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Abstract Background Antiepileptic drugs, levetiracetam (LEV) and brivaracetam (BRV), bind to synaptic vesicle glycoprotein 2A (SV2A). In their anti-seizure activity, speed of brain entry may be an important factor. BRV showed faster entry into the human and non-human primate brain, based on more rapid displacement of SV2A tracer 11C-UCB-J. To extract additional information from previous human studies, we developed a nonlinear model that accounted for drug entry into the brain and binding to SV2A using brain 11C-UCB-J positron emission tomography (PET) data and the time-varying plasma drug concentration, to assess the kinetic parameter K 1 (brain entry rate) of the drugs. Method Displacement (LEV or BRV p.i. 60 min post-tracer injection) and post-dose scans were conducted in five healthy subjects. Blood samples were collected for measurement of drug concentration and the tracer arterial input function. Fitting of nonlinear differential equations was applied simultaneously to time-activity curves (TACs) from displacement and post-dose scans to estimate 5 parameters: K 1 (drug), K 1(11C-UCB-J, displacement), K 1(11C-UCB-J, post-dose), free fraction of 11C-UCB-J in brain (f ND(11C-UCB-J)), and distribution volume of 11C-UCB-J (V T(UCB-J)). Other parameters (K D(drug), K D(11C-UCB-J), f P(drug), f P(11C-UCB-J, displacement), f P(11C-UCB-J, post-dose), f ND(drug), k off(drug), k off(11C-UCB-J)) were fixed to literature or measured values. Results The proposed model described well the TACs in all subjects; however, estimates of drug K 1 were unstable in comparison with 11C-UCB-J K 1 estimation. To provide a conservative estimate of the relative speed of brain entry for BRV vs. LEV, we determined a lower bound on the ratio BRV K 1/LEV K 1, by finding the lowest BRV K 1 or highest LEV K 1 that were statistically consistent with the data. Specifically, we used the F test to compare the residual sum of squares with fixed BRV K 1 to that with floating BRV K 1 to obtain the lowest possible BRV K 1; the same analysis was performed to find the highest LEV K 1. The lower bound of the ratio BRV K 1/LEV K 1 was ~ 7. Conclusions Under appropriate conditions, this advanced nonlinear model can directly estimate entry rates of drugs into tissue by analysis of PET TACs. Using a conservative statistical cutoff, BRV enters the brain at least sevenfold faster than LEV.