title: A population pharmacokinetic model of piperaquine in pregnant and non-pregnant women with uncomplicated Plasmodium falciparum malaria in Sudan.
abstract: BACKGROUND
  Pregnancy is associated with an increased risk of developing a malaria infection and a higher risk of developing severe malaria. The pharmacokinetic properties of many anti-malarials are also altered during pregnancy, often resulting in a decreased drug exposure. Piperaquine is a promising anti-malarial partner drug used in a fixed-dose combination with dihydroartemisinin. The aim of this study was to investigate the population pharmacokinetics of piperaquine in pregnant and non-pregnant Sudanese women with uncomplicated Plasmodium falciparum malaria.
  
  
  METHODS
  Symptomatic patients received a standard dose regimen of the fixed dose oral piperaquine-dihydroartemisinin combination treatment. Densely sampled plasma aliquots were collected and analysed using a previously described LC-MS/MS method. Data from 12 pregnant and 12 non-pregnant women were analysed using nonlinear mixed-effects modelling. A Monte Carlo Mapped Power (MCMP) analysis was conducted based on a previously published study to evaluate the power of detecting covariates in this relatively small study.
  
  
  RESULTS
  A three-compartment disposition model with a transit-absorption model described the observed data well. Body weight was added as an allometric function on all clearance and volume parameters. A statistically significant decrease in estimated terminal piperaquine half-life in pregnant compared with non-pregnant women was found, but there were no differences in post-hoc estimates of total piperaquine exposure. The MCMP analysis indicated a minimum of 13 pregnant and 13 non-pregnant women were required to identify pregnancy as a covariate on relevant pharmacokinetic parameters (80% power and p=0.05). Pregnancy was, therefore, evaluated as a categorical and continuous covariate (i.e. estimate gestational age) in a full covariate approach. Using this approach pregnancy was not associated with any major change in piperaquine elimination clearance. However, a trend of increasing elimination clearance with increasing gestational age could be seen.
  
  
  CONCLUSIONS
  The population pharmacokinetic properties of piperaquine were well described by a three-compartment disposition model in pregnant and non-pregnant women with uncomplicated malaria. The modelling approach showed no major difference in piperaquine exposure between the two groups and data presented here do not warrant a dose adjustment in pregnancy in this vulnerable population.
authors.affiliation: Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Hoglund
authors.forename: Ishag
authors.initials: I
authors.lastname: Adam
authors.forename: Warunee
authors.initials: W
authors.lastname: Hanpithakpong
authors.forename: Michael
authors.initials: M
authors.lastname: Ashton
authors.forename: Niklas
authors.initials: N
authors.lastname: Lindegardh
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.forename: Francois
authors.initials: F
authors.lastname: Nosten
authors.forename: Joel
authors.initials: J
authors.lastname: Tarning
mesh_terms: D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D037621:Artemisinins / Q000008:administration & dosage; D001682:Biological Availability; D004338:Drug Combinations; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood / Q000150:complications* / Q000188:drug therapy*; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D017711:Nonlinear Dynamics; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000097:blood / Q000188:drug therapy*; D011804:Quinolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013397:Sudan; D055815:Young Adult; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D011804:Quinolines; C039060:artenimol; C034759:piperaquine; D010879:Piperazines