Using MRI to Determine Drug Concentration in Convection-Enhanced Delivery: A Proof-of-Concept study

Convection-enhanced delivery (CED) bypasses the blood-brain barrier and avoids systemic exposure to the drug. However, systemic pharmacokinetic characteristics of a drug cannot be applied when delivered via CED. This study aims to provide a first proof-of-concept framework for noninvasively evaluating pharmacokinetics in CED. We investigated local concentration and the distribution of a gadolinium-based contrast agent in rat brains using magnetic resonance imaging (MRI). Standards of gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) were scanned on a 7.0 T MRI system in rat brain tissue suspension. T₁ values were mapped and T₁ relaxivity of Gd-DTPA was calculated. Subsequently, evaluation in live animals was performed by infusing Gd-DTPA into the rat striatum followed by scans for T₁ mapping. The quantitative relationship between imaging data and Gd-DTPA concentration deduced from standard scans was used to determine the voxel-level concentration of Gd-DTPA in rat brains. Concentration maps were constructed from voxel-level concentration data. The Gd-DTPA concentration in tissue suspension and 1/ T₁ showed a linear relationship with R² of 0.9919 (p < 0.0001). The T₁ relaxivity of Gd-DTPA at the experimental condition was 4.199 mM^-1 s^-1. Within the rat brain parenchyma, the mean volume of distribution to initial volume ratio (Vd/Vi) of Gd-DTPA was calculated to be 6.02. Notably, the infusion center's concentration exhibited a decreasing pattern, while the peripheral region's concentration remained relatively stable over the observed duration. This study showed the spatial distribution of Gd-DTPA concentration and its temporal change, suggesting that using MRI to determine the Gd-DTPA concentration is feasible with good accuracy and data quality.