Source: Health Products and Food Branch (CA) Revision Year: 2022
The precise mechanism by which brivaracetam exerts its antiepileptic effect in humans is unknown (see Preclinical Pharmacology below for experimental in vitro and in vivo data in animals).
Receptor Binding Studies: The primary mechanism of brivaracetam appears to relate to its high affinity for the synaptic vesicle protein 2A (SV2A) in the brain (pIC50 values=7.1 and 7.0 for the rat and human form respectively, as shown by displacement of the selective SV2A radioligand [3H] ucb 30889 by brivaracetam incubated with rat brain membrane proteins and CHO cells expressing human SV2A, respectively). Systemic administration of anticonvulsant doses of brivaracetam in mice was shown to be associated with significant occupancy of central SV2A, supporting the involvement of this target in its antiseizure properties. Furthermore, the binding of brivaracetam to SV2A appears selective as it did not (at 10 μmol) produce any inhibition >50% for binding to 50 different radioligands specific for various receptors, uptake systems and ion channels. Thus, binding to SV2A appears to be the primary mechanism for brivaracetam anticonvulsant activity, however, the precise mechanism by which brivaracetam exerts its anticonvulsant activity has not been fully elucidated.
The results of safety pharmacology studies conducted with brivaracetam did not raise any significant concerns regarding central nervous system (CNS), cardiovascular, respiratory, and gastrointestinal function.
Rotarod testing in rodents suggested that brivaracetam possesses a relatively wide safety margin between doses inducing seizure protection and acute motor adverse effects in models of partial and generalized seizures in man. CNS-related clinical signs (mainly transient CNS depression and decreased spontaneous locomotor activity) were seen at high oral doses (from 100 mg/kg) relative to pharmacologically active doses (ED50 ≥2 mg/kg i.p.). In addition, brivaracetam did not affect learning and memory in rats.
Brivaracetam in vitro did not interfere with human cardiac potassium (hERG), sodium, and calcium channels at concentrations up to 100 μmol/L in HEK293 cells indicating that it is unlikely to affect cardiac conduction, depolarization, and repolarization. It is also unlikely to alter QRS complex duration, QT interval, cardiac contractility, or ventricular conduction velocity based on studies in isolated canine cardiac Purkinje fibres. Significant cardiovascular liabilities were not identified in acute in vivo cardiovascular safety pharmacology studies in dogs or in repeated dose toxicology studies conducted in dogs and monkeys for up to 9 months.
The only finding in a respiratory study conducted in male rats was slightly reduced expiratory and relaxation times at ≥100 mg/kg, indicative of slight respiratory stimulation.
Dose-dependent decreases in gastrointestinal transit and gastric emptying in male rats were evident after 300 and 600 mg/kg, with 100 mg/kg identified as a no observed effect level (NOEL).
The abuse potential was investigated in rats and the studies did not indicate significant potential for abuse or dependence.
A statistically significant correlation has been demonstrated between brivaracetam plasma concentration and seizure frequency reduction from baseline in confirmatory clinical studies in adjunctive treatment of partial onset seizures. The EC50 (brivaracetam plasma concentration corresponding to 50% of the maximum effect) was estimated to be 0.57 mg/L. This plasma concentration is slightly above the median exposure obtained after BRIVLERA (brivaracetam) doses of 50 mg/day. Further seizure frequency reduction is obtained by increasing the dose to 100 mg/day and reaches a plateau at 200 mg/day.
The effect of BRIVLERA on cardiac electrophysiology was evaluated in a randomized, doubleblind, positive and placebo-controlled parallel group study in 184 healthy adult subjects. BRIVLERA was administered as 75 mg twice daily (150 mg/day) and 400 mg twice daily (800 mg/day) for 7 days. BRIVLERA 75 mg twice daily had no significant effect on the QTcF interval, the QRS duration, the PR interval, or heart rate during the 12 hour post-dosing ECG assessment on Day 7. The supratherapeutic BRIVLERA 400 mg BID treatment was associated with a reduction in heart rate (placebo-adjusted mean change from baseline ranging from -2 bpm to -6 bpm) and a transient shortening of the QTcF interval: mean placebo-adjusted change from baseline of -5.8 ms (90% CI -9.8, -1.8) at 1.5 h post-dose.
The primary pharmacodynamics of brivaracetam has been evaluated in a wide range of in vitro and in vivo models of seizures and epilepsy.
While only high dose treatment protects against acute seizures induced by electrical stimulation and chemoconvulsants in mice, brivaracetam exhibits significant and potent protection against seizures with focal onset in rodents. Brivaracetam produced protective ED50 values of 3.5 and 1.2 mg/kg i.p., respectively, against secondarily generalized seizures in fully 6 Hz- and corneally- kindled mice. In fully amygdala kindled rats, brivaracetam significantly elevated after discharge and generalized seizure threshold currents from a dose of 0.68 mg/kg i.p. and produced a protective ED50 value against expression of secondarily generalized seizures, induced by supra-threshold stimulation at a dose of 44 mg/kg i.p.. Finally, protective ED50 values were also observed against acute, partial 6 Hz seizures in mice (4.4 mg/kg i.p.) and against phenytoin-resistant secondarily generalized seizures (68 mg/kg i.p.) in fully amygdala-kindled mice.
Brivaracetam showed a protection against generalized seizures by a significant suppression of spontaneous spike-and-wave discharges from a dose of 6.8 mg/kg i.p. in Genetic Absence Epilepsy Rats (GAERS) from Strasbourg and by producing a protective ED50 value of 2.4 mg/kg i.p. against clonic convulsions in sound susceptible mice. In line with these findings, brivaracetam also significantly reduced the myoclonus and seizure score from a dose of 0.3 mg/kg i.p. in a rat model of post-hypoxic myoclonus.
