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

Abstract

Aims: To investigate whether coadministration of the antimalarials artesunate and artemisinin 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 artemisinin (500 mg) was coadministered on days 1 and 5. Another 10 subjects (Group AM) were given 500 mg oral artemisinin 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 quantified by h.p.l.c. with on-line postcolumn derivatization and u.v. detection.

Results: In Group AS, dihydroartemisinin oral clearance values (mean (95% CI)) 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 approximately three fold higher compared with day -5 after a single dose (95 (56, 159)). In this group, artemisinin oral clearance increased from 196 (165, 232) l h(-1) on day 1-315 (241, 410) l h(-1) on day 5. In Group AM, dihydroartemisinin 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 clearance 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, 1420) l h(-1) on day 5. The increase in artemisinin oral clearance between days -5 and 1 (in the absence of artesunate) was similar to that between days 1 and 5 in Group AS subjects who took daily artesunate. Dihydroartemisinin was not a significant metabolite of artemisinin.

Conclusions: Artesunate (dihydroartemisinin) did not alter the elimination of artemisinin. However, dihydroartemisinin elimination was inhibited by artemisinin. Artemisinin induced its own elimination even 5 days after a single oral dose. There was no evidence for the formation of dihydroartemisinin from artemisinin.

Figure 1

Chemical structure of artemisinin (a), artesunate (b) and its active metabolite dihydroartemisinin (c).

Figure 2

Individual oral clearance (CL/F) values for dihydroartemisinin determined on days −5, 1 and 5 (a, n = 10 except on day −5 when n = 7) and for artemisinin on days 1 and 5 (b, n = 10) when 100 mg artesunate was given orally once daily on day −5 and from day 1 through day 5 and with oral administration of 500 mg artemisinin on days 1 and 5 in healthy, male Vietnamese subjects (Group AS). Values above horizontal lines represent the geometric average and its 95% confidence interval of the intraindividual ratios of oral clearance values between study days (CL/F_{day 1}/CL/F_{day −5} and CL/F_{day 5}/CL/F_{day 1}), and vertical arrows depict occasions of drug administration.

Figure 3

Individual oral clearance (CL/F) values for dihydroartemisinin on days 1 and 5 (a, n = 10) and for artemisinin on days −5, 1 and 5 (b, n = 10) when 500 mg artemisinin was given orally once daily on day −5 and from day 1 through day 5 with single oral administrations of 100 mg artesunate on days 1 and 5 in healthy male Vietnamese subjects (Group AM). Values above horizontal lines represent the geometric average and its 95% confidence interval of the interindividual ratios of oral clearance values between study days (CL/F_{day 1}/CL/F_{day −5} and CL/F_{day 5}/CL/F_{day 1}), and vertical arrows depict occasions of drug administration.

Figure 4

Relationship between dihydroartemisinin AUC(0, t) and artemisinin AUC(0, t) (geometric means and 95% confidence intervals) in 10 healthy Vietnamese subjects (Group AS) who received the combination on days 1 (a) and 5 (b)) of a 5 day course of daily 100 mg artesunate preceded by a single artesunate administration on day −5 and in another 10 subjects (Group AM) who received the combination on days 1 (c) and 5 (d)) of a 5 day course of daily 500 mg artemisinin preceded by a single artemisinin dose on day −5. The fitted regression line for the four mean values is shown.