title: Pharmacokinetic evaluation of intravenous artesunate in adults with uncomplicated falciparum malaria in Kenya: a phase II study.
abstract: BACKGROUND
  Alternatives to treatment for malaria treatment of travellers are needed in the USA and in Europe for travellers who return with severe malaria infections. The objective of this study is to show the pharmacokinetic (PK) profile of intravenous artesunate (AS), which was manufactured under good manufacturing practice (GMP) conditions, in adults with uncomplicated falciparum malaria in Kenya.
  
  
  METHODS
  The PK parameters of intravenous AS manufactured under current cGMP were evaluated after a single dose of drug at 2.4 mg/kg infused over 2 min in 28 adults with uncomplicated Plasmodium falciparum malaria. Plasma concentrations of AS and dihydroartemisinin (DHA) were measured using a validated liquid chromatography-mass spectrometry (LC-MS/MS) methodology. Pharmacokinetic data were analysed with a compartmental analysis for AS and DHA.
  
  
  RESULTS
  The results suggest there were no drug-related adverse events in any of the patients. After intravenous infusion, the concentration of the parent drug rapidly declined, and the AS was converted to DHA. AS and DHA showed mean elimination half-lives of 0.17 hours and 1.30 hours, respectively. The high mean peak concentration (Cmax) of AS was shown to be 28,558 ng/mL while the Cmax of DHA was determined to be 2,932 ng/mL. Significant variability was noted in the PK profiles of the 28 patients tested. For example, Cmax values of AS were calculated to range from 3,362 to 55,873 ng/mL, and the Cmax value of DHA was noted to vary from 1,493 to 5,569 ng/mL. The mean area under the curve (AUC) of AS was shown to be approximately half that of DHA (1,878 ng · h/mL vs 3,543 ng · h/mL). The DHA/AS ratio observed was 1.94 during the one-day single treatment, and the AUC and half- life measured for DHA were significantly larger and longer than for AS.
  
  
  CONCLUSIONS
  Intravenous AS can provide much higher peak concentrations of AS when compared to concentrations achieved with oral therapy; this may be crucial for the rapid elimination of parasites in patients with severe malaria. Given the much longer half-life of DHA compared to the short half-life of AS, DHA also plays a significant role in treatment of severe malaria.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research (WRAIR), 503 Robert Grant Avenue, Silver Spring, MD, 20910-7500, USA. qigui.li.civ@mail.mil.
authors.forename: Qigui
authors.initials: Q
authors.lastname: Li
authors.forename: Shon
authors.initials: S
authors.lastname: Remich
authors.forename: Scott R
authors.initials: SR
authors.lastname: Miller
authors.forename: Bernhards
authors.initials: B
authors.lastname: Ogutu
authors.forename: Walter
authors.initials: W
authors.lastname: Otieno
authors.forename: Victor
authors.initials: V
authors.lastname: Melendez
authors.forename: Paktiya
authors.initials: P
authors.lastname: Teja-Isavadharm
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Weina
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hickman
authors.forename: Bryan
authors.initials: B
authors.lastname: Smith
authors.forename: Mark
authors.initials: M
authors.lastname: Polhemus
mesh_terms: D065767:Activation, Metabolic; D000328:Adult; D000368:Aged; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000600:supply & distribution / Q000627:therapeutic use; D037621:Artemisinins / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000600:supply & distribution / Q000627:therapeutic use; D000077332:Artesunate; D053626:Atovaquone / Q000627:therapeutic use; D002853:Chromatography, Liquid; D004338:Drug Combinations; D004339:Drug Compounding / Q000592:standards; D016903:Drug Monitoring; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007630:Kenya; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy*; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D002727:Proguanil / Q000627:therapeutic use; D012156:Reticulocytes / Q000187:drug effects; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; C109496:atovaquone, proguanil drug combination; D000077332:Artesunate; C039060:artenimol; D002727:Proguanil; D053626:Atovaquone