title: Plasmodium falciparum drug resistance phenotype as assessed by patient antimalarial drug levels and its association with pfmdr1 polymorphisms.
abstract: BACKGROUND
  Multidrug-resistant Plasmodium falciparum is a major threat to global malaria control. Parasites develop resistance by gradually acquiring genetic polymorphisms that decrease drug susceptibility. The aim of this study was to investigate the extent to which parasites with different genetic characteristics are able to withstand individual drug blood concentrations.
  
  
  METHODS
  We analyzed 2 clinical trials that assessed the efficacy and effectiveness of artemether-lumefantrine. As a proof of concept, we used measured day 7 lumefantrine concentrations to estimate the concentrations at which reinfections multiplied. P. falciparum multidrug resistance gene 1 (pfmdr1) genotypes of these parasites were then correlated to drug susceptibility.
  
  
  RESULTS
  Reinfecting parasites with the pfmdr1 N86/184F/D1246 haplotype were able to withstand lumefantrine blood concentrations 15-fold higher than those with the 86Y/Y184/1246Y haplotype.
  
  
  CONCLUSIONS
  By estimating drug concentrations, we were able to quantify the contribution of pfmdr1 single-nucleotide polymorphisms to reduced lumefantrine susceptibility. The method can be applied to all long-half-life antimalarial drugs, enables early detection of P. falciparum with reduced drug susceptibility in vivo, and represents a novel way for unveiling molecular markers of antimalarial drug resistance.
authors.affiliation: Malaria Research, Infectious Disease Unit, Department of Medicine Solna, Stockholm, Sweden. maja.malmberg@ki.se
authors.forename: Maja
authors.initials: M
authors.lastname: Malmberg
authors.forename: Pedro E
authors.initials: PE
authors.lastname: Ferreira
authors.forename: Joel
authors.initials: J
authors.lastname: Tarning
authors.forename: Johan
authors.initials: J
authors.lastname: Ursing
authors.forename: Billy
authors.initials: B
authors.lastname: Ngasala
authors.forename: Anders
authors.initials: A
authors.lastname: Björkman
authors.forename: Andreas
authors.initials: A
authors.lastname: Mårtensson
authors.forename: José P
authors.initials: JP
authors.lastname: Gil
mesh_terms: D000962:Antimalarials / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D004338:Drug Combinations; D004351:Drug Resistance; D004983:Ethanolamines / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D006801:Humans; D007223:Infant; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D055502:Secondary Prevention
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513498:Mdr1 protein, Plasmodium falciparum