Abstract
Objective: To determine the speed of brain entrance of the antiepileptic drugs (AEDs) brivaracetam (BRV) and levetiracetam (LEV) after single intravenous dosing in humans.
Background: BRV and LEV both bind to synaptic vesicle protein 2A (SV2A), but BRV has more rapid brain entry than LEV in mice and monkeys.1 SV2A can be quantified in the living human brain using PET imaging with [11C]UCB-J.2
Design/Methods: PET scans (n=13) were performed with [11C]UCB-J administered by a bolus-infusion protocol in healthy volunteers (n=9). Therapeutic dosages of BRV (50 mg, n=1; 100 mg, n=4; or 200 mg, n=2) or LEV (1500 mg, n=6) were administered as 5-minute intravenous infusions 60 minutes after the start of the first PET scan. Tracer displacement half-times were determined by subtracting the radioligand clearance half-time from the radioligand displacement half-times estimated by exponential fitting of the post-AED drop in distribution volumes (VT). Data were also analyzed using an advanced mathematical model that described the relationship between brain [11C]UCB-J PET data and time-varying AED plasma curves to directly estimate brain entrance (K1) of both AEDs and [11C]UCB-J, free fraction of [11C]UCB-J in the brain, and VT values.
Results: The radioligand clearance half-time was 8 minutes. Mean tracer displacement half-times were 22, 10, and 2 minutes for BRV 50, 100, and 200 mg, respectively, and 20 minutes for LEV. The advanced compartment model described well the time–activity curves in the displacement and post-dose scans. Using the advanced model, the BRV uptake rate (~50 uL/min/cm3) was found to be at least 8-fold higher than that of LEV (~6 uL/min/cm3).
Conclusions: The results demonstrate that BRV enters the human brain faster than LEV. The potential therapeutic benefit of this has yet to be determined.
Study Supported by: UCB Pharma
Disclosure: Dr. Finnema has nothing to disclose. Dr. Mercier has received personal compensation for activities with UCB Pharma as an employee. Dr. Mercier holds stock and/or stock options with UCB Pharma. Dr. Naganawa has nothing to disclose. Dr. Nabulsi has received royalty payments. Dr. Kervyn has received personal compensation for activities with UCB Pharma as an employee. Dr. Henry has nothing to disclose. Dr. Nicolas has received personal compensation for activities with UCB Pharma. Dr. Huang holds stock and/or stock options in Pfizer, Inc. Dr. Huang has received research support from Astellas, Eli Lilly, Pfizer, Taisho and UCB Pharma. Dr. Chen has nothing to disclose. Dr. Hannestad has nothing to disclose. Dr. Klitgaard has received personal compensation for activities with UCB Pharma as an employee. Dr. Klitgaard holds stock and/or stock options with UCB. Dr. Stockis has received personal compensation for activities with UCB Pharma as an employee. Dr. Stockis hold stock and/or stock options with UCB Pharma. Dr. Carson has received research support from AstraZeneca, BMS, Lilly, Pfizer, Taisho, UCB.
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