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Cancer Chemother Pharmacol. 2009 Sep;64(4):691-706. doi: 10.1007/s00280-008-0917-1. Epub 2009 Jan 25.

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

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  • 1Clinical Pharmacology, Roche LLC, Palo Alto, CA 94304, USA.

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.

PMID:
19169880
[PubMed - indexed for MEDLINE]
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