TITLE: Pharmacokinetic-Pharmacodynamic Modeling of Biomarker Response and Tumor Growth Inhibition to an Orally Available cMet Kinase Inhibitor in Human Tumor Xenograft Mouse Models DMD #19711 2 RUNNING TITLE: PKPD Modeling of cMet Inhibitor in Tumor Xenog

CL/F, oral clearance; EC 50 , drug concentration causing 50% of maximum effect; CV, coefficients of variation; E 0 , baseline of cMet phosphorylation; EC 90 , drug concentration causing 90% of maximum effect; E max , maximum effect; f u , free fraction in plasma; γ, Hill coefficient; HGF, hepatocyte growth factor; HPLC, high performance liquid chromatography; k a , absorption rate constant; k e0 , the rate constant for equilibration with the effect site; k in , formation rate constant; k out , degradation rate constant; LC- 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 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 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 DMD #19711 5 determining the appropriate dosing regimen and in guiding dose escalation to rapidly achieve efficacious systemic exposure in the clinic