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


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.


Sorafenib Protein binding Alpha1-acid glycoprotein Equilibrium dialysis Pharmacokinetics Cancer 



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.


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.


  1. 1.
    Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5(10):835–844PubMedCrossRefGoogle Scholar
  2. 2.
    Bayer Health Care Pharmaceuticals Inc. (2009) NEXAVAR (sorafenib) tablets, oral Package Insert. In: Wayne, NJGoogle Scholar
  3. 3.
    Strumberg D, Richly H, Hilger RA, Schleucher N, Korfee S, Tewes M, Faghih M, Brendel E, Voliotis D, Haase CG, Schwartz B et al (2005) Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43–9006 in patients with advanced refractory solid tumors. J Clin Oncol 23(5):965–972PubMedCrossRefGoogle Scholar
  4. 4.
    Clark JW, Eder JP, Ryan D, Lathia C, Lenz HJ (2005) Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43–9006, in patients with advanced, refractory solid tumors. Clin Cancer Res 11(15):5472–5480PubMedCrossRefGoogle Scholar
  5. 5.
    Moore M, Hirte HW, Siu L, Oza A, Hotte SJ, Petrenciuc O, Cihon F, Lathia C, Schwartz B (2005) Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43–9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol 16(10):1688–1694PubMedCrossRefGoogle Scholar
  6. 6.
    Lathia C, Lettieri J, Cihon F, Gallentine M, Radtke M, Sundaresan P (2006) Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics. Cancer Chemother Pharmacol 57(5):685–692PubMedCrossRefGoogle Scholar
  7. 7.
    Pratz KW, Cho E, Levis MJ, Karp JE, Gore SD, McDevitt M, Stine A, Zhao M, Baker SD, Carducci MA, Wright JJ et al (2010) A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias. Leukemia 24(8):1437–1444PubMedCrossRefGoogle Scholar
  8. 8.
    Awada A, Hendlisz A, Gil T, Bartholomeus S, Mano M, de Valeriola D, Strumberg D, Brendel E, Haase CG, Schwartz B, Piccart M (2005) Phase I safety and pharmacokinetics of BAY 43–9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br J Cancer 92(10):1855–1861PubMedCrossRefGoogle Scholar
  9. 9.
    Pacifici GM, Viani A (1992) Methods of determining plasma and tissue binding of drugs. Pharmacokinetic consequences. Clin Pharmacokinet 23(6):449–468PubMedCrossRefGoogle Scholar
  10. 10.
    Wright JD, Boudinot FD, Ujhelyi MR (1996) Measurement and analysis of unbound drug concentrations. Clin Pharmacokinet 30(6):445–462PubMedCrossRefGoogle Scholar
  11. 11.
    Jain L, Woo S, Gardner ER, Dahut WL, Kohn EC, Kummar S, Mould DR, Giaccone G, Yarchoan R, Venitz J, Figg WD (2011) Population pharmacokinetic analysis of sorafenib in patients with solid tumours. Br J Clin Pharmacol 72(2):294–305PubMedCrossRefGoogle Scholar
  12. 12.
    Jackson PR, Tucker GT, Woods HF (1982) Altered plasma drug binding in cancer: role of alpha 1-acid glycoprotein and albumin. Clin Pharmacol Ther 32(3):295–302PubMedCrossRefGoogle Scholar
  13. 13.
    Rosing H, Man WY, Doyle E, Bult A, Beijnen JH (2000) Bioanalytical liquid chromatographic method validation. A review of current practices and procedures. J Liq Chrom Relat Technol 23(3):329–354CrossRefGoogle Scholar
  14. 14.
    Zhao M, Rudek MA, He P, Hafner FT, Radtke M, Wright JJ, Smith BD, Messersmith WA, Hidalgo M, Baker SD (2007) A rapid and sensitive method for determination of sorafenib in human plasma using a liquid chromatography/tandem mass spectrometry assay. J Chromatogr B Anal Technol Biomed Life Sci 846(1–2):1–7CrossRefGoogle Scholar
  15. 15.
    Li L, Zhao M, Navid F, Pratz K, Smith BD, Rudek MA, Baker SD (2010) Quantitation of sorafenib and its active metabolite sorafenib N-oxide in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci 878(29):3033–3038CrossRefGoogle Scholar
  16. 16.
    Tod M, Mir O, Bancelin N, Coriat R, Thomas-Schoemann A, Taieb F, Boudou-Rouquette P, Ropert S, Michels J, Abbas H, Durand JP et al (2011) Functional and clinical evidence of the influence of sorafenib binding to albumin on sorafenib disposition in adult cancer patients. Pharm Res. doi: 10.1007/s11095-011-0499-1
  17. 17.
    Rossing N (1968) Albumin metabolism in neoplastic diseases. Scand J Clin Lab Invest 22(3):211–216PubMedCrossRefGoogle Scholar

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

Personalised recommendations