Evaluation of antiangiogenic treatment effects on tumorsʹ microcirculation by Bayesian physiological pharmacokinetic modeling and magnetic resonance imaging

A physiological pharmacokinetic (PBPK) model was used to estimate tumor microcirculation in nude mice with a grafted tumor. The kinetics of a rapid clearance blood pool agent, Vistarem, were investigated by dynamic MRI after bolus administration. Signal enhancements were recorded in arterial blood and in tumor tissue. To analyze these data, we developed a whole-body mathematical model of the agentʹs biodistribution using physiological parameters. The model included six compartments: arterial and venous plasma, tumor (split into capillaries and interstitium), and the rest of the body (also split into capillaries and interstitium). As an application, changes in tumor microcirculation parameters were evaluated in mice receiving either an antiangiogenic treatment (ZD4190) or a placebo. The analysis was performed in a Bayesian framework, and the model was fitted to experimental data using Markov Chain Monte Carlo techniques. Results showed a significant difference in tumor microcirculation between the two groups of mice when the microcirculation parameters are considered together. This whole-body physiological model enables to analyze jointly data in tumor tissue and in arterial blood. This leads to accurate estimates of microcirculation parameters and the evaluation of their uncertainty.