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01.09.2009 | Original Article

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

verfasst von: Joshua Ö. Haznedar, Shem Patyna, Carlo L. Bello, Geoffrey W. Peng, William Speed, Xiaoming Yu, Qingling Zhang, Juthamas Sukbuntherng, David J. Sweeny, Lida Antonian, Ellen Y. Wu

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2009

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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.

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Titel: Single- and multiple-dose disposition kinetics of sunitinib malate, a multitargeted receptor tyrosine kinase inhibitor: comparative plasma kinetics in non-clinical species
verfasst von: Joshua Ö. Haznedar
Shem Patyna
Carlo L. Bello
Geoffrey W. Peng
William Speed
Xiaoming Yu
Qingling Zhang
Juthamas Sukbuntherng
David J. Sweeny
Lida Antonian
Ellen Y. Wu
Publikationsdatum: 01.09.2009
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 4/2009
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-008-0917-1

Springer Medizin

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