PT  - JOURNAL ARTICLE
AU  - Mika Naganawa
AU  - Sjoerd Finnema
AU  - Joel Mercier
AU  - Nabeel Nabulsi
AU  - Sophie Kervyn
AU  - Shannan Henry
AU  - Jean-Marie Nicolas
AU  - Yiyun Huang
AU  - Ming-Kai Chen
AU  - Jonas Hannestad
AU  - Henrik Klitgaard
AU  - Armel Stockis
AU  - Richard Carson
TI  - Drug characteristics derived from PET kinetic modeling studies: Combined <sup>11</sup>C-UCB-J human PET with levetiracetam and brivaracetam occupancy of SV2A
DP  - 2017 May 01
TA  - Journal of Nuclear Medicine
PG  - 358--358
VI  - 58
IP  - supplement 1
4099  - http://jnm.snmjournals.org/content/58/supplement_1/358.short
4100  - http://jnm.snmjournals.org/content/58/supplement_1/358.full
SO  - J Nucl Med2017 May 01; 58
AB  - 358Objectives: The antiepileptic drugs, levetiracetam (LEV) and brivaracetam (BRV), bind to the synaptic vesicle protein 2A (SV2A). The speed of entry into the brain for these drugs is an important parameter to assess their anti-seizure activity. In monkey studies, BRV showed faster entry into the brain than LEV, as determined by more rapid displacement of the in vivo binding by the SV2A tracer, 11C-UCB-J. To extract maximum information from these displacement studies, we developed a non-linear mathematical model that describes the relationship between human brain 11C-UCB-J PET data and the time-varying drug concentration in the plasma, in order to estimate and compare the kinetic parameters of the drugs and the tracer, particularly K1 (speed of entry into brain tissue).Methods: A pair of displacement and post-dose bolus/infusion scans was conducted in five healthy subjects with 11C-UCB-J in a bolus-plus-infusion protocol. In the displacement scan, either LEV (1500 mg, n = 4) or BRV (50 mg, n = 1; 100 mg, n = 2; 200 mg, n = 2) was administered intravenously at 60 min post-injection of 11C-UCB-J. The post-dose PET scan started at 3 hours after the end of the displacement scan. Blood samples were collected for drug concentration measurement. Arterial blood samples were collected for measurement of tracer free fraction and the arterial input function. In addition to the conventional tracer modeling, the advanced model accounted for drug entry into the brain, and binding, using the measured drug input function. Fitting was performed using numerical solutions to these nonlinear differential equations and was applied simultaneously to the time-activity curves (TACs) from displacement and post-dose scans to estimate 5 parameters: brain entry parameters, K1(drug), K1(UCB-J, displacement), K1(UCB-J, post-dose), free fraction of 11C-UCB-J in the brain tissue, fND(UCB-J), and distribution volume of UCB-J, VT(UCB-J). Other parameters (KD(drug), KD(UCB-J), fP(drug), fP(UCB-J), fND(drug), koff(drug), koff(11C-UCB-J)) were fixed to literature or measured values.Results: The advanced compartment model described well the TACs in both displacement and post-dose scans in all subjects. 11C-UCB-J K1, frontal cortex VT and fND values were estimated as 0.43 ± 0.05 mL/min/cm3 (n = 18), 18.5 ± 0.8 mL/cm3 (n = 9), and 0.10 ± 0.02 (n = 9), respectively. In comparison to 11C-UCB-J K1 estimation (relative standard error (rSE): ~4%), estimates of LEV K1 (rSE: ~40%, 0.005 ± 0.001 mL/min/cm3, n = 4) and BRV K1 (rSE: 40-90%, 0.09 ± 0.07 mL/min/cm3, n = 5) were less stable. 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 K1/LEV K1, by finding the lowest BRV K1 or highest LEV K1 that were statistically consistent with the data. Specifically, we used the F-test to compare the residual sum of squares with fixed BRV K1 to that with floating BRV K1 to obtain the lowest possible BRV K1; the same analysis was performed to find the highest LEV K1. The lowest BRV K1 and highest LEV K1 were 50 and 6 μL/cm3/min, respectively. Thus, the lower bound of the ratio BRV K1/LEV K1 was ~8, i.e., BRV enters the brain at least 8-fold faster than LEV.Conclusion: Under appropriate conditions, this advanced nonlinear model can directly estimate entry rates of drugs into tissue by analysis of PET TACs. This analysis showed that BRV enters brain tissue much faster than LEV, consistent with results from previous studies in mice and monkeys. Research Support: UCB Pharma