Population Pharmacokinetics of Delayed Methotrexate Elimination in Children with Acute Lymphoblastic Leukemia

OBJECTIVE To establish the population pharmacokinetics of delayed methotrexate elimination in children with acute lymphoblastic leukemia, and to quantitatively explore the risk factors on delayed elimination for population characteristics. METHODS A total of 606 sparse plasma concentrations and clinical data from 147 cases of acute lymphoblastic leukemia children with delayed methotrexate were included and randomly divided into model group and verification group. Model fitting and population parameters were calculated by using NLME software. The effects of covariates on methotrexate pharmacokinetic parameters were examined. The final model was evaluated and verified by using goodness of fit, Bootstrapping, and external validation. RESULTS The final model was fitted by a two-compartment model. Vomiting and combined use of nephrotoxic drugs were significant covariates on the apparent volume of distribution of the peripheral compartment, while the amount of alkalization significantly affected the clearance of the central compartment, and the amount of hydration significantly affected the clearance of the peripheral compartment(P<0.05). The population pharmacokinetics parameters were the apparent volume of distribution and the clearance of the central compartment and the peripheral compartment with values of 51.16 L·m^-2(RSE=3.87%), 18.63 L·m^-2(RSE=5.73%), 9.62 L·m^-2·h^-1(RSE=3.38%), 0.75 L·m^-2·h^-1 (RSE=2.54%). CONCLUSION A population pharmacokinetic model of delayed methotrexate elimination in children with acute lymphoblastic leukemia is successfully established, which can provide a reference for individualized treatment.