Prediction of free imatinib concentrations based on total plasma concentrations in patients with gastrointestinal stromal tumours

Authors

  • Amina Haouala,

    1. Division of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
    2. Division of Thoracic and Vascular Surgery, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
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  • Nicolas Widmer,

    1. Division of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
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  • Monia Guidi,

    1. Division of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
    2. School of Pharmaceutical Sciences, University of Geneva and University of Lausanne, Geneva, Switzerland
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  • Michael Montemurro,

    1. Multidisciplinary Oncology Center, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
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  • Serge Leyvraz,

    1. Multidisciplinary Oncology Center, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
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  • Thierry Buclin,

    1. Division of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
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  • Chin B. Eap,

    1. Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
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  • Laurent A. Decosterd,

    1. Division of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
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  • Chantal Csajka

    Corresponding author
    1. School of Pharmaceutical Sciences, University of Geneva and University of Lausanne, Geneva, Switzerland
    • Division of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
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Correspondence

Dr Chantal Csajka PhD, Division of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland.

Tel.: +412 1314 4263

Fax: +412 1314 42 66

E-mail: chantal.csajka@chuv.ch

Abstract

Aim

Total imatinib concentrations are currently measured for the therapeutic drug monitoring of imatinib, whereas only free drug equilibrates with cells for pharmacological action. Due to technical and cost limitations, routine measurement of free concentrations is generally not performed. In this study, free and total imatinib concentrations were measured to establish a model allowing the confident prediction of imatinib free concentrations based on total concentrations and plasma proteins measurements.

Methods

One hundred and fifty total and free plasma concentrations of imatinib were measured in 49 patients with gastrointestinal stromal tumours. A population pharmacokinetic model was built up to characterize mean total and free concentrations with inter-patient and intrapatient variability, while taking into account α1-acid glycoprotein (AGP) and human serum albumin (HSA) concentrations, in addition to other demographic and environmental covariates.

Results

A one compartment model with first order absorption was used to characterize total and free imatinib concentrations. Only AGP influenced imatinib total clearance. Imatinib free concentrations were best predicted using a non-linear binding model to AGP, with a dissociation constant Kd of 319 ng ml−1, assuming a 1:1 molar binding ratio. The addition of HSA in the equation did not improve the prediction of imatinib unbound concentrations.

Conclusion

Although free concentration monitoring is probably more appropriate than total concentrations, it requires an additional ultrafiltration step and sensitive analytical technology, not always available in clinical laboratories. The model proposed might represent a convenient approach to estimate imatinib free concentrations. However, therapeutic ranges for free imatinib concentrations remain to be established before it enters into routine practice.

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