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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 12/2006

01-12-2006 | Original Research Article

Population Pharmacokinetics of High-Dose Methotrexate in Children with Acute Lymphoblastic Leukaemia

Authors: Dolores Aumente, Dolores Santos Buelga, John C. Lukas, Pedro Gomez, Antonio Torres, Prof. Maria José García

Published in: Clinical Pharmacokinetics | Issue 12/2006

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Abstract

Objective: To develop and a priori validate a methotrexate population pharmacokinetic model in children with acute lymphoblastic leukaemia (ALL), receiving high-dose methotrexate followed by folinic acid rescue, identifying the covariates that could explain part of the pharmacokinetic variability of methotrexate.
Methods: The study was carried out in 49 children (aged 6 months to 17 years) who received high-dose methotrexate (3 g/m2 per course) in long-term treatment. In an index group (37 individuals; 1236 methotrexate plasma concentrations), a population pharmacokinetic model was developed using a nonlinear mixed-effects model. The remaining patients’ data (12 individuals; 278 methotrexate plasma concentrations) were used for model validation. Age, sex, total bodyweight (TBW), height, body surface area, lowest urine pH during infusion, serum Creatinine, ALT, AST, folinic acid dose and length of rescue were analysed as possible covariates. The final predictive performance of the pharmacokinetic model was tested using standardised mean prediction errors.
Results: The final population pharmacokinetic model (two-compartmental) included only age and total bodyweight as influencing clearance (CL) and volume of distribution of central compartment (V1). For children aged ≤10 years: CL (L/h) = 0.287 · TBWO-876; V1 (L) = 0.465 · TBW, and for children aged >10 years: CL (L/h) = 0.149 · TBW; V1 (L) = 0.437 · TBW. From the base to the final model, the inter-individual variabilities for CL and V1 were significantly reduced in both age groups (30–50%). The coefficients of variation of the pharmacokinetic parameters were <30%, while residual and inter-occasional coefficients maintained values close to 40%. Validation of the proposed model revealed the suitability of the model.
Conclusion: A methotrexate population pharmacokinetic model has been developed for ALL children. The proposed model could be used in Bayesian algorithms with a limited sampling strategy to estimate the systemic exposure of individual patients to methotrexate and adapt both folinic acid rescue and methotrexate dosing accordingly.
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Metadata
Title
Population Pharmacokinetics of High-Dose Methotrexate in Children with Acute Lymphoblastic Leukaemia
Authors
Dolores Aumente
Dolores Santos Buelga
John C. Lukas
Pedro Gomez
Antonio Torres
Prof. Maria José García
Publication date
01-12-2006
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 12/2006
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.2165/00003088-200645120-00007

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