[Population pharmacokinetics of high-dose methotrexate administered in 329 children with acute lymphoblastic leukemia].
The aim of this study was to investigate the population pharmacokinetic characteristics of high-dose methotrexate (HDMTX) administered in children with acute lymphoblastic leukemia (ALL) for individualizing methotrexate dose regimen with routine plasma concentration data. The data of 329 children with acute lymphoblastic leukemia administering HDMTX in hospital were collected from 2003 to 2006. Population pharmacokinetics model, parameters, inter-and intra-individual variation were estimated by nonlinear mixed effect modes (NONMEM) software. The effects of the covariates including sex, age, body weight, alkalization and hydration volumes as well as biochemical parameters on the clearance and apparent volume of distribution of methotrexate were explored and the final model was established. The results showed that according to one compartment open pharmacokinetic model with first-order absorption and first-order elimination used in the modeling procedure, the factor that significantly influenced the clearance and apparent volume of distribution of methotrexate was weight (p<0.05). The final model in this study was: CL=7.0 x [1 + 0.0218 x (WT-31.1)] x EXP (eta(CL)) (L/h); V=32.8 x [1 + 0.0288 x (WT-31.1)] x EXP (eta(V)) (L), where 31.1 (kg) was the average body weight of the population. The inter individual variation (CV) of CL and V were 19.4% and 31.0% respectively. It is concluded that the population pharmacokinetic model of HDMTX in children with ALL is established. The obtained final model and population pharmacokinetics parameters of methotrexate may be useful for individualization treatment.
Zhang
Chun-Yan
CY
Department of Pharmacy, People Hospital, Peking University, Beijing 100044, China.
Gu
Jian
J
Li
Yu-Zhen
YZ
Lu
Wei
W
D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008954:Models, Biological; D017711:Nonlinear Dynamics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate