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

Xenobiotica. 2011 May;41(5):400-8. doi: 10.3109/00498254.2010.548534. Epub 2011 Feb 4.

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.

MeSH terms

  • Administration, Oral
  • Animals
  • Aurora Kinases
  • Biological Availability
  • Blood Proteins / metabolism
  • Cell Line
  • Fasting
  • Humans
  • Injections, Intravenous
  • Male
  • Phthalazines / blood
  • Phthalazines / chemistry
  • Phthalazines / pharmacokinetics*
  • Phthalazines / pharmacology*
  • Protein Binding / drug effects
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Transport / drug effects
  • Small Molecule Libraries / pharmacokinetics*
  • Small Molecule Libraries / pharmacology*
  • Species Specificity

Substances

  • Blood Proteins
  • N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine
  • Phthalazines
  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • Aurora Kinases
  • Protein Serine-Threonine Kinases