A PHARMACOKINETIC AND PHARMACODYNAMIC STUDY OF INTRAVENOUS VS ORAL ARTESUNATE IN UNCOMPLICATED FALCIPARUM-MALARIA

Aims To obtain comprehensive pharmacokinetic and pharmacodynamic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DH A) following i.v. and oral administration of ARTS to patients with acu te, uncomplicated falciparum malaria. Methods Twenty-six Vietnamese pa tients with falciparum malaria were randomized to receive either i.v. ARTS (120 mg; group 1) or oral ARTS (100 mg; group 2), with the altern ative preparation given 8 h later in an open crossover design. Mefloqu ine (750 mg) was administered at 24 h. Plasma concentrations of ARTS a nd DHA were determined by h.p.l.c. assay. Pharmacokinetic parameters w ere calculated by non-compartmental methods. The time to 50% parasite clearance (PCT50) was calculated by linear interpolation of parasite d ensity determinations. Linear least squares and multiple linear regres sion analyses were used to evaluate pharmacokinetic-pharmacodynamic re lationships. Results Following i.v. bolus, ARTS had a peak concentrati on of 29.5 mu M (11 mg l(-1)), elimination t(1/2)=2.7 min, CL=2.33 l h (-1) kg(-1) and V=0.14 l kg(-1). The C-max for DHA was 9.3 mu M (2.64 mg l(-1)), t(1/2)=40 min, CL=0.75 l h(-1) kg(-1) and V=0.76 l kg(-1). Following oral ARTS, relative bioavailability of DHA was 82%, C-max wa s 2.6 mu M (0.74 mg l(-1)), t(1/2)=39 min, and MAT=67 min. Overall, th e PCT50 and fever clearance time (FCT) were 6.5 h and 24 h, respective ly. There was no correlation between PCT50 or FCT and AUC, C-max or MR T for DHA. Conclusions Despite rapid clearance of ARTS and DHA in pati ents with uncomplicated falciparum malaria, prompt parasite and fever clearance were achieved. High relative bioavailability of DHA followin g oral ARTS administration, and clinical outcomes comparable with thos e after i.v. ARTS, support the use of the oral formulation in the prim ary care setting.