title: A limited sampling strategy to estimate individual pharmacokinetic parameters of methotrexate in children with acute lymphoblastic leukemia.
abstract: OBJECTIVE
  The objectives of this study were to characterize the population pharmacokinetics of MTX in patients with acute lymphoblastic leukemia (ALL) with ages ranging from 2 to 16 years and to propose a limited sampling strategy to estimate individual pharmacokinetic parameters.
  
  
  METHODS
  Seventy-nine children were enrolled in this study; they received 1-4 courses of chemotherapy. MTX was administered at a dose of 5 g/m2. MTX population parameters were estimated from 61 patients (231 courses; age range: 2-16 years). The data were analyzed by nonlinear mixed-effect modeling with use of a two-compartment structural model. The interoccasion variability was taken into account in the model. Eighteen additional patients (70 courses) were used to evaluate the predictive performances of the Bayesian approach and to devise a limited sampling strategy.
  
  
  RESULTS
  The following population parameters were obtained: total clearance (CL) = 8.8 l/h (inter-individual variability: 43%), initial volume of distribution (V1) = 17.3 l (48%), k12 = 0.0225 h(-1) (41%), and k21 = 0.0629 h(-1) (24%). The inter-individual variability in the initial volume of distribution was partially explained by the fact that this parameter was weight-dependent. Intercourse variability was limited, with a mean variation of 13.2%. The protocol involving two sampling times, 24 and 48 h after the beginning of infusion, allows precise and accurate determination of individual pharmacokinetic parameters and consequently, it was possible to predict the time at which the MTX concentration reached the predicted threshold (0.2 microM) below which the administration of folinic acid could be stopped.
  
  
  CONCLUSIONS
  The results of this study combine the relationships between the pharmacokinetic parameters of MTX and patient covariates that may be useful for dose adjustment, with a convenient sampling procedure that may aid in optimizing pediatric patient care.
authors.affiliation: Department of Paediatric Pharmacology and Pharmacogenetics, Robert Debré Hospital, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Plard
authors.forename: Christine
authors.initials: C
authors.lastname: Piard
authors.forename: Françoise
authors.initials: F
authors.lastname: Bressolle
authors.forename: May
authors.initials: M
authors.lastname: Fakhoury
authors.forename: Daolun
authors.initials: D
authors.lastname: Zhang
authors.forename: Karina
authors.initials: K
authors.lastname: Yacouben
authors.forename: André
authors.initials: A
authors.lastname: Rieutord
authors.forename: Evelyne
authors.initials: E
authors.lastname: Jacqz-Aigrain
mesh_terms: D000293:Adolescent; D001499:Bayes Theorem; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics*; D008962:Models, Theoretical; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D012494:Sampling Studies
chemical_list: D008727:Methotrexate