Multiple dose study of interactions between artesunate and artemisinin in healthy volunteers

Aims To investigate whether coadministration of the antimalarials artesunat e and arternisinin alters the clearance of either drug. Methods Ten healthy Vietnamese males (Group AS) were randomized to receive a single dose of 100 mg oral artesunate (pro-drug of dihydroartemisinin) on day -5 and then once daily for 5 consecutive days (days 1-5). Oral artemis inin (500 mg) was coadministered on days 1 and 5. Another 10 subjects (Grou p A-M) were given 500 mg oral arternisinin on day -5 and then further doses on days 1-5. Artesunate 100 mg was given on days 1 and 5. Artemisinin and dihydroartemisinin plasma concentrations on days -5, 1 and 5 were quantifie d by h.p.l.c. with on-line postcolumn derivatization and u.v. detection. Results In Group AS, dihydroartemisinin oral clearance values (mean (95% Cl )) were similar on day 1 (32 (22, 47)) l h(-1) and day 5 (38 (28, 51)) l h( -1) of daily artesunate administration but these mean values were approxima tely three fold higher compared with day -5 after a single dose (95 (56, 15 9)). In this group, arternisinin oral clearance increased from 196 (165, 23 2) l h(-1) on day 1-315 (241, 410) l h(-1) on day 5. In Group AM, dihydroar temisinin oral clearance on day 1 was 39 (34, 46) l h(-1) and increased 1.6 fold to 64 (48, 85) l h(-1) on day 5. In this group, artemisinin oral clea rance increased sequentially (1.5 and 4.7 fold, respectively) from 207 (151 , 285) l h(-1) on day -5-308 (257, 368) l h(-1) on day 1 and to 981 (678, 1 420) l h(-1) on day 5. The increase in arternisinin oral clearance between days -5 and 1 (in the absence of artesunate) was similar to that between da ys 1 and 5 in Group AS subjects who took daily artesunate. Dihydroartemisin in was not a significant metabolite of arternisinin. Conclusions Artesunate (dihydroartemisinin) did not alter the elimination o f arternisinin. However, dihydroartemisinin elimination was inhibited by ar temisinin. Artemisinin induced its own elimination even 5 days after a sing le oral dose. There was no evidence for the formation of dihydroartemisinin from artemisinin.