title: Bioavailability and preliminary clinical efficacy of intrarectal artesunate in Ghanaian children with moderate malaria.
abstract: 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 Ghanaian children with moderate falciparum malaria. The median relative bioavailability 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-dose i.r. group (20 mg/kg) (58 versus 23%; P = 0.018). There was wide interpatient 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. administered 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) (high-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 for the high-and low-dose i.r. groups compared with the i.v. groups, respectively). The median volumes of distribution for DHA were 1.5 liters kg (20 mg/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. administered ARS may be a useful alternative to parenterally administered ARS in the management of moderate childhood malaria and should be studied further.
authors.affiliation: Department of Infectious Diseases, St. George's Hospital Medical School, London SW17 ORE, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Krishna
authors.forename: T
authors.initials: T
authors.lastname: Planche
authors.forename: T
authors.initials: T
authors.lastname: Agbenyega
authors.forename: C
authors.initials: C
authors.lastname: Woodrow
authors.forename: D
authors.initials: D
authors.lastname: Agranoff
authors.forename: G
authors.initials: G
authors.lastname: Bedu-Addo
authors.forename: A K
authors.initials: AK
authors.lastname: Owusu-Ofori
authors.forename: J A
authors.initials: JA
authors.lastname: Appiah
authors.forename: S
authors.initials: S
authors.lastname: Ramanathan
authors.forename: S M
authors.initials: SM
authors.lastname: Mansor
authors.forename: V
authors.initials: V
authors.lastname: Navaratnam
mesh_terms: D000285:Administration, Rectal; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D037621:Artemisinins; D000077332:Artesunate; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D005869:Ghana; D006801:Humans; D007223:Infant; D007275:Injections, Intravenous; D008288:Malaria / Q000188:drug therapy*; D016779:Malaria, Cerebral / Q000188:drug therapy; D008297:Male; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; D000077332:Artesunate; D002738:Chloroquine