Comparison of Oral Artesunate and Dihydroartemisinin Antimalarial Bioavailabilities in Acute Falciparum Malaria

Abstract

Plasma antimalarial activity following oral artesunate or dihydroartemisinin (DHA) treatment was measured by a bioassay in 18 patients with uncomplicated falciparum malaria. The mean antimalarial activity in terms of the bioavailability of DHA relative to that of artesunate did not differ significantly from 1, suggesting that DHA can be formulated to be an acceptable oral alternative to artesunate.Drug resistance to Plasmodium falciparum is a growing problem in Southeast Asia (14). The artemisinin derivatives are effective, safe, and widely used alternative treatments. Artesunate is the most commonly prescribed derivative (1, 7). Each artesunate treatment for adults costs at least $1 (U.S.). Nearly all the antimalarial activity of artesunate results from the activity of its main metabolite, dihydroartemisinin (DHA) (1, 2, 6). DHA has also been formulated as an oral antimalarial drug and could be easier and cheaper to produce than artesunate. Clinical trials on the treatment of acute, uncomplicated falciparum malaria have demonstrated that oral DHA is a safe, effective oral treatment that achieves cure rates similar to those achieved with oral artesunate (8,9,15).A recent study with eight patients with uncomplicated falciparum malaria, in which high-performance liquid chromatography (HPLC) and UV detection (UVD) were used to determine the plasma DHA concentration, gave an estimated mean oral bioavailability of DHA relative to that of oral artesunate of 0.88 (4). Chemical methods for the assay of the artemisinin derivatives have a limit of accurate quantitation above the range of concentrations which provide a significant antimalarial effect. Bioassay gives an alternative and considerably more sensitive measure but does not distinguish between parent drugs and their active metabolites (12). We therefore compared the bioavailabilities of the two most widely used formulations of oral artesunate and oral DHA given at the same milligram doses to patients with uncomplicated malaria in a randomized crossover trial with bioassay measurements of antimalarial activity obtained with serial plasma samples (3,10,11,12).Nonpregnant, febrile (temperature, Ͼ37.5°C) adults (age, Ͼ14 years) hospitalized at the Mae Sot Hospital or the Mae La Camp of displaced Karen People, Tak Province, western Thailand, with uncomplicated acute P. falciparum malaria (defined as the presence of asexual stages of P. falciparum in peripheral blood and not fulfilling the World Health Organization [16] criteria for severe malaria) were included in the study, provided that they gave fully informed consent and they had not previously received significant antimalarial treatment. The study was approved by the ethical and scientific review subcommittee of the Thai Ministry of Public Health and by the Karen Refugee Committee. In the first 48 h the patients were given both artesunate (200 mg as 50-mg tablets; Guilin No. 1 Factory, Guangxi, People's Republic of China) and dihydroartemisinin (200 mg as 20-mg tablets; Cotecxin; Cotec New Technology Corp., Beijin...

Artemether Bioavailability after Oral or IntramuscularAdministration in Uncomplicated FalciparumMalaria

“…Comparisons of the pharmacokinetics of artesunate, artemether, and DHA have suggested that either oral DHA or artesunate provides greater antimalarial activity than similar doses of oral artemether in the combination treatment of uncomplicated falciparum malaria (10,14). This study suggests that intramuscular artemether has unfavorable pharmacokinetic characteristics in patients with uncomplicated malaria.…”

A comparison of the in vivo kinetics of Plasmodium falciparum ring–infected erythrocyte surface antigen–positive and –negative erythrocytes

“…25 Patients unable to take oral medication were treated, as part of clinical trials to be reported separately, with parenteral artesunate or quinine. Intravenous artesunate (Guilin No.…”

Population Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Malaria

“…Dihydroartemisinin pharmacokinetics are very different; it has a small apparent volume of distribution of approximately 1.5 to 3.8 liters/kg, an oral clearance of approximately 1.1 to 2.9 liters/h/kg, and a very short terminal elimination half-life of approximately 0.83 to 1.9 h in adult patients (27,37,39,40). The population pharmacokinetic properties of the fixed oral combination of dihydroartemisinin and piperaquine have not been studied in pregnant women with malaria.…”