Population Pharmacokinetics of Methotrexate in Children with Lymphoid Malignancy
I. Grabnar(1), B. Faganel(2), V. Dolzan(3), A. Mrhar(1), J. Jazbec(2)
(1)Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia; (2)Division of Oncology and Hematology, Department of Pediatrics, Medical Center Ljubljana, Ljubljana, Slovenia; (3)Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Objectives: High dose methotrexate (MTX) regimen is included in the treatment protocols of lymphoid malignancy. Due to high inter and intra individual variability therapeutic drug monitoring of MTX is essential . Recently, genetic polymorphism in the major MTX transporter - the reduced folate carrier gene 1 (RFC1) has been described and its effect on MTX plasma levels has been shown . This study aims to assess population pharmacokinetics of MTX in children and to estimate the influence of RFC1 polymorphism on systemic exposure.
Methods: Population pharmacokinetic analysis with NONMEM based on retrospectively collected clinical data was performed. Two-compartment model and FOCE method were used. The influence of patient age, weight, body surface area and RFC1 polymorphism G80A on clearance and volume of central compartment were examined.
Results: 62 patients, 6.6 +/- 5.0 years of age, provided 881 concentrations from 4 courses of MTX (2.0 - 5.7 g/m2) infused over 24 h. In an average 25 kg child clearance was 7.95 L/h, volumes of the central and peripheral compartment were 14.2 and 3.81 L, respectively and intercompartmental clearance was 0.132 L/h. Among the covariates evaluated the effect of weight on central compartment volume and clearance, and RFC1 polymorphism on clearance were included in the final model. Large interpatient (CV 32%) and interoccasion (CV 12%) variability in MTX clearance was observed. In patients, heterozygous for G80A, clearance was 8% higher (95%CI: 5-12%) compared to patients homozygous for G80A.
Conclusions: Developed population pharmacokinetic model is suitable for individualization of MTX dosing in children. Significant effect of RFC1 polymorphism on MTX clearance was observed, however this effect is hard to explain. Additional study including P-glycoprotein and methylenetetrahydrofolate reductase genotype is underway.
 Aumente D, Buelga DS, Lukas JC, Gomez P, Torres A, Garcia MJ. Population pharmacokinetics of high-dose methotrexate in children with acute lymphoblastic leukaemia. Clin Pharmacokinet. 2006;45(12):1227-38.
 Laverdiere C, Chiasson S, Costea I, Moghrabi A, Krajinovic M. Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia. Blood. 2002;100(10):3832-4.