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In vitro and in vivo pharmacokinetic characterizations of AMG 900, an orally bioavailable small molecule inhibitor of aurora kinases.

Authors
  • Huang, Liyue
  • Be, Xuhai
  • Berry, Loren
  • Moore, Earl
  • Janosky, Brett
  • Wells, Mary
  • Pan, Wei-Jian
  • Zhao, Zhiyang
  • Lin, Min-Hwa Jasmine
Type
Published Article
Journal
Xenobiotica; the fate of foreign compounds in biological systems
Publication Date
May 01, 2011
Volume
41
Issue
5
Pages
400–408
Identifiers
DOI: 10.3109/00498254.2010.548534
PMID: 21294625
Source
Medline
License
Unknown

Abstract

AMG 900 is a small molecule being developed as an orally administered, highly potent, and selective pan-aurora kinase inhibitor. The aim of the investigations was to characterize in vitro and in vivo pharmacokinetic (PK) properties of AMG 900 in preclinical species. AMG 900 was rapidly metabolized in liver microsomes and highly bound to plasma proteins in the species tested. It was a weak Pgp substrate with good passive permeability. AMG 900 exhibited a low-to-moderate clearance and a small volume of distribution. Its terminal elimination half-life ranged from 0.6 to 2.4 h. AMG 900 was well-absorbed in fasted animals with an oral bioavailability of 31% to 107%. Food intake had an effect on rate (rats) or extent (dogs) of AMG 900 oral absorption. The clearance and volume of distribution at steady state in humans were predicted to be 27.3 mL/h/kg and 93.9 mL/kg, respectively. AMG 900 exhibited acceptable PK properties in preclinical species and was predicted to have low clearance in humans. AMG 900 is currently in Phase I clinical testing as a treatment for solid tumours. Preliminary human PK results appear to be consistent with the predictions.

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