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Investigational New Drugs

, Volume 30, Issue 6, pp 2096–2102 | Cite as

Plasma protein binding of sorafenib, a multi kinase inhibitor: in vitro and in cancer patients

  • Maria Cristina Villarroel
  • Keith W. Pratz
  • Linping Xu
  • John J. Wright
  • B. Douglas Smith
  • Michelle A. Rudek
PRECLINICAL STUDIES

Summary

Sorafenib is an orally administered multikinase inhibitor that exhibits antiangiogenic and antitumor activity. Few investigators have been able to correlate cumulative sorafenib dose or total exposure to pharmacodynamic effects. This discrepancy may be in part due to poorly understood protein binding characteristics. Since unbound drug concentrations are believed to be more relevant to pharmacological and toxicological responses than total drug, an equilibrium dialysis method using 96-well microdialysis plates was optimized and validated for determining the fraction unbound (Fu) sorafenib in human plasma and in isolated protein solutions. Unbound sorafenib concentrations were determined in cancer patients receiving the drug orally at a dose of 400 mg and 600 mg twice daily. Sorafenib was extensively bound with mean Fu value of 0.3% in both non-cancer and cancer patient’s plasma. The binding in plasma was concentration independent, indicating a low-affinity, possibly nonspecific and nonsaturable process. In isolated protein solutions, 99.8% and 79.3% of sorafenib was bound to human serum albumin (HSA) (4 g/dL) and α1-acid glycoprotein (AAG) (0.1 g/dL) with binding constants of 1.24 × 106 M−1 and 1.40 × 105 M−1, respectively. In cancer patients receiving sorafenib, unbound sorafenib was not correlated with patient characteristics or laboratory values. In conclusion, sorafenib is highly protein bound in human plasma with a higher affinity towards albumin and limited free drug may be partly responsible for its borderline clinical activity.

Keywords

Sorafenib Protein binding Alpha1-acid glycoprotein Equilibrium dialysis Pharmacokinetics Cancer 

Notes

Acknowledgement

Sharyn Baker and Ming Zhao for their scientific input; Aleksandr Mnatsakanyan, Ping He and Yelena Zabelina for their technical assistance with analysis of samples; and Rana Rais for constructive suggestions regarding the manuscript.

Funding

This research was supported by NIH grant U01 CA070095 and the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH grants P30 CA006973 and UL1 RR025005). This publication was made possible by Grant Number UL1RR025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Maria Cristina Villarroel
    • 1
    • 2
  • Keith W. Pratz
    • 1
  • Linping Xu
    • 1
  • John J. Wright
    • 3
  • B. Douglas Smith
    • 1
  • Michelle A. Rudek
    • 1
  1. 1.The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreUSA
  2. 2.NovartisBostonUSA
  3. 3.Investigational Drug Branch/CTEP/NCIRockvilleUSA

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