14691 Background: TKI258 (dovitinib lactate), an inhibitor of type III-V receptor tyrosine kinases (RTK), is being evaluated in multiple Phase I trials, including acute myeloid leukemia (AML), multiple myeloma, and other tumor types. VEGF and PLGF have been identified as potential pharmacodynamic biomarkers of VEGFR inhibition by TKI258. A population pharmacokinetic-pharmacodynamic (PK/PD) model was developed to characterize TKI258 systemic exposure and effect on biomarkers in the ongoing Phase I trials, and to allow simulation of alternative dosing schedules for potential application in future studies. Methods: TKI258 plasma concentrations (measured by LC/MS/MS) from 87 patients were fitted to a one-compartmental PK model with first order oral absorption and Michaelis-Menten type elimination. The time-dependency of the drug’s kinetics was characterized by an indirect-response function. The PD data (VEGF, PLGF) were fitted to an indirect response model combining with the PK model. Results: The population ...