Pharmacokinetics and Comparative Bioavailability of Artesunate and Mefloquine Administered Separately or as a Fixed Combination Product to Healthy Volunteers and Patients with Uncomplicated Plasmodium falciparum Malaria.

Purpose: The current World Health Organization recommendation for the treatment of uncomplicated Plasmodium falciparum malaria is with artemisinin-based combination therapy.Artesunate and mefl oquine combination therapy has achieved consistently high effi cacy rates and reduced malaria morbidity; however, the current standard treatment regimen is complex and may be diffi cult to comply with outside of a research setting.Consequently, an artesunatemefl oquine fi xed dose oral co-formulation has been developed and is now registered in Brazil.This study was conducted in order to assess the pharmacokinetics and comparative bioavailabilities of artesunate and mefl oquine administered as separate products and the new co-formulated product.Methods: The pharmacokinetics of artesunate, dihydroartemisinin, the artesunate metabolite and predominant species and mefl oquine were assessed in a single-dose, randomised, crossover design study in healthy volunteers and in a multiple-dose, randomised, parallel group study in patients with uncomplicated falciparum malaria.Results: For artesunate/dihydroartemisinin the lower bound of the 90% confi dence intervals for the comparison between co-formulated and separate products extended below the 80% bioequivalence limit; area under the curve and C max values were 15-25% and 25-40% lower than those observed after administration of the separate products.The two formulations were bioequivalent in terms of mefl oquine pharmacokinetics in uncomplicated falciparum malaria patients; the 90% confi dence intervals for dose-normalised area under the curve (AUC last and AUC inf ) and maximum observed concentration (C max ) were within the 80 -125% limits.In contrast, mefl oquine area under the curve and C max values were 15% and 30% lower for the co-formulated products compared to the separate products in healthy volunteers.Conclusions: These differences in the exposure to artesunate, dihydroartemisinin and mefl oquine are unlikely to be of clinical relevance based on in vitro and clinical data.However, the results of this study do emphasise the importance of evaluating the bioavailability and bioequivalence of new formulations, particularly in specifi c patient groups.