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A limited sampling strategy to estimate individual pharmacokinetic parameters of methotrexate in children with acute lymphoblastic leukemia

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An Erratum to this article was published on 04 July 2007

Abstract

Purpose

The objectives of this study were to characterize the population pharmacokinetics of MTX in patients with acute lymphoblastic leukemia (ALL) with ages ranging from 2 to 16 years and to propose a limited sampling strategy to estimate individual pharmacokinetic parameters.

Methods

Seventy-nine children were enrolled in this study; they received 1–4 courses of chemotherapy. MTX was administered at a dose of 5 g/m². MTX population parameters were estimated from 61 patients (231 courses; age range: 2–16 years). The data were analyzed by nonlinear mixed-effect modeling with use of a two-compartment structural model. The interoccasion variability was taken into account in the model. Eighteen additional patients (70 courses) were used to evaluate the predictive performances of the Bayesian approach and to devise a limited sampling strategy.

Results

The following population parameters were obtained: total clearance (CL) = 8.8 l/h (inter-individual variability: 43%), initial volume of distribution (V 1) = 17.3 l (48%), k 12 = 0.0225 h−1 (41%), and k 21 = 0.0629 h−1 (24%). The inter-individual variability in the initial volume of distribution was partially explained by the fact that this parameter was weight-dependent. Intercourse variability was limited, with a mean variation of 13.2%. The protocol involving two sampling times, 24 and 48 h after the beginning of infusion, allows precise and accurate determination of individual pharmacokinetic parameters and consequently, it was possible to predict the time at which the MTX concentration reached the predicted threshold (0.2 μM) below which the administration of folinic acid could be stopped.

Conclusion

The results of this study combine the relationships between the pharmacokinetic parameters of MTX and patient covariates that may be useful for dose adjustment, with a convenient sampling procedure that may aid in optimizing pediatric patient care.

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Acknowledgments

To the children and their parents, to Maria-Claude Linus-Sorbet for secretary assistance in preparing the manuscript.

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Authors and Affiliations

  1. Department of Paediatric Pharmacology and Pharmacogenetics, Robert Debré Hospital, Paris, France

    Christine Piard, May Fakhoury, Daolun Zhang & Evelyne Jacqz-Aigrain

  2. Clinical Pharmacokinetic Laboratory, Faculty of Pharmacy, University Montpellier I, 15 Avenue Ch. Flahault, B.P. 14491, 34093, Montpellier Cedex 5, France

    Françoise Bressolle

  3. Department of Pharmacy, Robert Debré Hospital, Paris, France

    André Rieutord

  4. Department of Paediatric Immunohematology, Robert Debré Hospital, Paris, France

    Karina Yacouben

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  1. Christine Piard
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Correspondence to Françoise Bressolle.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s00280-007-0550-4

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Piard, C., Bressolle, F., Fakhoury, M. et al. A limited sampling strategy to estimate individual pharmacokinetic parameters of methotrexate in children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 60, 609–620 (2007). https://doi.org/10.1007/s00280-006-0394-3

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