A population pharmacokinetics-pharmacodynamics model evaluates the bone marrow depression following high-dose methotrexate chemotherapy

WANG Yang; YE Qi; ZHANG Hua-nian; XU Hua; LI Si-chan; XU Qiong; CHEN Yu-jun; LI Hui

Abstract：Objective:To establish a population pharmacokinetics-pharmacodynamics (PPK-PD) model to evaluate the bone marrow depression following high-dose methotrexate (HDMTX) chemotherapy,and to facilitate individualized therapeutic regimens.Methods:Data from 114 children with acute lymphoblastic leukemia (ALL) during HDMTX treatment were collected.The serum concentrations of MTX were selected as the pharmacokinetics index,and decreased percentage in white blood count (WBC) after 5 days from HDMTX infusion as pharmacodynamics index,respectively.A nonlinear mixed-effects population modelling approach was carried out for data analysis.A two-compartment,open kinetic model and a sigmoid Emax model with an effect compartment were selected as the structure models for pharmacokinetic and pharmacodynamic analysis,respectively.The predictive performance of final model was evaluated by goodness-of-fit,Bootstrapping and normalized predictive distribution error (NPDE).Results:The typical population values of pharmacokinetic and pharmacodynamic parameters estimated in final model were as follows:V1 (volume of the central compartment) =15.46 L,V2 (volume of the peripheral compartment) =1.95 L,CL (total body clearance) =4.76 L· h-1,CL2 (intercompartmental clearance) =0.11 L· h-1,ke0 (elimination rate constant of the effect compartment) =0.003 6 h-1,EC50 (the effect compartment concentration resulting in 50％ of maximum effect) =0.87 mg· L-1,γ(sigmoidicity factor) =1.91,and Emax (maximum drug effect) =79.87％.The final model structure indicated that MTX clearance was impacted by total sodium bicarbonate dose during chemotherapy.The stability and the predictive performance of final model were accepted by goodness-of-fit,Bootstrapping and NPDE.Conclusion:The PPK-PD model has been successfully established in this study to evaluate the bone marrow depression following HDMTX chemotherapy,which will be useful for optimizing the administration protocol of HDMTX.