title: How much fat is necessary to optimize lumefantrine oral bioavailability?
abstract: BACKGROUND
  Artemether-lumefantrine (AL) is the only fixed, artemisinin-based combination antimalarial drug which is registered internationally and deployed on a large scale. Absorption of the hydrophobic lipophilic lumefantrine component varies widely between individuals and is greatly increased by fat coadministration; but patients with acute malaria are frequently nauseated and anorexic, making dietary advice difficult to comply with. The aim of this study was to describe the dose-response relationship between coadministration of fat and relative lumefantrine bioavailability, in order to determine the minimum amount of fat necessary to optimize absorption.
  
  
  METHODS
  We conducted a multiple crossover pharmacokinetic study in 12 healthy volunteers. This compared the area under the plasma concentration-time curve (AUC) for lumefantrine after administration of a single dose of AL in the fasting state given with 0, 10, 40, 150 and 500 ml of soya milk corresponding to 0, 0.32, 1.28, 4.8 and 16 g of fat. All volumes of milk supplements were tested in all subjects with a 3- to 4-week washout period in-between.
  
  
  RESULTS
  A dose-response relationship was demonstrated between the volume of soya milk administered and lumefantrine bioavailability. AL administration with soya milk increased the lumefantrine AUC more than five fold. The population mean estimated volume of soya milk required to obtain 90% of maximum effect (in terms of lumefantrine AUC) was 36 ml (corresponding to 1.2 g of fat).
  
  
  CONCLUSIONS
  Coadministration of artemether-lumefantrine with a relatively small amount of fat (as soya milk) was required to ensure maximum absorption of lumefantrine in healthy adult volunteers.
authors.affiliation: Shoklo Malaria Research Unit, Mae Sot, Thailand. smru@tropmedres.ac
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Ashley
authors.forename: Kasia
authors.initials: K
authors.lastname: Stepniewska
authors.forename: Niklas
authors.initials: N
authors.lastname: Lindegårdh
authors.forename: Anna
authors.initials: A
authors.lastname: Annerberg
authors.forename: Am
authors.initials: A
authors.lastname: Kham
authors.forename: Al
authors.initials: A
authors.lastname: Brockman
authors.forename: Pratap
authors.initials: P
authors.lastname: Singhasivanon
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.forename: François
authors.initials: F
authors.lastname: Nosten
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage; D001682:Biological Availability; D018592:Cross-Over Studies; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004983:Ethanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005215:Fasting; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018565:Food-Drug Interactions; D006801:Humans; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D041942:Soy Milk / Q000008:administration & dosage*
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D000078102:Lumefantrine