Abstract 1277: Modeling the correlation of linifanib (ABT-869) pharmacokinetic (PK) exposure and DCE-MRI response in patients with advanced or metastatic solid tumors
Authors: Li Xiaohui , Jahn Patrick , Ashton Edward , Noertersheuser Peter A. , Carlson Dawn M. , Pradhan Rajendra S. 
Published: June 2012

Background: Vascular endothelial growth factor (VEFG) has a pivotal role in tumor angiogenesis, which is required for the growth of most solid tumors and progression to metastases. Linifanib is a novel orally active, potent and selective inhibitor of VEGF and platelet derived growth factor (PDGF) receptor tyrosine kinases. DCE-MRI is a non-invasive functional imaging technique that permits indirect measurement of tumor hemodynamics, therefore, suitable for monitoring VEGF inhibition response in tumor vasculature. This population PK-PD modeling analysis was to assess the correlation between linifanib PK exposures and DCE-MRI response in patients with advanced or metastatic solid tumors.

Methods: DCE-MRI variables including Ktrans were available from one phase 1 clinical trial (N=17) on Day 0, Day 3 and Day 15 and three phase 2 clinical trials (N=122) on Day 0 and Day 15. Linifanib exposures were obtained by estimating AUC at steady-state (AUCss) using a population PK model (Previously established). PK-PD modeling was performed by using NONMEM (Version VII) to fit the available data to an inhibitory maximum effect (Emax) model with time component. The percentage of change from baseline in Ktrans was the response variable and AUCss was the PK-exposure variable. The mixture function of NONMEM was used by examining the decrease function of individual Ktrans data fit over time to allow separation between responding patients (with decrease function) and non-responding patients (with non-decrease function). This model was defined as base model and was used for identification of covariates that influence the PK-PD relationship. Covariates were tested using an iterative forward addition (p&lt;0.01) and backward elimination (p&lt;0.001) procedure. The final model was defined as the model containing only the most significant covariate relations. Goodness-of-fit plots were used to assess the adequacy of the final model. Robustness of the parameter estimates from the final model was also assessed using bootstrap validation.

Results: An inhibitory maximum effect (Emax) model with time component described the data well. Two populations, responders (88.5%) and non-responders (11.5%), were characterized using the mixture model approach. Following model selection criteria, the final model included baseline Ktrans and baseline ECOG as covariates on EC50 (EAUCss50). The estimated median EAUCss50 from the final model was approximately 6 μg·hr/mL, which corresponded to a dose of 17.5 mg QD, the maximum tolerated dose (MTD) identified for linifanib as a single-agent.

Conclusions: The PK-PD relationship between PK exposure (AUCss) and biologic response (percentage of change from baseline in Ktrans) shows that the linifanib dose of 17.5 mg QD, implemented in the phase 3 monotherapy trial in patients with hepatocellular carcinoma, is biologically effective.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1277. doi:10.1158/1538-7445.AM2011-1277