PHARMACOKINETICS OF ARTEMETHER AFTER ORAL-ADMINISTRATION TO HEALTHY THAI MALES AND PATIENTS WITH ACUTE, UNCOMPLICATED FALCIPARUM-MALARIA

1 The pharmacokinetics of artemether were investigated (a) in six healthy male Thai volunteers after single 200 mg oral doses and (b) in eight male Thai patients with acute uncomplicated falciparum malaria after an initial 200 mg oral dose followed by 100 mg at 12 h then 100 mg daily for 4 days. 2 In the healthy subjects, median (range) maximum plasma concentrations of artemether of 118 (112-127) ng ml(-1) were reached at 3 (1-10) h. Thereafter, drug concentrations declined monoexponentially with a median (range) t(1/2,z) of 3.1 (1.0-9.6) h. The median (range) AUC and MRT values were 1.10 (0.33-4.44) mu g ml(-1) h and 8.3 (3.5-20.8) h. The median C-max value of dihydroartemisinin, an active metabolite, was 379 (162-702) ng ml(-1) at 6 (2-12) h. Its median AUC value was 6.6 (0.83-38.7) mu g ml(-1) h; the apparent t(1/2,z) was 10.6 (4.7-19.2) h and the median MRT value was 16.0 (5.0-41.0) h. 3 In the patients, a higher C-max value of parent drug than those observed in healthy subjects (median and range of 231 (116-411) ng ml(-1)), was reached at 3 (1-3) h after the first dose. Steady state was reached after the third dose (24 h) and concentrations fluctuated over the range of 36-60 ng ml(-1). The respective median (range) values of AUC and t(1/2,z) were 5.8 (3.76-12.9) mu g ml(-1) h and 4.2 (2.5-5.3) h. Compared with the parent compound, dihydroartemisinin reached higher peak concentrations at later times (C-max: 593 (483-729) ng ml(-1); t(max) 7.4 (3-20) h). The high concentrations were sustained until the final dose of artemether (96 h). The t(1/2,z) of 12.5 (9.9-21.2) h was significantly longer than that of the parent drug and AUC was significantly greater (49.6 (29.0-60.5) mu g ml(-1) h). 4 All patients showed a rapid initial response to treatment with median values for fever clearance time (FCT) and parasite clearance time (PCT) of 30 and 36 h, respectively, However, one patient recrudesced on day 19 after treatment. C-max and the AUC of artemether and dihydroartemisinin in this patient were lower than those in other patients (116 ng ml(-1) and 29.0 mu g ml(-1) h).