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

Abstract

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.

• Authors: P A Baxter, P A Thompson, L M McGuffey, B W Gibson, R C Dauser, J G Nuchtern, C Shi, R Inloes, G Choy, S Redkar, S M Blaney
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 67 Issue 4 Pg. 809-12 (Apr 2011) ISSN: 1432-0843 [Electronic] Germany
• PMID: 20563581 (Publication Type: Journal Article)

Chemical References

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

Topics

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