title: Artemisinin kinetics and dynamics during oral and rectal treatment of uncomplicated malaria.
abstract: OBJECTIVE
  To compare parasite clearance times after oral and rectal administration of artemisinin in adults with uncomplicated malaria and to relate pharmacodynamics with artemisinin kinetics and to disclose any pharmacokinetic changes during treatment.
  
  
  METHODS
  Thirty male Vietnamese patients with falciparum malaria were randomized to treatment with 500 mg artemisinin daily by either the oral or rectal route of administration. Parasite densities in capillary blood were determined by microscopy every 4 to 6 hours. Artemisinin plasma concentrations on the first and last day of treatment were determined by HPLC and unbound fractions in plasma were determined by ultrafiltration.
  
  
  RESULTS
  Mean parasite clearance times and 95% confidence intervals (95% CI) were 25 (95% CI, 16 to 33) and 29 (95% CI, 23 to 35) hours during oral and rectal treatment, respectively. The bioavailability after rectal relative to oral artemisinin was 30%. Artemisinin areas under the plasma concentration-time curve (AUC) on the fifth (last) day of oral or rectal treatment were 30% (95% CI, 4% to 56%) and 40% (95% CI, -6% to 91%), respectively, of those after the first dose. The fraction unbound in plasma was 15% (95% CI, 12% to 19%), increasing marginally during treatment. No relationship was found between main clinical end points and drug exposure, although indices for the rapidity of response onset were lower after oral treatment and correlated to unbound AUC values (rS = -0.7; p < 0.001).
  
  
  CONCLUSIONS
  The similarity in parasite clearance times despite lower drug levels during rectal treatment suggests that initial oral doses may be unnecessarily high. The singular time dependency of artemisinin pharmacokinetics, attributed to autoinduction of drug elimination, has possible implications for combination chemotherapy. Decreasing artemisinin concentrations during treatment may partly explain recrudescences and increase the risk for resistance development.
authors.affiliation: Department of Pharmacy, Uppsala University, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Ashton
authors.forename: D S
authors.initials: DS
authors.lastname: Nguyen
authors.forename: V H
authors.initials: VH
authors.lastname: Nguyen
authors.forename: T
authors.initials: T
authors.lastname: Gordi
authors.forename: N H
authors.initials: NH
authors.lastname: Trinh
authors.forename: X H
authors.initials: XH
authors.lastname: Dinh
authors.forename: T N
authors.initials: TN
authors.lastname: Nguyen
authors.forename: D C
authors.initials: DC
authors.lastname: Le
mesh_terms: D000284:Administration, Oral; D000285:Administration, Rectal; D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D037621:Artemisinins; D006801:Humans; D008288:Malaria / Q000097:blood* / Q000188:drug therapy* / Q000208:ethnology; D008297:Male; D008875:Middle Aged; D012717:Sesquiterpenes / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013997:Time Factors; D014744:Vietnam
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; C031327:artemisinin