Purpose: The current World Health Organisation recommendation for the treatment of uncomplicated Plasmodium falciparum malaria is to use artemisinin-based combination therapy. Artesunate and mefloquine combination therapy has achieved consistently high efficacy rates and reduced malaria morbidity; however, the current standard treatment regimen is complex and may be difficult to comply with outside of a research setting. Consequently, an artesunate-mefloquine fixed 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 mefloquine administered as separate products and on the new co-formulated product. Methods: The pharmacokinetics of artesunate, dihydroartemisinin, the artesunate metabolite and predominant species and mefloquine 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. Both studies were conducted in Thailand. Results: The two formulations were bioequivalent in terms of mefloquine pharmacokinetics in healthy volunteers and uncomplicated falciparum malaria patients; the 90% confidence intervals for dose-normalised area under the curve (AUC<sub>last</sub> and AUC<sub>inf</sub>) and maximum observed concentration (C<sub>max</sub>) were within the 80 - 125% bioequivalence limits. For artesunate/dihydroartemisinin the lower bound of the 90% confidence intervals for the comparison between coformulated and separate products extended below the 80% limit; AUC and C<sub>max</sub> values were 15-25% and 25-40% lower than those observed after administration of the separate products. Conclusions: These differences in the exposure to artesunate/dihydroartemisinin 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.
Journal of Bioequivalence & Bioavailability (2010) 2 (3) 059-066 [doi:10.4172/jbb.1000032].
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.