title: Pharmacokinetic-pharmacodynamic modeling of biomarker response and tumor growth inhibition to an orally available cMet kinase inhibitor in human tumor xenograft mouse models.
abstract: (R)-3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine (PF02341066) 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) the pharmacokinetic-pharmacodynamic relationship of the plasma concentrations of PF02341066 to cMet phosphorylation in tumor (biomarker) and 2) the relationship of cMet phosphorylation to antitumor 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 ED(50) values. 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 EC(50) and EC(90) values were estimated to be 19 and 167 ng/ml, respectively. For tumor growth inhibition, the exponential tumor growth model fitted the time courses of individual tumor growth inhibition well. The EC(50) for the GTL16 tumor growth inhibition was estimated to be 213 ng/ml. Thus, the EC(90) for the inhibition of cMet phosphorylation corresponded to the EC(50) 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.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, La Jolla Laboratories, Pfizer Global Research and Development, 10777 Science Center Dr., San Diego, CA 92121, USA. shinji.yamazaki@pfizer.com
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Judith
authors.initials: J
authors.lastname: Skaptason
authors.forename: David
authors.initials: D
authors.lastname: Romero
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
authors.forename: Helen Y
authors.initials: HY
authors.lastname: Zou
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Koup
authors.forename: Bill J
authors.initials: BJ
authors.lastname: Smith
authors.forename: Tatiana
authors.initials: T
authors.lastname: Koudriakova
mesh_terms: D000818:Animals; D015415:Biomarkers; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D053719:Tandem Mass Spectrometry; D014183:Transplantation, Heterologous
chemical_list: D015415:Biomarkers; D047428:Protein Kinase Inhibitors; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases