title: Pharmacokinetics and pharmacodynamics of intravenous artesunate during severe malaria treatment in Ugandan adults.
abstract: BACKGROUND
  Severe malaria is a medical emergency with high mortality. Prompt achievement of therapeutic concentrations of highly effective anti-malarial drugs reduces the risk of death. The aim of this study was to assess the pharmacokinetics and pharmacodynamics of intravenous artesunate in Ugandan adults with severe malaria.
  
  
  METHODS
  Fourteen adults with severe falciparum malaria requiring parenteral therapy were treated with 2.4 mg/kg intravenous artesunate. Blood samples were collected after the initial dose and plasma concentrations of artesunate and dihydroartemisinin measured by solid-phase extraction and liquid chromatography-tandem mass spectrometry. The study was approved by the Makerere University Faculty of Medicine Research and Ethics Committee (Ref2010-015) and Uganda National Council of Science and Technology (HS605) and registered with ClinicalTrials.gov (NCT01122134).
  
  
  RESULTS
  All study participants achieved prompt resolution of symptoms and complete parasite clearance with median (range) parasite clearance time of 17 (8-24) hours. Median (range) maximal artesunate concentration (Cmax) was 3260 (1020-164000) ng/mL, terminal elimination half-life (T1/2) was 0.25 (0.1-1.8) hours and total artesunate exposure (AUC) was 727 (290-111256) ng·h/mL. Median (range) dihydroartemisinin Cmax was 3140 (1670-9530) ng/mL, with Tmax of 0.14 (0.6 - 6.07) hours and T1/2 of 1.31 (0.8-2.8) hours. Dihydroartemisinin AUC was 3492 (2183-6338) ng·h/mL. None of the participants reported adverse events.
  
  
  CONCLUSIONS
  Plasma concentrations of artesunate and dihydroartemisinin were achieved rapidly with rapid and complete symptom resolution and parasite clearance with no adverse events.
authors.affiliation: Infectious Diseases Institute, Makerere University, PO Box 22418, Kampala, Uganda. pbyakika@idi.co.ug
authors.forename: Pauline
authors.initials: P
authors.lastname: Byakika-Kibwika
authors.forename: Mohammed
authors.initials: M
authors.lastname: Lamorde
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mayito
authors.forename: Lillian
authors.initials: L
authors.lastname: Nabukeera
authors.forename: Harriet
authors.initials: H
authors.lastname: Mayanja-Kizza
authors.forename: Elly
authors.initials: E
authors.lastname: Katabira
authors.forename: Warunee
authors.initials: W
authors.lastname: Hanpithakpong
authors.forename: Celestino
authors.initials: C
authors.lastname: Obua
authors.forename: Nadine
authors.initials: N
authors.lastname: Pakker
authors.forename: Niklas
authors.initials: N
authors.lastname: Lindegardh
authors.forename: Joel
authors.initials: J
authors.lastname: Tarning
authors.forename: Peter J
authors.initials: PJ
authors.lastname: de Vries
authors.forename: Concepta
authors.initials: C
authors.lastname: Merry
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D037621:Artemisinins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077332:Artesunate; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D010949:Plasma / Q000737:chemistry; D053719:Tandem Mass Spectrometry; D014454:Uganda
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; C039060:artenimol