Tumor Growth Model with PK Input for Neuroblastoma Drug Development.

摘要

The long-term goal for our project is to develop a multi-scale integrated PBPK/PD CC3D framework for modeling neuroblastoma tumor-drug interactions. During this past year we made significant progress toward this goal by developing a whole-body PBPK model with an individualized tumor compartment for topotecan in mice bearing NB5 neuroblastoma tumors. The output from the individualized tumor compartment from the PBPK model will be used to predict individual tumor concentration-time data that could be used as an input for CC3D model to characterize intratumoral heterogeneity in drug perfusion and effect. In the development of the PBPK model, we utilized contrast-enhanced ultrasound (CEUS) derived individual tumor blood flow and blood volume measurements from NB5 tumor bearing mice. We were able to include CEUS derived individual tumor blood flow and blood volume measurements in our PBPK model development because we made substantial progress with our nonlinear contrast enhanced ultrasound (CEUS) studies. We used a custom program to acquire the CEUS perfusion images over a 3D volume that included the tumor and a kidney. We used the kidney as a reference organ to normalize whole tumor perfusion data. We used a log-normal perfusion model to estimate perfusion parameters for individualized tumors.