A pharmacokinetic and pharmacodynamic study of intravenous vs oral artesunate in uncomplicated falciparum malaria

Abstract

Aims: To obtain comprehensive pharmacokinetic and pharmacodynamic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following i.v. and oral administration of ARTS to patients with acute, uncomplicated falciparum malaria.

Methods: Twenty-six Vietnamese patients with falciparum malaria were randomized to receive either i.v. ARTS (120 mg; group 1) or oral ARTS (100 mg; group 2), with the alternative preparation given 8 h later in an open crossover design. Mefloquine (750 mg) was administered at 24 h. Plasma concentrations of ARTS and DHA were determined by h.p.l.c. assay. Pharmacokinetic parameters were calculated by non-compartmental methods. The time to 50% parasite clearance (PCT50) was calculated by linear interpolation of parasite density determinations. Linear least squares and multiple linear regression analyses were used to evaluate pharmacokinetic-pharmacodynamic relationships.

Results: Following i.v. bolus, ARTS had a peak concentration of 29.5 microM (11 mg l[-1]), elimination t1/2 = 2.7 min, CL = 2.33 l h(-1) kg(-1) and V = 0.14 l kg(-1). The Cmax for DHA was 9.3 microM (2.64 mg l[-1]), t1/2 = 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%, Cmax was 2.6 microM (0.74 mg l[-1]), t1/2 = 39 min, and MAT = 67 min. Overall, the PCT50 and fever clearance time (FCT) were 6.5 h and 24 h, respectively. There was no correlation between PCT50 or FCT and AUC, Cmax or MRT for DHA.

Conclusions: Despite rapid clearance of ARTS and DHA in patients with uncomplicated falciparum malaria, prompt parasite and fever clearance were achieved. High relative bioavailability of DHA following oral ARTS administration, and clinical outcomes comparable with those after i.v. ARTS, support the use of the oral formulation in the primary care setting.

Figure 1

Plasma concentration-time profile for artesunate (▴) and dihydroartemisinin (•) following 312.5 μmol (120 mg) i.v. dose (a) of artesunate to 26 Vietnamese patients, and for dihydroartemisinin (○) following 260.4 μmol (100 mg) oral dose (b) of artesunate to 19 Vietnamese patients. Data are shown as mean+s.d.

Figure 2

Parasite clearance curves, as a percentage of the original parasite count, for group 1 (i.v. • at 0, oral ○ at 8 h; data are mean+s.d.) and group 2 (oral ARTS □ at 0, i.v. ▪ at 8 h; data are mean−s.d.). The arrow (↓) highlights the time at which the second dose (by alternative route) was administered.