Dovitinib is an oral multitargeted kinase inhibitor with potent activity against 
receptors for vascular endothelial growth factor, platelet-derived growth 
factor, and basic fibroblast growth factor. Initial phase 1 to 2 studies of 
dovitinib using a continuous daily dosing schedule has shown that dovitinib 
exhibits a prolonged and overproportional increase in dose and exposure 
relationship above 400 mg/d. To address this, intermittent dosing schedules were 
explored using a model-based approach. A semi-mechanistic population 
pharmcokinetic/pharmacodynamic (PD) model was developed from 4 dovitinib phase 1 
studies with daily dosing schedules. Autoinduction of cytochrome P450 1A (CYP1A) 
responsible for dovitinib metabolism was described using an indirect response 
model. Simulation of dovitinib plasma concentration profiles following 4 
intermittent dosing schedules suggested that intermittent dosing could prevent 
prolonged drug accumulation. Based on the simulated plasma profiles, PD 
response, and patient compliance, a 5-days-on/2-days-off intermittent dosing 
schedule was selected for a phase 1 to 2 clinical study. The observed dovitinib 
plasma concentrations in this study confirmed the model predictions. 
Furthermore, dovitinib was well tolerated, and antitumor activity was observed 
as well in this new study. The 5-days-on/2-days-off dosing schedule is currently 
used in a dovitinib registration trial and other clinical trials.