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Antimicrobial Agents and Chemotherapy, March 2002, p. 778-782, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.778-782.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Oral Artesunate Dose-Response Relationship in Acute Falciparum Malaria

Faculty of Tropical Medicine, Mahidol University, Bangkok 10400,¹ Sangklaburi Hospital, Sangklaburi, Kanchanaburi Province, Thailand,³ Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, United Kingdom²

Received 27 February 2001/ Returned for modification 18 August 2001/ Accepted 11 November 2001

The combination of an oral artemisinin derivative (usually artesunate) and mefloquine has become standard treatment for multidrug-resistant falciparum malaria in several parts of Southeast Asia. The doses of artesunate used in monotherapy and combination treatment have largely been derived empirically. In order to characterize the in vivo dose-response relationship for artesunate and thus rationalize dosing, 47 adult patients with acute uncomplicated falciparum malaria and parasitemia 1% were randomized to receive a single oral dose of artesunate varying between 0 and 250 mg together with a curative dose of oral mefloquine. Acceleration of parasite clearance was used as the pharmacodynamic variable. An inhibitory sigmoidal maximum effect (E_max) pharmacodynamic model typical of a dose-response curve was fitted to the relationship between dose and shortening of parasite clearance time (PCT). The E_max was estimated as 28.6 oral h, and the 50% effective concentration was 1.6 mg/kg of body weight. These results imply that there is no reduction in PCTs with the use of single doses of artesunate higher than 2 mg/kg, and this therefore reflects the average lower limit of the maximally effective dose.

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