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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

Abstract

Purpose

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

Methods

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.

Results

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.

Conclusions

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

Keywords

Sunitinib SU12662 Nonclinical Pharmacokinetics Disposition 

Abbreviations

AUC0–∞

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

AUC0–t last

AUC from time zero to the last measurable concentration

AUC0–24

AUC from time zero to 24 h

CLplasma

Total plasma clearance

Cmax

Maximum plasma concentration

%F

Total percent bioavailability

FLT3

Fms-like tyrosine kinase-3 receptor

GIST

Gastrointestinal stromal tumors

K

Terminal rate constant

KIT

Stem cell factor receptor

Kp

Red blood cell to plasma radioactivity partitioning ratio

LC–MS/MS

High-performance liquid chromatography–tandem mass spectrometry

MRM

Multiple reaction monitoring

NF

National Formulary

PDGFR

Platelet-derived growth factor receptor

QWBA

Quantitative whole body autoradiography

RET

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

RTK

Receptor tyrosine kinase

t1/2

Half-life

Tmax

Time to maximum concentration

USP

US Pharmacopeia

VEGFR

Vascular endothelial growth factor receptor

Vss

Volume of distribution at steady-state

Notes

Acknowledgments

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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