title: Intramuscular bioavailability and clinical efficacy of artesunate in gabonese children with severe malaria.
abstract: Artesunate (ARS) is a water-soluble artemisinin derivative that is a potential alternative to quinine for the treatment of severe childhood malaria. We studied the pharmacokinetics and bioavailability of ARS given by the intramuscular (i.m.) route in an open crossover study design. Fourteen children were randomized to receive intravenous (i.v.) ARS in a loading dose (2.4 mg/kg of body weight) followed 12 h later by an i.m. dose (1.2 mg/kg) (group I), and 14 children were randomized to receive i.m. ARS (2.4 mg/kg) followed by an i.v. dose of ARS (1.2 mg/kg) (group II). We carried out a two-compartment analysis of ARS and dihydroartemisinin (DHA; the principal antimalarial metabolite) levels in 21 children (groups I and II combined). Absorption of i.m. ARS was rapid, with the maximum concentration of DHA in serum being achieved in less than 1 h in most children (median time to the maximum concentration of drug in serum, 35.1 min; range, 10.8 to 71.9 min). The absolute bioavailability of DHA was a median of 86.4% (range, 11.4 to 462.1%), the median steady-state volume of distribution was 1.3 liters/kg (range, 0.5 to 7.9 liters/kg), and the median clearance was 0.028 liters/kg/min (range, 0.001 to 1.58 liters/kg/min). There were no major adverse events attributable to ARS. Parasite clearance kinetics were comparable between the two treatment groups. These results support the use of i.m. ARS in children with severe malaria.
authors.affiliation: Department of Infectious Diseases, St. George's Hospital Medical School, London SW17 ORE, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Nealon
authors.forename: Arnaud
authors.initials: A
authors.lastname: Dzeing
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller-Römer
authors.forename: Timothy
authors.initials: T
authors.lastname: Planche
authors.forename: Veronique
authors.initials: V
authors.lastname: Sinou
authors.forename: Maryvonne
authors.initials: M
authors.lastname: Kombila
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kremsner
authors.forename: Daniel
authors.initials: D
authors.lastname: Parzy
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Krishna
mesh_terms: D000962:Antimalarials / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D037621:Artemisinins / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077332:Artesunate; D001682:Biological Availability; D002675:Child, Preschool; D018592:Cross-Over Studies; D005260:Female; D005681:Gabon; D006207:Half-Life; D006801:Humans; D007223:Infant; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D012717:Sesquiterpenes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; D000077332:Artesunate