title: Prediction of methotrexate elimination after high dose infusion in children with acute lymphoblastic leukaemia using a population pharmacokinetic approach.
abstract: High-dose methotrexate (HD-MTX) with leucovorin rescue is a component of therapy in children with acute lymphoblastic leukaemia. Since MTX toxicity is related to drug exposure, a monitoring of serum MTX concentrations at H24, H48, H72 and until the concentration is less than 0.2 micromol/L is commonly performed. However, a number of patients may reach concentrations of less than 0.2 micromol/L long before the next sampling is scheduled. The aim of our study was to develop a Bayesian method predicting the time at which MTX concentration reaches 0.2 micromol/L in order to decrease the number of samples drawn and to allow for a more rapid patient discharge. Methotrexate population parameters were estimated from a retrospective analysis of 60 infusions in 23 children and MTX concentrations were predicted from an independent set of 20 courses in 14 children with a Bayesian approach using either one (H48) or two (H24 and H48) samples. The following population parameters were obtained using a two-compartment model: CL = 3.51 L/h (inter-individual variability: 66%), Vd = 8.67 L (58%), k12 = 0.0044 h(-1)(105%), k21 = 0.039 h(-1)(25%). Clearance and Vd were found to increase with weight and age respectively. Both sampling schedules tested for the Bayesian estimation enabled accurate prediction of concentrations and provided satisfactory precision despite a small bias. When considering the ability to predict the time at which the threshold was reached, the one-sample (H48) schedule gave the best results. We conclude that a sampling schedule involving only one sample and Bayesian parameter estimation may be able to predict the delay necessary to reach 0.2 micromol/L in each individual.
authors.affiliation: Department of Pharmacology, Tours University Hospital, France.
authors.forename: F
authors.initials: F
authors.lastname: Odoul
authors.forename: C
authors.initials: C
authors.lastname: Le Guellec
authors.forename: J P
authors.initials: JP
authors.lastname: Lamagnère
authors.forename: D
authors.initials: D
authors.lastname: Breilh
authors.forename: M C
authors.initials: MC
authors.lastname: Saux
authors.forename: G
authors.initials: G
authors.lastname: Paintaud
authors.forename: E
authors.initials: E
authors.lastname: Autret-Leca
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics*; D001499:Bayes Theorem; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000097:blood / Q000493:pharmacokinetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D013997:Time Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate