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.

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