title: Supervised versus unsupervised antimalarial treatment with six-dose artemether-lumefantrine: pharmacokinetic and dosage-related findings from a clinical trial in Uganda.
abstract: BACKGROUND
  A six-dose antimalarial regimen of artemether-lumefantrine (A/L) may soon become one of the most widely used drug combination in Africa, despite possible constraints with adherence and poor absorption due to inadequate nutrition, and a lack of pharmacokinetic and effectiveness data.
  
  
  METHODS
  Within a trial of supervised versus unsupervised A/L treatment in a stable Ugandan Plasmodium falciparum transmission setting, plasma lumefantrine concentrations were measured in a subset of patients on day 3 (C [lum]day3) and day 7 (C [lum]day7) post-inclusion. Predictors of lumefantrine concentrations were analysed to show how both C [lum]day7 and the weight-adjusted lumefantrine dose affect 28-day recrudescence and re-infection risks. The implications of these novel findings are discussed in terms of the emergence of lumefantrine-resistant strains in Africa.
  
  
  RESULTS
  C [lum]day3 and C [lum]day7 distributions among 241 supervised and 238 unsupervised patients were positively skewed. Unsupervised treatment and decreasing weight-adjusted lumefantrine dose were negatively associated with C [lum]day3. Unsupervised treatment and decreasing age showed strong negative associations with C [lum]day7. Both models were poorly predictive (R-squared < 0.25). There were no recrudescences in either arm, but decreasing lumefantrine dose per Kg resulted in up to 13-fold higher adjusted risks of re-infection. Re-infections occurred only among patients with C [lum]day7 below 400 ng/mL (p < 0.001).
  
  
  CONCLUSIONS
  Maintaining the present six-dose regimen and ensuring high adherence and intake are essential to maximize the public health benefits of this valuable drug combination.
authors.affiliation: Epicentre, Paris, France. francesco.checchi@lshtm.ac.uk
authors.forename: Francesco
authors.initials: F
authors.lastname: Checchi
authors.forename: Patrice
authors.initials: P
authors.lastname: Piola
authors.forename: Carole
authors.initials: C
authors.lastname: Fogg
authors.forename: Francis
authors.initials: F
authors.lastname: Bajunirwe
authors.forename: Samuel
authors.initials: S
authors.lastname: Biraro
authors.forename: Francesco
authors.initials: F
authors.lastname: Grandesso
authors.forename: Eugene
authors.initials: E
authors.lastname: Ruzagira
authors.forename: Joseph
authors.initials: J
authors.lastname: Babigumira
authors.forename: Isaac
authors.initials: I
authors.lastname: Kigozi
authors.forename: James
authors.initials: J
authors.lastname: Kiguli
authors.forename: Juliet
authors.initials: J
authors.lastname: Kyomuhendo
authors.forename: Laurent
authors.initials: L
authors.lastname: Ferradini
authors.forename: Walter R J
authors.initials: WR
authors.lastname: Taylor
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Guthmann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000553:Ambulatory Care / Q000379:methods; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage*; D000077549:Artemether; D037621:Artemisinins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D023801:Directly Observed Therapy; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D007223:Infant; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010349:Patient Compliance; D012008:Recurrence; D016896:Treatment Outcome; D014454:Uganda
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D000077549:Artemether; D000078102:Lumefantrine