The pharmacokinetic properties of oral and intravenous artesunate (2 mg/kg of body weight) were studied in 19 adult patients with acute uncomplicated Plasmodium falciparum malaria by using a randomized crossover design. A sensitive bioassay was used to measure the antimalarial activity in plasma which results from artesunate and its principal metabolite, dihydroartemisinin. The oral study was repeated with 15 patients during convalescence. The mean absolute oral bioavailability of the antimalarial agent in patients with acute malaria was 61% (95% confidence interval [CI], 52 to 70%). The absorption and elimination of oral artesunate were rapid, with a mean elimination half-life of antimalarial activity of 43 min (95% CI, 33 to 53 min). Following oral administration to patients with acute falciparum malaria, peak antimalarial activity in plasma and the area under the plasma concentration-time curve were approximately double those during convalescence and the apparent volume of distribution and clearance were approximately half those during convalescence (P < 0.005). Acute malaria is associated with a significant reduction in the clearance of artesunateassociated antimalarial activity.Artemisinin (qinghaosu) and its derivatives are a major advance in antimalarial treatment (8). These drugs are increasingly used in southeast Asia for the treatment of multidrugresistant Plasmodium falciparum malaria (2,8,15,22). Artesunate, the most widely available of the artemisinin-related compounds, is a hemisuccinate derivative of dihydroartemisinin (DHA). It may be given parenterally, intravenously, intramuscularly, orally, or rectally. Oral artesunate is used either alone or in combination, usually with mefloquine (15). Despite considerable use in areas where malaria is endemic, there are relatively few data on the pharmacokinetics of artesunate in the treatment of malaria (2-4, 6, 9, 13, 21, 27). There are concerns that the various artesunate formulations may have different bioavailabilities and that the development of resistance will be accelerated if suboptimal doses are used (13,24). Optimization of dosing recommendations is also important because of evidence that high doses of parenteral artemisinin derivatives (artemether, arteether) are neurotoxic in experimental mammals (16).Oral artesunate and artemether, but not artemisinin, are hydrolyzed rapidly back to the common metabolite DHA, which is intrinsically more active as an antimalarial agent. Oral artesunate may be considered mainly a prodrug for DHA, as the metabolite is the main contributor to overall antimalarial activity (2, 6). Thus, in order to compare different formulations of these drugs accurately and to guide the accurate choice of compound, the bioavailability of the antimalarial agent must be assessed.Chemical methods for the assay of DHA and the related derivatives have a limit of accurate quantitation above the range of concentrations which provide significant antimalarial effect. High-performance liquid chromatography (HPLC) with electrochemical detect...
