Cancer Chemotherapy and Pharmacology

, Volume 64, Issue 4, pp 691–706 | Cite as

Single- and multiple-dose disposition kinetics of sunitinib malate, a multitargeted receptor tyrosine kinase inhibitor: comparative plasma kinetics in non-clinical species

  • Joshua Ö. Haznedar
  • Shem PatynaEmail author
  • Carlo L. Bello
  • Geoffrey W. Peng
  • William Speed
  • Xiaoming Yu
  • Qingling Zhang
  • Juthamas Sukbuntherng
  • David J. Sweeny
  • Lida Antonian
  • Ellen Y. Wu
Original Article



The purpose of these extensive non-clinical studies was to assess pharmacokinetics and dispositional properties of sunitinib and its primary active metabolite (SU12662).


Sunitinib was administered in single and repeat oral doses in mice, rats, and monkeys. Assessments were made using liquid-chromatography–tandem mass spectrometric methods, radioactive assays, and quantitative whole body autoradiography.


Sunitinib was readily absorbed with good oral bioavailability and linear kinetics at clinically-relevant doses. SU12662 plasma levels were less than those of sunitinib in mice and monkeys, but greater in rats. Sunitinib was extensively distributed with moderate-to-high systemic clearance and eliminated primarily into feces. Single- and repeat-dosing kinetics were similar. A prolonged half-life allowed once-daily dosing, enabling adequate systemic exposure with limited-to-moderate accumulation. In multiple-dose studies with cyclic dosing, drug plasma concentrations cleared from one cycle to the next.


Sunitinib exhibited advantageous pharmacokinetic and dispositional properties in non-clinical species, translating into favorable properties in humans.


Sunitinib SU12662 Nonclinical Pharmacokinetics Disposition 



Total area under the concentration–time curve from time zero to infinity

AUC0–t last

AUC from time zero to the last measurable concentration


AUC from time zero to 24 h


Total plasma clearance


Maximum plasma concentration


Total percent bioavailability


Fms-like tyrosine kinase-3 receptor


Gastrointestinal stromal tumors


Terminal rate constant


Stem cell factor receptor


Red blood cell to plasma radioactivity partitioning ratio


High-performance liquid chromatography–tandem mass spectrometry


Multiple reaction monitoring


National Formulary


Platelet-derived growth factor receptor


Quantitative whole body autoradiography


Glial cell-line derived neurotrophic factor receptor (REarranged during Transfection)


Receptor tyrosine kinase




Time to maximum concentration


US Pharmacopeia


Vascular endothelial growth factor receptor


Volume of distribution at steady-state



Pfizer Inc. provided financial support for this study. Editorial assistance was provided by ACUMED® (Tytherington, UK) and was funded by Pfizer Inc.

Supplementary material

280_2008_917_MOESM1_ESM.doc (462 kb)
ESM1 (DOC 461 kb)


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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Joshua Ö. Haznedar
    • 1
  • Shem Patyna
    • 2
    Email author
  • Carlo L. Bello
    • 3
  • Geoffrey W. Peng
    • 4
  • William Speed
    • 5
  • Xiaoming Yu
    • 6
  • Qingling Zhang
    • 7
  • Juthamas Sukbuntherng
    • 8
  • David J. Sweeny
    • 9
  • Lida Antonian
    • 7
  • Ellen Y. Wu
    • 4
  1. 1.Clinical PharmacologyRoche LLCPalo AltoUSA
  2. 2.Clinical DevelopmentPfizer Inc.San DiegoUSA
  3. 3.Clinical Pharmacology, Pfizer Inc.New YorkUSA
  4. 4.Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc.San DiegoUSA
  5. 5.Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc.KentUK
  6. 6.Bioanalytical/Drug Metabolism and PharmacokineticsBioDuro (Beijing) Co. LtdBeijingChina
  7. 7.Drug Metabolism and PharmacokineticsGenelabs TechnologiesRedwood CityUSA
  8. 8.Drug Metabolism and PharmacokineticsXenoport Inc.Santa ClaraUSA
  9. 9.Pharmacokinetics, Dynamics and MetabolismRigel Inc.South San FranciscoUSA

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