title: Population pharmacokinetics of pyrimethamine and sulfadoxine in children with congenital toxoplasmosis.
abstract: OBJECTIVE
  To develop a population pharmacokinetic model for pyrimethamine (PYR) and sulfadoxine (SDX) in children with congenital toxoplasmosis.
  
  
  METHODS
  Children were treated with PYR (1.25 mg kg(-1)) and SDX (25 mg kg(-1)) (Fansidar) plus folinic acid (Lederfoline) 5 mg). Plasma concentrations, available from a therapeutic drug monitoring database, were determined by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using a nonlinear mixed effects model.
  
  
  RESULTS
  Eighty-nine children, aged 1 week to 14 years and weighing 2.9-59 kg, were available for evaluation. Both PYR and SDX concentration-time profiles were best described by a one-compartment open model. Volume of plasma distribution (V) and clearance (CL) were significantly related to body weight (BW) using an allometric function. Typical CL and V estimates (95% confidence interval), for a child weighing 11 kg were 5.50 (5.28, 5.73) l day(-1) and 36 (33, 39) l for PYR and 0.26 (0.25, 0.27) l day(-1) and 2.1 (1.9, 2.3) l for SDX. For BW between 3.5 and 60 kg, plasma half-lives were predicted to vary from 4.0 to 5.2 days for PYR, and from 5.0 to 7.5 days for SDX.
  
  
  CONCLUSIONS
  This study indicated that body weight influences PYR and SDX pharmacokinetics in children. To optimize PYR/SDX combination treatment in congenital toxoplasmosis, short dosing intervals in very young low-wight children are probably appropriate.
authors.affiliation: Laboratoire de Pharmacologie-Toxicologie, CHU, Reims, France. ttrenque@chu-reims.fr
authors.forename: T
authors.initials: T
authors.lastname: Trenque
authors.forename: N
authors.initials: N
authors.lastname: Simon
authors.forename: I
authors.initials: I
authors.lastname: Villena
authors.forename: C
authors.initials: C
authors.lastname: Chemla
authors.forename: C
authors.initials: C
authors.lastname: Quereux
authors.forename: B
authors.initials: B
authors.lastname: Leroux
authors.forename: R
authors.initials: R
authors.lastname: Jaussaud
authors.forename: G
authors.initials: G
authors.lastname: Rémy
authors.forename: D
authors.initials: D
authors.lastname: Dupouy
authors.forename: H
authors.initials: H
authors.lastname: Millart
authors.forename: J-M
authors.initials: JM
authors.lastname: Pinon
authors.forename: S
authors.initials: S
authors.lastname: Urien
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011739:Pyrimethamine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013413:Sulfadoxine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014125:Toxoplasmosis, Congenital / Q000188:drug therapy*
chemical_list: D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D011739:Pyrimethamine