Plasma and cerebrospinal fluid pharmacokinetics of MP470 in non-human primates.
OBJECTIVE
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.
Baxter
P A
PA
Texas Children's Cancer Center, Baylor College of Medicine, 6621 Fannin St., CCC1400.00, Houston, TX 77030, USA. pabaxter@txccc.org
Thompson
P A
PA
McGuffey
L M
LM
Gibson
B W
BW
Dauser
R C
RC
Nuchtern
J G
JG
Shi
C
C
Inloes
R
R
Choy
G
G
Redkar
S
S
Blaney
S M
SM
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002853:Chromatography, Liquid; D006207:Half-Life; D008253:Macaca mulatta; D008297:Male; D008954:Models, Biological; D010879:Piperazines; D047428:Protein Kinase Inhibitors / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D013890:Thiourea
D000970:Antineoplastic Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013890:Thiourea; C521047:amuvatinib