Using Hybrid Population Pharmacokinetic (Pk)- Scaled Efficacy Exponential Tumor Model To Determine Possible Efficacious Dose For An Anticancer Agent

Background: The proto-oncogene c-Met and its ligand HGF have both been shown to be frequently dysregulated in and correlate with poor prognostic outcomes in a number of human cancers (Christensen et al, Liu et al). The c-Met pathway can be activated by abnormal c-Met expression levels, activating mutations, gene amplifications autocrine/paracrine HGF stimulation, making inhibiting c-Met tyrosine kinase activity a viable therapeutic approach. INC280 is a highly selective small molecule c-Met inhibitor developed jointly by Novartis and Incyte for the treatment of solid tumors with activation of the c-Met pathway. Aim: The goal of the present work is to predict a possible efficacious dose for INC280 for treatment of solid tumors using a combination of a human population PK model with an efficacy exponential tumor model scaled from mouse. The use of population modeling that helps identify factors affecting drug behavior or explain variability within a target population has been endorsed by the regulatory agencies as a viable alternative to extensive clinical studies. A nice summary of tumor growth models and their use in Oncology can be found in Pharmacokinetics in Drug Development: Advances and Applications. Methods: To construct the human population PK model, data from 22 patients from a Phase I trial receiving multiple doses up to 150 mg of INC280 were used. An exponential tumor growth model was fitted to multiple dose data in GTL-16 MET-amplified tumor bearing mice. As the pharmacokinetics of INC280 in this mouse model was needed, a separate PK/PD model in mouse was first established using data from a single dose mouse study. The scaling from mouse to human was done by adjusting the model to account for reported values of tumor doubling in HCC human clinical trials as opposed to those observed in the mouse studies. Model parameters intrinsic to INC280 efficacy (Emax, EC50) were assumed constant across species. Results: A preliminary one compartment linear PK model described the data adequately. The dose predictions were conducted using the mean population PK parameters. Simulations were run for different initial tumor volumes, different EC50 values (to account for uncertainty for parameter estimate), and different tumor growth rates with doubling times of 30 days and 114 days (Kubota et al.). Efficacious dose was predicted to fall in the range of 100-400 mg total daily dose, depending on aggressiveness of tumor growth. Conclusions: The use of modeling and simulation to aid decision points in drug development is becoming increasingly common. Here we present an integrative modeling framework incorporating both preclinical and clinical data to provide dose estimation. The assumptions in the model are clearly stated and the model can be changed with the availability of new data. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3774. doi:1538-7445.AM2012-3774