Population pharmacokinetics of long-term methotrexate in children with lymphoblastic leukemia
M.J. García1, D. Santos Buelga1,D. Aumente2, P. Gomez2 ,JC.Lukas1A high dose Methotrexate (HD MTX) protocol was used for long-term treatment of 37 children, 20 males and 17 females with lymphoblastic leukemia. The treatment consisted of administration of a fast followed by a slow perfusion of MTX with a mean dose of 1850 mg in 2 to 5 treatment cycles (mean 3.5) per child, with 2- 8 plasma concentration measurements (mean 3.3) per cycle. An index group of 30 individuals was used for population model development and the remaining 7 subjects were used for validation of the final covariate model. The index and validation groups had [mean (range)] AGE = 7.7 (1.2-16) and 7.6 (2 – 17) years and weight (WT) = 33 (9.5-80) and 35 (12-59) kg respectively. A bicompartmental pharmacokinetic model was fitted with the non linear mixed effects package NONMEM and the first order conditional estimation (FOCE) method, to obtain the distribution of the parameters of MTX in children. Covariate models were developed on a random subset of 30 children (830 concentrations) within population fits with age, body surface, height, sex and weight. The models were for central clearance, CL = 3.67 + 0.042WT (L/h) and central volume of distribution, Vc = 6.23 + 0.14.WT (L). For the typical child (CV%) CL= 4.42 (27% ) L/h and Vc = 9.73 (28%) L which implied a drop tin the interindividual variability of 27% and 32% for CL and V respectively, compared to the basic model. The covariate model was validated by predicting the concentrations in the remaining 7 patients (validation group). Bias was –1.65 (I.C. ) and precision was 7.38. The model could be used in children with this pathology as Bayesian prior for the individualized prediction of dose titration within the therapeutic protocol.