Evaluating the pharmacodynamic effects of padsevonil in healthy volunteers using simultaneous [C]-UCB-J PET and MR Arterial Spin Labeling measurements.

INTRODUCTION

Integrated PET-MR scanners can measure simultaneously tracer binding, downstream cerebral blood flow (CBF) and neuronal activation. An integrated GE Signa PET-MR system was used to combine [C]-UCB-J PET scanning with MR Arterial Spin Labeling (ASL) measurements to evaluate the effects of padsevonil (PSL) on SV2A occupancy and CBF simultaneously.

METHODS

PET-MR scanning was performed in 10 healthy controls (8M/2F; 27.6 ​± ​10.0 ​yrs) at baseline, and at two timepoints (post1: 2-24h and post2: 6-30h) after administration of a single PSL dose (6.2-100 ​mg). Dynamic [C]-UCB-J PET scanning with arterial blood sampling was performed to estimate distribution volumes and corresponding SV2A occupancies. Simultaneously, MR ASL data were acquired and spatially normalized to Montreal Neurological Institute (MNI) space for voxel wise analysis while brain Volume-Of-Interest (VOI) were defined using a simplified Hammers atlas.

RESULTS

PET measurements showed a SV2A occupancy range of 57-98% and 16-63% and a corresponding PSL plasma concentration range of 3.6-189.23 ​ng/mL and 1.3-9.8 ​ng/mL for post1 and post2, respectively. When comparing post1 to baseline ASL measurements, a VOI-based analysis detected a significant CBF decrease in thalamus, insula, cerebellum, posterior cingulate cortex, and brain stem, which was confirmed by a voxel-wise analysis comparing baseline and post1 ASL measurements and identifying significantly different clusters covering the same brain regions. In addition, we demonstrated CBF recovery in these brain regions for the post2 ASL measurements compared to baseline measurements. For the thalamus, a VOI-based correlation analysis detected a significant correlation between PSL plasma concentration and CBF decrease relative to baseline conditions.

DISCUSSION

A pattern of local and dose dependent CBF decrease was demonstrated following PSL administration. More generally, these findings present the potential of simultaneous PET and ASL measurements to follow the time course of drug effects and to differentiate between the efficacy of different drugs in patient groups.