Population Pharmacokinetic Assessment of the Effect of Food on Piperaquine Bioavailability in Patients with Uncomplicated Malaria

Previously published literature reports various impacts of food on the oral bioavailability of piperaquine. The aim of this study was to use a populationmodeling approach to investigate the impact of concomitant intake of a small amount of food on piper-aquine pharmacokinetics. This was an open, randomized comparison of piperaquine pharmacokinetics when administered as a fixed oral formulation once daily for 3 days with (n 15) and without (n 15) concomitant food to patients with uncompli-cated Plasmodium falciparummalaria in Thailand. Nonlinear mixed-effects modeling was used to characterize the pharmacoki-netics of piperaquine and the influence of concomitant food intake. AmodifiedMonte Carlo mapped power approach was ap-plied to evaluate the relationship between statistical power and various degrees of covariate effect sizes of the given study design. Piperaquine population pharmacokinetics were described well in fasting and fed patients by a three-compartment distribution model with flexible absorption. The final model showed a 25 % increase in relative bioavailability per dose occasion during re-covery frommalaria but demonstrated no clinical impact of concomitant intake of a low-fat meal. Body weight and age were both significant covariates in the final model. The novel power approach concluded that the study was adequately powered to detect a food effect of at least 35%. This modifiedMonte Carlo mapped power approachmay be a useful tool for evaluating the power to detect true covariate effects in mixed-effects modeling and a given study design. A small amount of food does not affect piperaquine absorption significantly in acute malaria. Malaria is the most important parasitic disease in humans andkills approximately 660,000 people each year (1). Artemis