title: Population pharmacokinetics of mefloquine, administered as a fixed-dose combination of artesunate-mefloquine in Indian patients for the treatment of acute uncomplicated Plasmodium falciparum malaria.
abstract: BACKGROUND
  Fixed-dose combinations of artemisinin combination therapy are strongly recommended to facilitate drug administration and compliance. New fixed-dose combinations must nevertheless be evaluated in relevant populations in terms of efficacy and pharmacokinetics.
  
  
  METHODS
  A single-arm, open-label, clinical trial was performed in Indian patients with acute uncomplicated Plasmodium falciparum malaria to investigate the efficacy and the pharmacokinetics of mefloquine when combined with artesunate in a fixed-dose combination (400/200 mg of mefloquine base/artesunate). The pharmacokinetic analysis was performed using a population approach.
  
  
  RESULTS
  Seventy-seven patients were included in the study. Mefloquine pharmacokinetics obeys a two-compartment model with first-order absorption and elimination. Mean parameter estimates (% inter-individual variability) were as follows: 0.16 h(-1) (75%) for the absorption rate constant, 1.13 L/h (30%) for the apparent plasma clearance, 271 L (21%) for the apparent central distribution volume, 344 L (54%) for the apparent peripheral distribution volume, and 1.43 L/h for the apparent distribution clearance. These values were consistent with the pharmacokinetic results described in Thai patients. No significant covariate was found for clearance. Body weight explained the inter-individual variability of the apparent central and peripheral distribution volumes. The PCR-adjusted efficacy of the treatment was 100%.
  
  
  CONCLUSIONS
  The lack of significant covariate explaining the inter-individual variability of mefloquine clearance, combined with the excellent efficacy, supports the use of the standard 200/400 mg of artesunate-mefloquine fixed-dose combination in Indian patients with uncomplicated P. falciparum malaria.
  
  
  BACKGROUND
  
  
  
  BACKGROUND
  ISRCTN70618692.
authors.forename: Vincent
authors.initials: V
authors.lastname: Jullien
authors.forename: Neena
authors.initials: N
authors.lastname: Valecha
authors.forename: Bina
authors.initials: B
authors.lastname: Srivastava
authors.forename: Bhawna
authors.initials: B
authors.lastname: Sharma
authors.affiliation: Drugs for Neglected Diseases initiative, 15 chemin Louis-Dunant, 1202 Geneva, Switzerland. jean-rene.kiechel@wanadoo.fr.
authors.forename: Jean-René
authors.initials: JR
authors.lastname: Kiechel
mesh_terms: D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics*; D037621:Artemisinins / Q000008:administration & dosage; D000077332:Artesunate; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007194:India; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D015767:Mefloquine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D000077332:Artesunate; D015767:Mefloquine