Multiple dose pharmacokinetics of oral artemisinin and comparison of its efficacy with that of oral artesunate in falciparum malaria patients

Abstract

The study compared the clinical efficacy and safety of oral artemisinin and oral artesunate as well as artemisinin pharmacokinetics during and after resolution of falciparum malaria. Forty adults with symptomatic falciparum malaria were allocated at random to treatment with either oral artemisinin (500 mg single dose on day 1 followed by 250 mg twice daily for 4 d and then another 500 mg single dose on day 6) or with oral artesunate (100 mg single dose on day 1 followed by 50 mg twice daily for 5 d). Patients were admitted to hospital at the Kibaha Designated District Hospital, Kibaha, Tanzania for the duration of treatment. The patients were seen once weekly for 3 more weeks. The time to parasite clearance (PCT) after oral artesunate (26·4 ± 3·6 h) was shorter (P = 0·002) than after artemisinin (31 ± 3·6 h). The fever subsidence time (FST) after oral artesunate (18·9 ± 4·0 h) was also shorter (P = 0.04) than after artemisinin (21·8±4·6 h). Parasites were detected in 4 (20%) and 7 (35%) patients after completing treatment with artesunate and artemisinin respectively. In these patients the parasitaemia reappeared at the 3rd or 4th week of follow-up. Standard haematology, blood biochemistry and urinanalysis, performed before drug intake and again on days 6 and 14, were normal. No clinical abnormality was observed during the study period. Artemisinin plasma concentrations, determined by high performance liquid chromatography with post-column derivatization and detection by ultraviolet light, were followed up to 8 h after drug administration on days 1 and 6. Artemisinin absorption was rapid, the maximum plasma concentrations C_max) being attained at about 3 h. Artemisinin areas under the plasma concentration-time curve (AUC) and the C_max values were about 6 times higher after the first dose on day 1 than on day 6. This decrease in artemisinin plasma concentration is suggestive of an increase in metabolic capacity due to pronounced autoinduction.