BRIVIACT® (brivaracetam) tablets, oral solution and injection
|Mechanism of Action||Brivaracetam has a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain, which may contribute to the anticonvulsant effect.|
|Pharmacodynamics (PD)||BRIVIACT did not prolong the QT interval to a clinically relevant extent.
Co-administration of BRIVIACT and ethanol caused a larger decrease from baseline in saccadic peak velocity, smooth pursuit, adaptive tracking performance, and Visual Analog Scale alertness, and a larger increase from baseline in body sway and in saccadic reaction time. The immediate word recall scores were generally lower.
|Pharmacokinetics (PK)||The median Tmax for tablets taken without food is 1 hour (range 0.25 to 3 hours). Effect of food is on Cmax (decreased by 37%) and Tmax (delayed by 3 hours), and not on AUC.
Brivaracetam is weakly bound to plasma proteins (≤20%). The volume of distribution is 0.5 L/kg, a value close to that of the total body water.
Brivaracetam metabolism involves CYP2C19. Variations in CYP2C19, production of the hydroxy metabolite is decreased 2-fold or 10-fold, while the blood level of brivaracetam is increased by 22% or 42%, respectively.
Brivaracetam is eliminated primarily by metabolism and by excretion in the urine. More than 95% of the dose, including metabolites and is excreted in the urine within 72 hours after intake.
The terminal half-life is approximately 9 hours.
|PK-PD Analysis||Co-administration of Phenobarbital, Phenytoin or Carbamazepine with Brivaracetam (25 mg twice daily to 100 mg twice daily) decreases plasma concentrations of Brivaracetam by 19%, 21% or 26%, respectively. Conversely, Brivaracetam increases the plasma concentrations of Phenytoin or epoxy metabolite of Carbamazepine. Interactions with carbamazepine and phenytoin can be clinically important.|
|Population PK||There was no significant different in PK in Caucasian and non-Caucasian patients.|
|Special Populations||Steady-state plasma clearance of brivaracetam was slightly lower (0.76 mL/min/kg) in elderly subjects (65 to 79 years old) than in young healthy controls (0.83 mL/min/kg).
AUC of brivaracetam was increased (21%) in subjects with severe renal impairment, while the AUCs of the acid, hydroxy, and hydroxyacid metabolites were increased 3-fold, 4-fold, and 21-fold, respectively. The renal clearance of these inactive metabolites was decreased 10-fold. Hepatic Impairment
Brivaracetam exposure increased by 50%, 57%, and 59% in subjects with hepatic cirrhosis, Child-Pugh grades A, B, and C, respectively.
|Drug Interactions||CYP inhibitors or transporter inhibitors has no significant effect on brivaracetam exposure. Rifampin decreases brivaracetam plasma concentrations by 45%, an effect that is probably the result of CYP2C19 induction.|