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 µm (16 mg l⁻¹), elimination t_1/2 = 3.2 min, CL = 2.8 l h⁻¹ kg⁻¹ and V = 0.22 l kg⁻¹. The C_max for DHA was 9.7 µm (2.7 mg l⁻¹), t_1/2 = 59 min, CL = 0.64 l h⁻¹ kg⁻¹ and V = 0.8 l kg⁻¹. Following i.m. ARTS, C_max was 2.3 µm (3.7 mg l⁻¹), the apparent t_1/2 = 41 min, CL = 2.9 l h⁻¹ kg⁻¹ and V = 2.6 l kg⁻¹. The relative bioavailability of DHA was 88%, C_max was 4.1 µm (1.16 mg l⁻¹) and t_1/2 = 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.