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Functional and Clinical Evidence of the Influence of Sorafenib Binding to Albumin on Sorafenib Disposition in Adult Cancer Patients

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Abstract

Purpose

Sorafenib, an oral multitargeted tyrosine kinase inhibitor, is highly bound to plasma proteins (>99.5%). Little is known about the influence of variations in sorafenib protein binding on its disposition. The aims of this study were to characterize in vitro sorafenib binding properties to albumin using the quenching fluorescence method and investigate the influence of albuminemia and bilirubinemia on sorafenib disposition in 54 adult cancer patients.

Results

In vitro estimate of sorafenib dissociation constant (Kd) for albumin was 0.22 μM [CI95 0.20–0.23]. In physiological conditions, sorafenib unbound fraction would increase 1.7-fold as albuminemia decreased from 45 g/L (680 μM) to 30 g/L (453 μM). In presence of bilirubin, apparent Kd of sorafenib was ~1.5-fold greater for bilirubin/albumin molar ratio of 1:4. In clinical settings, median sorafenib clearance (CL) was 1.42 L/h (0.75–2.13 L/h). In univariate analysis, sex, body mass index, and albuminemia were associated with CL (p = 0.04, 0.048, and 0.008, respectively). In multivariate analysis, albuminemia (p = 0.0036) was the single parameter independently associated with CL.

Conclusion

These findings highlight the major influence of albuminemia on sorafenib clearance and its disposition in cancer patients.

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Abbreviations

AAG:

α1-acid glycoprotein

ALP:

alkaline phosphatase

ALT:

aspartate alaninetransferase

AST:

aspartate aminotransferase

Bmax :

common binding capacity

BMI:

body mass index

Cb :

bound drug concentration

CL:

total clearance

CRP:

protein C-reactive

Ct :

total concentration of drug

CU :

unbound concentration of drug

CV:

coefficient of variation

DMSO:

dimethyl sulfoxide

fu:

unbound fraction

GGT:

Gamma-glutamyl transpeptidase

HSA:

human serum albumin

ICD:

induced circular dichroism

Kd:

dissociation constant

Kdapp :

apparent dissociation constant 

Ki:

inhibitor constant

Lt :

concentration of interacting ligand

MYR:

myristic acid

PDGFR:

platelet-derived growth factor receptor

Pu :

unbound protein concentration

VEGFR:

vascular endothelial growth factor receptor

λexc:

maximum excitation wavelength

λmax:

maximum emission wavelength

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Acknowledgments & Disclosures

We acknowledge the help of J. Lecas (Centre de Langues de la Maison des Langues, Université Paris Descartes) in proofreading the manuscript.

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Authors and Affiliations

  1. Pharmacie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69000, Lyon, France

    Michel Tod

  2. Université de Lyon, F69008, Lyon, France

    Michel Tod

  3. Centre d’Études et de Recours sur les Inhibiteurs de l’Angiogénèse, AP-HP, Hôpital Cochin, 75014, Paris, France

    Olivier Mir, Romain Coriat, Pascaline Boudou-Rouquette, Stanislas Ropert, Judith Michels, Jean Philippe Durand, Francois Goldwasser & Benoit Blanchet

  4. Unité de Cancérologie Médicale, AP-HP, Hôpital Cochin, 75014, Paris, France

    Olivier Mir, Romain Coriat, Pascaline Boudou-Rouquette, Stanislas Ropert, Judith Michels, Jean Philippe Durand & Francois Goldwasser

  5. Université Paris Descartes, 75005, Paris, France

    Olivier Mir, Romain Coriat, Audrey Thomas-Schoemann, Michel Vidal & Francois Goldwasser

  6. Laboratoire de Pharmacologie-Toxicologie, Service de Pharmacie, AP-HP, Hôpital Cochin, 75014, Paris, France

    Natacha Bancelin, Audrey Thomas-Schoemann, Fabrice Taieb, Halim Abbas, Alain Dauphin, Michel Vidal & Benoit Blanchet

  7. UMR 8638 CNRS, Faculté de Pharmacie, 4 Avenue de l’Observatoire, 75006, Paris, France

    Audrey Thomas-Schoemann & Michel Vidal

  8. Laboratoire de Pharmacologie-Toxicologie, Service de Pharmacie, GH Cochin-Saint Vincent-de-Paul, 75014, Paris, France

    Benoit Blanchet

Authors
  1. Michel Tod
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  2. Olivier Mir
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  3. Natacha Bancelin
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  15. Benoit Blanchet
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Correspondence to Benoit Blanchet.

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Tod, M., Mir, O., Bancelin, N. et al. Functional and Clinical Evidence of the Influence of Sorafenib Binding to Albumin on Sorafenib Disposition in Adult Cancer Patients. Pharm Res 28, 3199–3207 (2011). https://doi.org/10.1007/s11095-011-0499-1

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  • DOI: https://doi.org/10.1007/s11095-011-0499-1

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