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.
P A Baxter  1 ,  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
Affiliations
  • 1. Texas Children's Cancer Center, Baylor College of Medicine, 6621 Fannin St., CCC1400.00, Houston, TX 77030, USA. [email protected]
PMID: 20563581 DOI: 10.1007/s00280-010-1380-3
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.

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