The pharmacokinetic properties of intramuscular artesunate and rectal dihydroartemisinin in uncomplicated falciparum malaria

Abstract

Aims: To obtain pharmacokinetic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following i.m. ARTS and rectal DHA administration.

Methods: Twelve Vietnamese patients with uncomplicated falciparum malaria were randomized to receive either i.v. or i.m. ARTS (120 mg), with the alternative preparation given 8 h later in an open crossover design. A further 12 patients were given i.v. ARTS (120 mg) at 0 h and rectal DHA (160 mg) 8 h later.

Results: Following i.v. bolus, ARTS had a peak concentration of 42 microm (16 mg l(-1), elimination t1/2 = 3.2 min, CL = 2.8 l h(-1) kg(-1) and V = 0.22 l kg(-1) . The Cmax for DHA was 9.7 microm (2.7 mg l(-1) ), t1/2 = 59 min, CL = 0.64 l h(-1) kg(-1) and V = 0.8 l kg(-1) . Following i.m. ARTS, Cmax was 2.3 microm (3.7 mg l(-1)), the apparent t1/2 = 41 min, CL = 2.9 l h(-1) kg(-1) and V = 2.6 l kg(-1). The relative bioavailability of DHA was 88%, Cmax was 4.1 microm (1.16 mg l(-1)) and t1/2 = 64 min. In the rectal DHA study, relative bioavailability of DHA was 16%.

Conclusions: For patients with uncomplicated falciparum malaria i.m. ARTS is a suitable alternative to i.v. ARTS, at equal doses. To achieve plasma DHA concentrations equivalent to parenteral administration of ARTS, rectal DHA should be given at approximately four-fold higher milligram doses. Further studies are needed to determine whether these recommendations can be applied to patients with severe malaria.

Figure 1

Plasma concentration-time profile for artesunate (▴) and dihydroartemisinin (•) following 312.5 µmol (120 mg) i.v. ARTS, and for artesunate (▵) and dihydroartemisinin (○) following 312.5 µmol i.m. ARTS, administered to 11 Vietnamese patients with uncomplicated falciparum malaria. Data are shown as mean+s.d..

Figure 2

Plasma concentration-time profile for artesunate (▴) and dihydroartemisinin (•) following 312.5 µmol (120 mg) i.v. ARTS (n = 12), and for dihydroartemisinin (•) following 563 µmol (160 mg) rectal DHA (n = 11), administered to Vietnamese patients with uncomplicated falciparum malaria. Data are shown as mean+s.d.. Inset shows individual concentration-time profile for each patient (grey lines) and mean data (black line±s.d.).

Figure 3

Simulated plasma concentration-time profile for dihydroartemisinin after simultaneous administration of 120 mg i.m. ARTS and 320 mg rectal DHA (——; AUC(0,8 h) = 15.7 µmol l⁻¹ h), simultaneous administration of 120 mg i.v. ARTS and 100 mg oral ARTS (····; AUC(0,8 h) = 14.2 µmol l⁻¹ h) and administration of 120 mg i.v. ARTS followed by 100 mg oral ARTS 4 h later (– –; AUC(0,8 h) = 13.5 µmol l⁻¹ h). Simulations are based on data from present study and Batty et al. [14].