Population pharmacokinetic study of methotrexate in patients with lymphoid malignancy.
OBJECTIVE
A population pharmacokinetic model was developed to describe dose-exposure relationships of methotrexate (MTX) in adults with lymphoid malignancy; this is in order to explore the interindividual variability in relationship with the different physiopathological variables. The final model was applied to the Bayesian estimation of MTX concentrations using two blood samples.


METHODS
Fifty-one patients receiving 136 courses of MTX (1-6 per patient) were included in this study. The data was analysed using NONMEM software. A linear two-compartment model with linear elimination best described the data. Setting mean parameters values and variabilities to population values, we obtained Bayesian prediction of MTX pharmacokinetic parameters and concentrations. The predictive performance was evaluated by comparing the Bayesian estimated and observed concentrations and the Bayesian estimated parameters with the individual final model estimated parameters.


RESULTS
The population pharmacokinetic parameters and the inter-subject variablities expressed as coefficient of variation were: the total body clearance CL, 7.1 l h-1 (22%), the volume of the central and peripheral compartments V1, 25.1 l (22.5%), V2, 2.7 l (64%), respectively, and the transfer constant Q, 2.7 (51%) l h-1. Inter-course variability was only significant on CL. Age and serum creatinine had significant effects on CL and was included in the final model. A good correlation was obtained between Bayesian estimated and experimental concentrations (r2=0.85).
Faltaos
Demiana William
DW
Pharmacology department, Pitié-Salpêtrière University Hospital, Assistance-Publique Hôpitaux de Paris, Paris 6 University, Paris, France. demianawilliam@yahoo.com
Hulot
Jean Sebastian
JS
Urien
Saïk
S
Morel
Veronique
V
Kaloshi
Gentian
G
Fernandez
Christine
C
Xuan
khe Hoang
kH
Leblond
Veronique
V
Lechat
Philippe
P
D000328:Adult; D000367:Age Factors; D000368:Aged; D000465:Algorithms; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D001499:Bayes Theorem; D002051:Burkitt Lymphoma / Q000097:blood / Q000188:drug therapy*; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D016403:Lymphoma, Large B-Cell, Diffuse / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy*; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D003404:Creatinine; D008727:Methotrexate