Plasma and cerebrospinal fluid pharmacokinetics of MP470 in non-human primates

Cancer Chemother Pharmacol. 2011 Apr;67(4):809-12. doi: 10.1007/s00280-010-1380-3. Epub 2010 Jun 19.


Purpose: MP470 is a multi-targeted tyrosine kinase inhibitor with potent activity against mutant c-Kit, PDGFRα, Flt3, c-Met and c-Ret that is being evaluated as an anticancer agent. The plasma and cerebrospinal fluid (CSF) pharmacokinetics of MP470 were studied in a non-human primate model that is highly predictive of CSF penetration in humans.

Methods: Oral MP470, 300 mg, was administered to four non-human primates. Serial samples of blood were collected from four animals and CSF samples from three animals for pharmacokinetic studies. Plasma and CSF concentrations were measured using an LC-MS/MS assay. Both model-independent and model-dependent methods were used to analyze the pharmacokinetic data.

Results: Following a one-time oral dose of 300 mg, the MP470 plasma area under the curve (AUC) was 1,690 ± 821 nM h (mean ± SD). The half-life of MP470 in the plasma was 11.0 ± 3.4 h. There was no measurable MP470 in the CSF.

Conclusions: Although CSF penetration is minimal, MP470 has demonstrated potent activity against cancer cell lines in vitro and in vivo, and further clinical investigation is warranted.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / cerebrospinal fluid
  • Antineoplastic Agents / pharmacokinetics*
  • Area Under Curve
  • Chromatography, Liquid
  • Half-Life
  • Macaca mulatta
  • Male
  • Models, Biological
  • Piperazines
  • Protein Kinase Inhibitors / cerebrospinal fluid
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Pyrimidines / cerebrospinal fluid
  • Pyrimidines / pharmacokinetics*
  • Tandem Mass Spectrometry
  • Thiourea


  • Antineoplastic Agents
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Thiourea
  • amuvatinib