P16.33 * AN IN SILICO ESTIMATION OF THE PHARMACOKINETIC PROFILE AND THE DISPOSITION OF GD-DTPA IN BRAIN TUMOR LESIONS OF DIFFERENT VASCULATURE THROUGH PBPK MODELS
Authors: M. Spanakis, M. E. Oraiopoulou, E. Tzamali, V. Sakkalis, T. G. Maris, E. Papadaki, A. Karantanas, K. Marias
Journal: Neuro-Oncology (2014)

Brain tumor lesions (BTL), i.e. high grade gliomas, are known to have a prominence of vasculature, which is promoted through hypoxia mechanisms and differential expression of vascular endothelial growth factor (VEGF). Imaging techniques such as dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) with intra-venous (i.v.) administration of a Gd-based contrast agent (GBCA) are successfully used for the diagnosis and characterization of the BTLs. Tracer kinetics plays an important role in DCE-MRI by assessing the vessel leakage through estimation of the transfer and disposition of GBCAs in a lesion. Physiologically-based pharmacokinetic modeling (PBPK) represents a well-documented approach to estimate in silico the disposition of pharmacologic agents in the body. In this work, we sought to i)present a whole-body PBPK approach in order to estimate the PK profile of Gd-DTPA (Gadopentetic acid, Magnevist®) and ii)evaluate the impact of vascular fraction of tracer's extravascular-extracellular disposition in a simulated BTL. PK profile was assessed through the application of Simcyp® simulator platform and the generation of whole-body PBPK model. BTL was introduced as an additional compartment (∼5% of total brain weight) with tissue characteristics matching those of a brain tumor. In silico clinical trials (ISCTs) were designed by integrating literature data for a virtual population of patients with cancer for Simcyp® and Gd-DTPA properties. The ISCTs were generated for a representative individual and concentrations were estimated for 15 minutes following i.v. bolus injection of Gd-DTPA (0.1 mmol/kg). Given the simulated BTL's size, all parameters were kept constant except for capillary fraction in order to evaluate the impact of vasculature. RESULTS: from the whole-body PBPK simulations estimate the maximum plasma concentration of Gd-DTPA to be 3.0 mM whereas the intracranial blood concentration to be 1.7 mM. Regarding the simulated BTL, concentrations varied between 1.5-1.7 mM for the extravascular-extracellular space following modulation of tissue percentage in capillaries. Finally, zero concentrations are predicted for brain parenchyma and intracellular tissues due to the presence of blood-brain barrier and the absence of cellular intake, transfer or passive mediated, for Gd-DTPA, respectively. The presented in silico approach was capable of assessing the PK profiles of Gd-DTPA and especially its disposition in the extravascular-extracellular space of a putative BTL. The need for exploitation of the imaging techniques with studies correlating image analysis with clinical outcome and in silico tools is of great interest. The incorporation of PBPK models along with in silico tools for tumor growth and/or clinical data could reveal novel approaches for improving DCE-MRI techniques applied in diagnosis and treatment protocols (i.e. novel anti-VEGF treatments).