Marios Spanakis (1), Vangellis Sakkalis (1), Kostas Marias (1)
(1) Computational BioMedicine Laboratory, Institute of Computer Science, Foundation for Research and Technology - Hellas, Vassilika Vouton, GR-71110 Heraklion, Crete, Greece
Objectives:Gadolinium based contrast agents (GBCA) are used in dynamic –contrast enhanced magnetic resonance imaging (DCE-MRI) for diagnosis of lesions such as brain tumors with implementation of pharmacokinetic analysis for quantification of the vessel leakage of tumor’s abnormal vasculature [1]. The aim of this work was to assess through physiologically-based pharmacokinetic modeling (PBPK) the impact of different fraction of vasculature of a brain tumor on the PK profile of Gd-DOTA (gadoteric acid, DOTAREM®).
Methods: The PK profiles were generated through whole body-PBPK models and in silico clinical trials with Simcyp® simulator platform [2]. The typically administered dose (i.v., 0.1 mmol/kg) was simulated for the estimation of tracer’s concentration for up to 15 minutes post administration in order to be in line with the typical DCE-MRI clinical setting. The brain tumor lesion (BTL) compartment was introduced as an additional organ in the simulator with tissue characteristics modified to fit those of brain and brain tumors. Keeping all parameters constant for BTL (size, composition) and the same virtual profile, simulations run modulating each time the proportion of capillary bed in the BTL (0.01-10% of the total tissue).
Results: The results from the simulations for Gd-DOTA estimate a mean systemic plasma concentration Cmax=2.3 mΜ, a mean AUC =163.16 μΜ.h and clearance CL= 5.6 L/h. The mean Cmax,int of intracranial blood was 1.6 mΜ with an AUC=159.73 μΜ.h. Regarding BTL, the maximum extravascular concentrations of Gd-DOTA ranged from 1.6-1.7 mΜ following the BTL’s increased vasculature. Taken into consideration blood brain barrier permeability, Simcyp® predicted a zero concentration-time profile for the brain mass revealing the impact of BBB regarding tracer’s limited disposition in the brain as it is observed in clinical settings of DCE-MRI.
Conclusions: The results of the PBPK approach through the application of Simcyp® reveal a suitable method to describe in silico the impact of different vasculature of a brain tumor on tracer’s PK profile. The evaluation of tracer kinetics through in silico clinical trials and PBPK models represent novel approaches for DCE-MRI in population and/or individual level [3,4]. This methodology shows potentials on the possible coupling of the results with studies correlating image analysis with tumor growth models regarding the estimation of GBCA profiles in different population cohorts.
References:
[1] Koh TS, Bisdas S, Koh DM, Thng CH. Fundamentals of tracer kinetics for dynamic contrast-enhanced MRI. J Magn Reson Imaging (2011) 34(6):1262-76.
[2] Jamei M, Marciniak S, Feng K, Barnett A, Tucker G, Rostami-Hodjegan A. The Simcyp population-based ADME simulator. Expert Opin Drug Metab Toxicol. (2009) 5(2):211-23
[3] Spanakis M, Marias K. In silico evaluation of gadofosveset pharmacokinetics in different population groups using the Simcyp® simulator platform In Silico Pharmacology (2014) 2:2
[4] Spanakis M, Oraiopoulou ME, Tzamali E, Sakkalis V, Maris TG, Papadaki E, Karantanas A, Marias K. An in silico estimation of the pharmacokinetic profile and the disposition of Gd-DTPA in brain tumor lesions of different vasculature through PBPK models. (2014) Neuro Oncol (2014) 16 (suppl 2) Abstracts from the 11th Congress of the European Association of Neuro-Oncology, Turin, Italy, 10/2014
Reference: PAGE 24 (2015) Abstr 3474 [www.page-meeting.org/?abstract=3474]
Poster: Drug/Disease modeling - Absorption & PBPK