OBJECTIVE To develop a population pharmacokinetic model of high dose methotrexate(HD-MTX) infusion in patients with lymphoid malignancy,to investigate the biological and clinical covariates related to the drug distribution and elimination,and to propose a limited sampling strategy(LSS) for the estimation of the time above the threshold(0.2 μmol·L-1).METHODS A total 82 patients with lymphoid malignancy receiving high dose methotrexate treatment were involved in the study.A pharmacokinetic model was developed using nonlinear mixed-effect model.The influence of demographic characteristics,biological factors,and concurrent administration were investigated.The final predictive performance was validated by bootstrap and cross-validation.Bayesian estimation was evaluated.RESULTS The pharmacokinetics of high dose methotrexate were described by a two-compartment model.The pharmacokinetic parameters and the inter-individual variability were as follows:the clearance CL 7.45 L·h-1(inter-individual variability 51.4%),the volume of the central and peripheral compartment V1 25.9 L(22.4%),V2 9.23 L(42.3%),respectively,and the transfer constant Q 0.333 L·h-1(70.7%).The influence of serum creatinine on CL and weight on V1 was remained in the final model.The protocol involved one sampling time,44 h after the beginning of the infusion,allowed to predict the time at which the methotrexate concentration reached the expected threshold(0.2 μmol·L-1).CONCLUSION Serum creatinine and weight showed significant influence on methotrexate CL and V1,respectively.Furthermore,a Bayesian estimation based the covariates and 44 h sample was developed,allowing predict the individual methotrexate pharmacokinetic parameters and the time to 0.2 μmol·L-1.
YE Min;FU Qing;LI Peng;ZHU Zhu.
High Dose Methotrexate Population Pharmacokinetics and Bayesian Estimation in Patients with Lymphoid Malignancy [J]. Chinese Pharmaceutical Journal, 2009, 44(05): 367-372
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