Abstracts

Rationale: Both Levetiracetam(LEV) and Brivaracetam(BRV) have been shown to abolish an EEG photoparoxysmal response (PPR) in a human Phase-IIa ‘Photosensitivity Model’ (Kasteleijn, Epil Res 1996;25:225+Neurology 2007;69:1027). BRV has different physiochemical properties--higher potency, lipophilicity & 10-15x-greater SV2A affinity (Klitgaard, Epilepsia 2016;57:538; Nicolas, Epilepsia 2016;57:201) than LEV. PET imaging in healthy volunteers shows BRV has faster CNS penetration than LEV (Finnema, Epilepsia 2019;60:958). Thus, we compared the rapidity of CNS effects of both AEDs in patients with photosensitive epilepsy (PwPE) using PPR as a pharmacodynamic endpoint: time to PPR abolition post 15-min and 5-min intravenous infusion of BRV or LEV. Methods: We used a randomized, double-blind, two-period crossover design, testing 8 PwPE with 1500 mg LEV and 100 mg BRV post-15-min i.v. infusion (Part 1) and 7 same PwPE again, same AED doses, post-5-min i.v. infusion (Part 2); according to protocol, based on Part 1 Results, 1 PwPE had a 500 mg LEV & 50 mg BRV dose, both over-15-min (Fig. 1). Our protocol was IRB-approved (NCT03580707). Concomitant AED(s) were maintained throughout the study. All PwPE had a history of GTCS or myoclonic seizures or both. Photic stimulation was performed in an adapted version (best eye condition determined at screening + upper limit threshold (Reed: ISCTM poster 2018) to allow repeated determination of photosensitivity ranges within a very short time period ([baseline=0]+1,2,5,10,15,20,30,60&120 min post-i.v. BRV or LEV). Plasma concentrations were determined by LC-MS/MS. Results: Nine PwPE (6F; age=27.8 [18-42]yr) participated in/completed the study; seven (4F) did both Parts 1&2. All PwPE showed PPR abolition (15/16 instances). BRV showed complete abolition of PPR in <2 min in 11 PwPE compared to 4 with LEV. In mixed-effects-model analysis for time, BRV abolished PPRs more quickly than LEV; BRV:LEV time ratio = 0.39 (95% CI: 0.16-0.90) p=0.029 for Parts 1&2. A greater BRV:LEV difference in PPR abolition was observed for 15-min infusion vs. 5-min. Greater variability in time to PPR abolition was seen in Part 2. No period nor carryover effects were seen. No serious nor severe adverse effects occurred; mild, transient lightheadedness occurred in 4 BRV, 2 LEV patients; drowsiness in 4 LEV, but not in BRV. At PPR abolition (n=16), median plasma [BRV]=250 (range=20-4,100) ng/ml; [LEV]= 28.3 [range 1-83.1] mcg/mL. Conclusions: BRV displayed faster efficacy than LEV in suppressing/abolishing the pharmacodynamic EEG biomarker of photosensitivity (PPR) in the majority of PwPE. Our preliminary results are in line with PET study findings (faster BRV brain penetration, SV2A occupancy) in volunteers and may support the use of BRV in treating acute seizure conditions. Clinical studies are needed to confirm our findings. Funding: UCB funded our investigator-initiated study (IIS).