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Bayesian Estimation of Methotrexate Pharmacokinetic Parameters and Area Under the Curve in Children and Young Adults with Localised Osteosarcoma

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Abstract

Background

Methotrexate is the most efficient anticancer drug in osteosarcoma. It requires individual exposure monitoring because of the high doses used, its wide interpatient pharmacokinetic variability and the existence of demonstrated relationships between efficacy, toxicity and serum drug concentrations.

Objective

To develop a maximum a posteriori (MAP) Bayesian estimator able to predict individual pharmacokinetic parameters and exposure indices such as area under the curve (AUC) for methotrexate from a few blood samples, in order to prevent toxicity and facilitate further studies of the relationships between efficacy and exposure.

Methods

Methotrexate population pharmacokinetics were estimated by a retrospective analysis of concentration data from 40 children and young adults by using the nonparametric expectation maximisation method NPEM. A linear two-compartment model with elimination from the central compartment was assumed. Individual pharmacokinetic parameters and AUC were subsequently estimated in 30 other young patients, using MAP Bayesian estimation as implemented in two programs, ADAPT II and an inhouse program Winphar®.

Results

The pharmacokinetic parameters used in the model were the volume of the central compartment (V1) and the transfer constants (k10, k12 and k21). The mean values (with percentage coefficient of variation) obtained were: 18.24L (54.1%) and 0.41 (42.3%), 0.0168 (68.7%), and 0.1069 (61.3%) h-1, respectively. Bayesian forecasting enabled nonbiased estimation of AUC and systemic clearance using a schedule with two sampling times (6 and 24 hours after the beginning of the infusion) and either program. Collection of a third sample at 4 hours improved the precision.

Conclusion

The Bayesian adaptive method developed herein allows accurate estimation of individual exposure to methotrexate and can easily be used in clinical practice.

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Acknowledgements

This study was supported by a grant from Limoges University, France.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University Hospital, Limoges, France

    Annick Rousseau, Christophe Sabot, Jean Debord, Gérard Lachâtre & Pierre Marquet

  2. Laboratory of Biophysics, Faculty of Pharmacy, Limoges, France

    Annick Rousseau

  3. Avicenne University Hospital, Bobigny, France

    Nicole Delepine & Gérard Delepine

  4. Laboratory of Toxicology, Faculty of Pharmacy, Limoges, France

    Gérard Lachâtre

Authors
  1. Annick Rousseau
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  2. Christophe Sabot
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  3. Nicole Delepine
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  4. Gérard Delepine
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  5. Jean Debord
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  6. Gérard Lachâtre
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  7. Pierre Marquet
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Correspondence to Annick Rousseau.

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Rousseau, A., Sabot, C., Delepine, N. et al. Bayesian Estimation of Methotrexate Pharmacokinetic Parameters and Area Under the Curve in Children and Young Adults with Localised Osteosarcoma. Clin Pharmacokinet 41, 1095–1104 (2002). https://doi.org/10.2165/00003088-200241130-00006

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  • DOI: https://doi.org/10.2165/00003088-200241130-00006

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