نبذة مختصرة : BackgroundAntiepileptic 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 tracer11C-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 brain11C-UCB-J positron emission tomography (PET) data and the time-varying plasma drug concentration, to assess the kinetic parameterK1(brain entry rate) of the drugs.MethodDisplacement (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:K1(drug),K1(11C-UCB-J, displacement),K1(11C-UCB-J, post-dose), free fraction of11C-UCB-J in brain (fND(11C-UCB-J)), and distribution volume of11C-UCB-J (VT(UCB-J)). Other parameters (KD(drug),KD(11C-UCB-J),fP(drug),fP(11C-UCB-J, displacement),fP(11C-UCB-J, post-dose),fND(drug),koff(drug),koff(11C-UCB-J)) were fixed to literature or measured values.ResultsThe proposed model described well the TACs in all subjects; however, estimates of drugK1were unstable in comparison with11C-UCB-JK1estimation. To provide a conservative estimate of the relative speed of brain entry for BRV vs. LEV, we determined a lower bound on the ratio BRVK1/LEVK1, by finding the lowest BRVK1or highest LEVK1that were statistically consistent with the data. Specifically, we used theFtest to compare the residual sum of squares with fixed BRVK1to that with floating BRVK1to obtain the lowest possible BRVK1; the same analysis was performed to find the highest LEVK1. The lower bound of the ratio BRVK1/LEVK1was ~ 7.ConclusionsUnder 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.
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