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

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 registered ) 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 registered simulator platform and the generation of whole-body PBPK model. BTL was introduced as an additional compartment ( similar to 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 registered 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