Bioavailability and preliminary clinical efficacy of intrarectal artesunate in Ghanaian children with moderate malaria

We report the first detailed pharmacokinetic assessment of intrarectal (i.r .) artesunate (ARS) in African children. Artesunate was given intravenously (i.v.; 2.4 mg/kg of body weight) and i.r. (10 or 20 mg/kg formulated as 50 - or 200-mg suppositories [Rectocaps]) in a crossover study design to 34 Gh anaian children with moderate falciparum malaria. The median relative bioav ailability of dihydroartemisinin (DHA), the active antimalarial metabolite of ARS, was higher in the low-dose i.r. group (10 mg/kg) than in the high-d ose i.r. group (20 mg/kg) (58 versus 23%; P = 0.018). There was,vide interp atient variation in the area under the concentration-time curve after i.r. ARS administration (up to 9-fold in the high-dose group and 20-fold in the low-dose group). i.r. administered ARS was more rapidly absorbed in the low -dose group than the high-dose group (median [range] absorption half-lives, 0.7 h [0.3 to 1.24 h] versus 1.1 h [0.6 to 2.7 h] [P = 0.023]. i.r. admini stered ARS was eliminated with a median (range) half-life of 0.8 h (0.4 to 2.7 h) (low-dose group and 0.9 h (0.1 to 2.5 h) thigh-dose group) (P = 1). The fractional clearances of DHA were 3.9, 2.6, and 1.5 liters/kg/h for the 20-mg/kg, 10-mg/kg and i.v. groups, respectively (P = 0.001 and P = 0.06 f or the high-and low-dose i.r. groups compared with the i.v. groups, respect ively), The median volumes of distribution for DHA were 1.5 liters kg (20 m g/kg, i.r. group), 1.8 liters/kg (10 mg/kg, i.r. group), and 0.6 liters/kg (i.v. group) (P < 0.05 for both i.r. groups compared with the i.v. group). Parasite clearance kinetics were comparable in all treatment groups. i.r. a dministered ARS may be a useful alternative to parenterally administered AR S in the management of moderate childhood malaria and should be studied fur ther.