2006 - Brugge/Bruges - Belgium

PAGE 2006: Applications- Oncology
Demiana William

Population pharmacokinetic study of methotrexate in patient with lymphoid malignancy

William Faltaos, D (1), S. Urien (1), V.Morel (2), G. Kaloshi (3), k. Hoang Xuan (3), V.Leblond (2), Philippe Lechat (1).

1) Pharmacology department, Pitié-Salpêtrière University Hospital, Paris, France; (2) Haematology department, Pitié-Salpêtrière University Hospital, Paris, France; (3) Neurology Department, Pitié-Salpêtrière University Hospital, Paris, France.

Objectives: 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: 51 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 were included in the final model. A good correlation was obtained between Bayesian estimated and experimental concentrations (r²=0.84).

Conclusion: The pharmacokinetic parameters of MTX were accurately estimated. Our Bayesian approach enabled good estimation of MTX concentrations and pharmacokinetic parameters using only two sampling time (24 and 48 hours after the beginning of the infusion).

Reference: PAGE 15 (2006) Abstr 919 [www.page-meeting.org/?abstract=919]
Poster: Applications- Oncology