Journal of Bioequivalence & Bioavailability

Abstract

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.

Piero Olliaro, Surash Ramanathan, Michel Vaillant, Stephanie E Reuter, Allan M Evans, Srivicha Krudsood, Sornchai Looareesuwan, Jean-René Kiechel, Walter RJ Taylor and Visweswaran Navaratnam

Purpose: The current World Health Organization recommendation for the treatment of uncomplicated Plasmodium falciparum malaria is with 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 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. Results: For artesunate/dihydroartemisinin the lower bound of the 90% confidence intervals for the comparison between co-formulated and separate products extended below the 80% bioequivalence limit; area under the curve and Cmax 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 mefloquine pharmacokinetics in uncomplicated falciparum malaria patients; the 90% confidence intervals for dose-normalised area under the curve (AUClast and AUCinf) and maximum observed concentration (Cmax) were within the 80 - 125% limits. In contrast, mefloquine area under the curve and Cmax 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 mefloquine 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 specific patient groups.