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

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.

DOI: 10.1046/j.0306-5251.2001.01461.x

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