2010 - Berlin - Germany

PAGE 2010: Applications- Oncology
Jebabli Nadia

Pharmacokinetic Modelling Of Methotrexate From Routine Clinical Data In Patients With Acute Lymphoblastic Leukemia

N. Jebabli, I. Salouage, S.Trabelsi, E. Ga´es, H. El jebari, Ch. Belkahia, M. Lakhal, A. Klouz

Service de Pharmacologie Clinique, Centre National de Pharmacovigilance, Tunis Tunisie

Objectives: To develop population pharmacokinetic model for methotrexate (MTX) in patients with acute lymphoblastic leukaemia (ALL), receiving high-dose MTX followed by folinic acid rescue

Methods: Pharmacokinetic modelling was performed in NONMEM using a dataset including 273 patients (aged 2 to 23 years) who received high-dose MTX (5 g/m2 per course) in long-term treatment. 2582 methotrexate plasma concentrations were performed by fluorescence polarisation immunoassay (FPIA).

Results: A three­compartment open model with elimination from the central compartment described the pharmacokinetics of methotrexate. The most important covariates affecting the disposition of methotrexate were age (AGE, year), body weight (BW, Kg), and creatinine clearance (CLR, lh-1). The final model with exponential disposition of MTX was clearance (CL, lh-1) = (6.11 + WT*6.7310-2)+(1.0810-4*CLR )*EXP(1.9510-1) , (V, l)= 10,8+(AGE * 9.310-2) * EXP(9.110-1) , Q(lh-1) = 2.0410-3 * WT. Pharmacokinetic parameters (%CV) in this study were CL, 8.72 lh-1 (44 %); V1, 17.49 l (95%); V2, 6.048 l (56%); V3, 0.015 l (52%) . The model predictions in the qualification group were found to have no bias and satisfactory precision

Conclusions: The MTX population pharmacokinetics in patient with ALL is well described by this investigation. Substantial interpatient variability is explained by incorporating patient specific data into regression equations predicting pharmacokinetic parameters.  

[1] Aumente D, Buelga DS, Lukas JC, Gomez P, Torres A, Garcia MJ. Population pharmacokinetics of high-dose methotrexate in children with acute lymphoblastic leukemia. Clin Pharmacokinet 2006; 45(12): 1227-38.
[2] Piard CH, Bressolle FR, May F, Daolun Z, Karina Y, Andre R, Evelyne J. A limited sampling strategy to estimate individual pharmacokinetic parameters of methotrexate in children with acute lymphoblastic leukaemia. Cancer Chemother Pharmacol 2007; 60:609-620. 

Reference: PAGE 19 (2010) Abstr 1713 [www.page-meeting.org/?abstract=1713]
Poster: Applications- Oncology
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