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

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Author(s): Piero Olliaro | Surash Ramanathan | Michel Vaillant | Stephanie E Reuter | Allan M Evans | Srivicha Krudsood | Sornchai Looareesuwan | Jean-René Kiechel | Walter RJ Taylor | Visweswaran Navaratnam

Journal: Journal of Bioequivalence & Bioavailability
ISSN 0975-0851

Volume: 02;
Issue: 03;
Start page: 059;
Date: 2010;
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Keywords: Artesunate | Dihydroartemisinin | Mefloquine | Pharmacokinetics

ABSTRACT
Purpose: The current World Health Organisation 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 artesunate - mefl 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: The two formulations were bioequivalent in terms of mefl oquine pharmacokinetics in healthy volunteersand uncomplicated falciparum malaria patients; the 90% confi dence intervals for dose-normalised area under the curve (AUClast and AUCinf) and maximum observed concentration (Cmax) were within the 80 - 125% bioequivalence limits. For artesunate/dihydroartemisinin the lower bound of the 90% confi dence intervals for the comparison between coformulated and separate products extended below the 80% limit; AUC and Cmax 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 clinicalrelevance based on in vitro and clinical data. However, the results of this study do emphasise the importance ofevaluating the bioavailability and bioequivalence of new formulations.
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