title: Optimal designs for population pharmacokinetic studies of the partner drugs co-administered with artemisinin derivatives in patients with uncomplicated falciparum malaria.
abstract: BACKGROUND
  Artemisinin-based combination therapy (ACT) is currently recommended as first-line treatment for uncomplicated malaria, but of concern, it has been observed that the effectiveness of the main artemisinin derivative, artesunate, has been diminished due to parasite resistance. This reduction in effect highlights the importance of the partner drugs in ACT and provides motivation to gain more knowledge of their pharmacokinetic (PK) properties via population PK studies. Optimal design methodology has been developed for population PK studies, which analytically determines a sampling schedule that is clinically feasible and yields precise estimation of model parameters. In this work, optimal design methodology was used to determine sampling designs for typical future population PK studies of the partner drugs (mefloquine, lumefantrine, piperaquine and amodiaquine) co-administered with artemisinin derivatives.
  
  
  METHODS
  The optimal designs were determined using freely available software and were based on structural PK models from the literature and the key specifications of 100 patients with five samples per patient, with one sample taken on the seventh day of treatment. The derived optimal designs were then evaluated via a simulation-estimation procedure.
  
  
  RESULTS
  For all partner drugs, designs consisting of two sampling schedules (50 patients per schedule) with five samples per patient resulted in acceptable precision of the model parameter estimates.
  
  
  CONCLUSIONS
  The sampling schedules proposed in this paper should be considered in future population pharmacokinetic studies where intensive sampling over many days or weeks of follow-up is not possible due to either ethical, logistic or economical reasons.
authors.affiliation: Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Melbourne, Australia. kjamsen@pgrad.unimelb.edu.au
authors.forename: Kris M
authors.initials: KM
authors.lastname: Jamsen
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Duffull
authors.forename: Joel
authors.initials: J
authors.lastname: Tarning
authors.forename: Niklas
authors.initials: N
authors.lastname: Lindegardh
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.forename: Julie A
authors.initials: JA
authors.lastname: Simpson
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D037621:Artemisinins / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D015233:Models, Statistical; D004364:Pharmaceutical Preparations; D011247:Pregnancy; D012107:Research Design; D013997:Time Factors
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004364:Pharmaceutical Preparations; C031327:artemisinin