PK/PD modeling based on mouse xenograft tumor growth inhibition and the correlation to clinical exposure for VEGF/PDGF receptor tyrosine kinase inhibitor AG-013736

3003 AG-013736 is a potent and selective VEGF/PDGF RTK inhibitor that is being evaluated in phase II clinical trials as an oral drug for its anti-cancer activity. Preclinically, the compound inhibited vascular endothelial cell proliferation, migration, survival and induced apoptosis. The compound dose-dependently inhibited tumor growth and metastasis in numerous xenograft and syngeneic models in mice. The in vivo activity of the agent was associated with the inhibition of tissue VEGFR2 and PDGFRβ phosphorylation, reduction of microvessel density and vascular permeability. We also observed that the magnitude of the reduction of these pharmacodynamic endpoints generally correlated with the plasma exposure of the agent. Here we report the quantitative assessment of the relationship between plasma concentrations of AG-013736 and human xenograft tumor growth inhibition (TGI) by the PK/PD modeling. Mice bearing human colon carcinoma MV522 tumors were treated with AG-013736 via either the PO dosing (BID) or continuous infusion across a wide range of doses/concentrations. Dose-dependent and saturable tumor growth inhibition was observed under both treatment regimens. Plasma concentrations collected at various time points of treatment were analyzed by LC/MS/MS using the electronic ionization method. An EC50,SS of 12 ng/ml was estimated from the continuous infusion TGI and the corresponding steady state plasma concentrations of AG-013736. A naive-pooled PK analysis was used to estimate the PK parameters of the compound for each oral dose level using the one-compartment model. Indirect response PK/PD modeling for tumor growth inhibition produced by oral dosing was performed using the estimated PK parameters. The EC50,PO derived by this approach was similar to EC50,SS. Based on the clinical PK parameters and the parameters from the mouse PK/PD modeling, human PK/PD simulation was performed to investigate clinical dose projection. The relationship between the simulated human PK/PD results and the actual clinical PK/PD will be discussed. This line of research emphasizes the complexity of PK/PD modeling and the necessity of understanding and conducting the appropriate preclinical PK/PD studies in order to better aid clinical dose projection for the development of anti-cancer agents.