A single-center, open-label positron emission tomography study to evaluate brivaracetam and levetiracetam synaptic vesicle glycoprotein 2A binding in healthy volunteers

Abstract

Objective: Brivaracetam (BRV) and levetiracetam (LEV) are antiepileptic drugs that bind synaptic vesicle glycoprotein 2A (SV2A). In vitro and in vivo animal studies suggest faster brain penetration and SV2A occupancy (SO) after dosing with BRV than LEV. We evaluated human brain penetration and SO time course of BRV and LEV at therapeutically relevant doses using the SV2A positron emission tomography (PET) tracer 11 C-UCB-J (EP0074; NCT02602860).

Methods: Healthy volunteers were recruited into three cohorts. Cohort 1 (n = 4) was examined with PET at baseline and during displacement after intravenous BRV (100 mg) or LEV (1500 mg). Cohort 2 (n = 5) was studied during displacement and 4 hours postdose (BRV 50-200 mg or LEV 1500 mg). Cohort 3 (n = 4) was examined at baseline and steady state after 4 days of twice-daily oral dosing of BRV (50-100 mg) and 4 hours postdose of LEV (250-600 mg). Half-time of 11 C-UCB-J signal change was computed from displacement measurements. Half-saturation concentrations (IC50 ) were determined from calculated SO.

Results: Observed tracer displacement half-times were 18 ± 6 minutes for BRV (100 mg, n = 4), 9.7 and 10.1 minutes for BRV (200 mg, n = 2), and 28 ± 6 minutes for LEV (1500 mg, n = 6). Estimated corrected half-times were 8 minutes shorter. The SO was 66%-70% for 100 mg intravenous BRV, 84%-85% for 200 mg intravenous BRV, and 78%-84% for intravenous 1500 mg LEV. The IC50 of BRV (0.46 μg/mL) was 8.7-fold lower than of LEV (4.02 μg/mL). BRV data fitted a single SO versus plasma concentration relationship. Steady state SO for 100 mg BRV was 86%-87% (peak) and 76%-82% (trough).

Significance: BRV achieves high SO more rapidly than LEV when intravenously administered at therapeutic doses. Thus, BRV may have utility in treating acute seizures; further clinical studies are needed for confirmation.

Keywords: 11C-UCB-J; brivaracetam; levetiracetam; positron emission tomography; synaptic vesicle glycoprotein 2A.

Conflict of interest statement

S.J.F., S.R., M.N., S.H., H.G., R.P., D.M., N.B.N., and Y.H. have no conflicts of interest to report. R.P.M., J.M., S.K., J.‐M.N., H.K., S.D., C.O., P.Ma., P.Mu., and A.S. are current employees of UCB Pharma. R.M.K. and J.H. were employees of UCB Pharma at the time this work was conducted; J.H. is currently a full‐time employee of Alkahest. R.E.C. has received research support from Astellas Pharma, Astra‐Zeneca, Bristol‐Myers Squibb, Lilly, Pfizer, Taisho Pharmaceutical, and UCB Pharma, outside of the submitted work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

© 2019 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.

Figures

Figure 1

Representative regional time‐activity curves of VT, EQ values in five brain regions (Cer, cerebellum; CS, centrum semiovale; FCx, frontal cortex; Put, putamen; TCx, temporal cortex) (Cohort 1). Brivaracetam (BRV) or levetiracetam (LEV) was administered intravenously (vertical dotted lines) and reduced the binding of 11C‐UCB‐J. Data were fitted to estimate tracer displacement half‐time (solid line, see Equation (1) in Materials and Methods section). Horizontal dotted lines indicate the VND value estimated from the CS value from 90‐120 minutes postinjection

Figure 2

Representative Lassen occupancy plots for brivaracetam (BRV; red) and levetiracetam (LEV; blue) for two different doses. The values on the x‐axis represent regional VT values during baseline and on the y‐axis represent the difference between VT values during baseline and VT values postdrug. The SV2A occupancy was derived from the slope of the linear fit, that is, 50% for BRV (50 mg), 85% for BRV (200 mg), 52% for LEV (250 mg), and 84% for LEV (1500 mg)

Figure 3

The relationship between the measured drug plasma concentration during each positron emission tomography measurement and SV2A occupancy is shown for all subjects in Cohorts 2 and 3. (Top) One‐parameter saturable binding fits are shown for SV2A occupancy versus brivaracetam (BRV) concentration (red) or levetiracetam (LEV) concentration (blue). Model comparison is shown between one‐parameter saturable binding fit (solid line) to estimate IC50, and two‐parameter saturable binding fit (dotted line) to estimate IC50 and maximal occupancy (Emax) for BRV (middle) and LEV (bottom)