Received for publication November 14, 2007.
Revised March 18, 2008.
Accepted for publication March 31, 2008.

Pharmacokinetic-Pharmacodynamic Modeling of Biomarker Response and Tumor Growth Inhibition to an Orally Available c-Met Kinase Inhibitor in Human Tumor Xenograft Mouse Models

Abstract

PF02341066, (R)-3-[1-(2, 6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, was identified as an orally available, ATP-competitive small molecule inhibitor of cMet receptor tyrosine kinase. The objectives of the present studies were to characterize 1) pharmacokinetic-pharmacodynamic relationship of the plasma concentrations of PF02341066 to cMet phosphorylation in tumor (biomarker) and 2) the relationship of cMet phosphorylation to anti-tumor efficacy (pharmacological response). Athymic mice implanted with GTL16 gastric carcinoma or U87MG glioblastoma xenografts were treated with PF02341066 once daily at doses selected to encompass ED50's. Plasma concentrations of PF02341066 were best described by a one-compartment pharmacokinetic model. A time-delay (hysteresis) was observed between the plasma concentrations of PF02341066 and the cMet phosphorylation response. A link model was therefore used to account for this hysteresis. The model fitted the time-courses of cMet phosphorylation well, suggesting that the main reason for the hysteresis is a rate-limiting distribution from plasma into tumor. The EC50 and EC90 values were estimated to be 19 ng/mL and 167 ng/mL, respectively. For tumor growth inhibition, the exponential tumor growth model fitted the time-course of individual tumor growth inhibition well. The EC50 for the GTL16 tumor growth inhibition was estimated to be 213 ng/mL. Thus, the EC90 for the inhibition of cMet phosphorylation corresponded to the EC50 for the tumor growth inhibition, suggesting that near- complete inhibition of cMet phosphorylation (>90%) is required to significantly inhibit tumor growth (>50%). The present results will be helpful in determining the appropriate dosing regimen and in guiding dose escalation to rapidly achieve efficacious systemic exposure in the clinic.

Key words: pharmacokinetic/pharmacodynamic modeling, pharmacokinetic modeling, pharmacokinetics