Pharmacokinetic Modelling Of Methotrexate From Routine Clinical Data In Patients With Acute Lymphoblastic Leukemia
N. Jebabli, I. Salouage, S.Trabelsi, E. Gaïes, 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.
References:
[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.
