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 heal thy male Thai volunteers after single 200 mg oral doses and (b) in eig ht male Thai patients with acute uncomplicated falciparum malaria afte r an initial 200 mg oral dose followed by 100 mg at 12 h then 100 mg d aily for 4 days. 2 In the healthy subjects, median (range) maximum pla sma concentrations of artemether of 118 (112-127) ng ml(-1) were reach ed at 3 (1-10) h. Thereafter, drug concentrations declined monoexponen tially 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 th e 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 r eached at 3 (1-3) h after the first dose. Steady state was reached aft er 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. Compare d with the parent compound, dihydroartemisinin reached higher peak con centrations 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 dos e of artemether (96 h). The t(1/2,z) of 12.5 (9.9-21.2) h was signific antly longer than that of the parent drug and AUC was significantly gr eater (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 t ime (FCT) and parasite clearance time (PCT) of 30 and 36 h, respective ly, 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).