatric malaria patients

25 Despite the important role of the antimalarial artesunate, and its active metabolite 26 dihydroartesmisinin (DHA), in malaria treatment efforts, there are limited data on the 27 pharmacokinetics of these agents in pediatric patients. This study evaluated the effects of body 28 size and gender on the pharmacokinetics of artesunate/DHA using data from pediatric and adult 29 malaria patients. Nonlinear mixed effects modeling was used to obtain a base model consisting 30 of first-order artesunate absorption and one-compartment models for artesunate and for DHA. 31 Various methods of incorporating body size descriptors on clearance and volume parameters 32 were tested. An allometric scaling model for weight and a linear body surface area (BSA) model 33 were deemed optimal. The apparent clearance and volume of distribution of DHA obtained with 34 the allometric scaling model, and normalized to a 38 kg patient, were 63.5 L/h and 65.1 L, 35 respectively. Estimates for the linear BSA model were similar. The 95% confidence intervals 36 for the estimated gender effects on clearance and volume parameters for artesunate fell outside 37 the pre-defined no relevant clinical effect interval of 0.75 – 1.25. However, the effect of gender 38 on apparent DHA clearance was almost entirely contained within this interval, suggesting a lack 39 of influence of gender on this parameter. Overall, the pharmacokinetics of artesunate and DHA 40 following oral artesunate can be described for pediatric patients using either an allometric scaling 41 or linear BSA model. Both models predict that, for a given mg/kg artesunate dose, younger 42 children are expected to have lower DHA exposure than older children or adults. 43 44