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Prediction of methotrexate elimination after high dose infusion in children with acute lymphoblastic leukaemia using a population pharmacokinetic approach
Author(s) -
Odoul Franck,
Guellec Chantal Le,
Lamagnère JeanPierre,
Breilh Dominique,
Saux MarieClaude,
Paintaud Gilles,
AutretLeca Elisabeth
Publication year - 1999
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.1999.tb00366.x
Subject(s) - methotrexate , pharmacokinetics , population , medicine , toxicity , therapeutic drug monitoring , sampling (signal processing) , bayesian probability , dosing , pharmacology , statistics , mathematics , computer science , environmental health , filter (signal processing) , computer vision
— 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 H 24 , H 48 , H 72 and until the concentration is less than 0.2 μmol/L is commonly performed. However, a number of patients may reach concentrations of less than 0.2 μmol/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 μmol/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 (H 48 ) or two (H 24 and H 48 ) 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%), k 12 = 0.0044 h −1 (105%), k 21 = 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 (H 48 ) 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 μmol/L in each individual.