Prediction of methotrexate elimination after high dose infusion in children with acute lymphoblastic leukaemia using a population pharmacokinetic approach

High-dose methotrexate (HD-MTX) with leucovorin rescue is a component of th erapy 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 mu mol/L is commo nly performed. However, a number of patients may reach concentrations of le ss than 0.2 mu mol/L long before the next sampling is scheduled. The aim of our study was to develop a Bayesian method predicting the time at which MT X concentration reaches 0.2 mu mol/L in order to decrease the number of sam ples drawn and to allow for a more rapid patient discharge. Methotrexate po pulation parameters were estimated from a retrospective analysis of 60 infu sions in 23 children and MTX concentrations were predicted from an independ ent 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 paramet ers were obtained using a two-compartment model: CL = 3.51 L/h (inter-indiv idual 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 weigh t and age respectively. Both sampling schedules tested for the Bayesian est imation enabled accurate prediction of concentrations and provided satisfac tory precision despite a small bias. When considering the ability to predic t the time at which the threshold was reached, the one-sample (H-48) schedu le gave the best results. We conclude that a sampling schedule involving on ly one sample and Bayesian parameter estimation may be able to predict the delay necessary to reach 0.2 mu mol/L in each individual. (C) 1999 Editions scientifiques et medicales Elsevier SAS.