BRIVLERA tablets, oral solution, and solution for injection are bioequivalent. Brivaracetam exhibits linear and time-independent pharmacokinetics with low intra- and inter-subject variability.
Brivaracetam is highly permeable and is rapidly and completely absorbed after oral administration. Pharmacokinetics are dose-proportional from 10 to 600 mg. The median Tmax for tablets taken without food is 1 hour (Tmax range is 0.25 to 3 h). Co-administration with a high-fat meal slowed down the absorption rate of brivaracetam while the extent of absorption remained unchanged. When BRIVLERA (50 mg tablet) is administered with a high fat meal, Cmax is decreased by 37% and Tmax is delayed by 3 hours while AUC is decreased by 5%.
Brivaracetam is weakly bound (≤20%) to plasma proteins. The volume of distribution is 0.5 L/kg, a value close to that of the total body water. Due to its favourable lipophilicity (Log P) resulting in high cell membrane permeability, brivaracetam penetrates rapidly into the brain. Brivaracetam is rapidly and evenly distributed in most tissues. In rodents, the brain-to-plasma concentration ratio equilibrates rapidly, indicating fast brain penetration, and is close to 1, indicating absence of active transport.
Brivaracetam is primarily metabolized by hydrolysis of the amide moiety to form the corresponding carboxylic acid, and secondarily by hydroxylation on the propyl side chain.
The hydrolysis of the amide moiety leading to the carboxylic acid metabolite (34% of the dose in urine) is supported by hepatic and extra-hepatic amidase. In vitro, the hydroxylation pathway is mediated primarily by CYP2C19. In vivo, in human subjects possessing ineffective mutations of CYP2C19, production of the hydroxy metabolite is decreased 2- or 10-fold while brivaracetam itself is increased by 22% or 42% in individuals with one or both mutated alleles, respectively. Therefore, hydroxylation of brivaracetam is a secondary biotransformation pathway (mediated by CYP2C19) and inhibitors of CYP2C19 are unlikely to have a significant effect on BRIVLERA. An additional metabolite (the hydroxy acid metabolite) is created predominantly by hydroxylation of the propyl side chain on the carboxylic acid metabolite (mainly by CYP2C9). The 3 metabolites are not pharmacologically active.
Brivaracetam is eliminated primarily by metabolism and by excretion in the urine. More than 95% of the dose, including metabolites, is excreted in the urine within 72 hours after intake. Fecal excretion accounts for less than 1% of the dose. Less than 10% of the dose is excreted unchanged in the urine. The terminal plasma half-life (t1/2) is approximately 9 hours.
An open-label, single-arm, multicenter, pharmacokinetic study with a 3-week evaluation period and fixed 3-step up-titration using BRIVLERA oral solution was conducted in 99 pediatric patients with epilepsy in the age range from 1 month to less than 16 years, of which 59 were aged at least 4 years and contributed plasma concentration levels BRIVLERA was administered at weekly increasing doses of approximately 1 mg/kg/day, 2 mg/kg/day, and 4 mg/kg/day. All doses were adjusted by body weight, and did not exceed a maximum of 50 mg/day, 100 mg/day, and 200 mg/day. In those patients, plasma concentrations were shown to be dose-proportional. A weight-based dosing regimen is necessary to achieve brivaracetam exposures in pediatric patients 4 years to less than 18 years of age that are similar to those observed in adults treated at effectives doses of BRIVLERA (see 4 DOSAGE AND ADMINISTRATION).
The estimated weight-normalized plasma clearance for children weighing 20 kg, 30 kg and 50 kg are, respectively: 0.080 L/h/kg, 0.073 L/h/kg, 0.064 L/h/kg. In comparison, estimation for adults (70 kg) is 0.051 L/h/kg. No clinical data are available in neonates.
In a study in 15 elderly subjects (65 to 79 years old; with creatinine clearance 53 to 98 mL/min/1.73 m²) receiving BRIVLERA 400 mg/day (200 mg twice daily), the plasma half-life of brivaracetam was 7.9 hours and 9.3 hours in the 65 to 75 and >75 years groups, respectively. At steady-state, Cmaxwas increased by 47% and AUC was decreased by 13% compared to single dose administration. The steady-state plasma clearance of brivaracetam was slightly lower (0.76 mL/min/kg) than in young healthy controls (0.83 mL/min/kg). No dose adjustments are required.
There are no differences in the pharmacokinetics of brivaracetam by gender.
Approximately 74% of the patients in controlled adjunctive epilepsy studies in adults were Caucasian. A population pharmacokinetic analysis comparing Caucasian (n=904) and non-Caucasian patients (n=344) showed no significant pharmacokinetic differences.
A 100 mg single-dose pharmacokinetic study in adult subjects with hepatic cirrhosis (Child-Pugh grades A, B, and C) showed that, compared to matched healthy controls, exposure to brivaracetam increased by 50%, 57%, and 59%, respectively, in patients with mild, moderate, and severe hepatic impairment (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, and 4.2 Recommended Dose and Dosage Adjustment, Patients with Hepatic Impairment).
A study in adult subjects with severe renal impairment (creatinine clearance <30 mL/min/1.73m² and not requiring dialysis) revealed that the plasma AUC of brivaracetam (200 mg single dose) was moderately increased (+21%) relative to healthy controls, while the AUC of the acid, hydroxy and hydroxyacid metabolites were increased 3-, 4- , and 21-fold, respectively. The renal clearance of these metabolites was also decreased by approximately 10-fold. Nonclinical studies were performed to characterize the safety of the hydroxyacid metabolite, and they did not reveal any safety issues.
There are limited clinical data on the use of BRIVLERA in patients with pre-existing renal impairment as these patients were excluded from pre-market clinical studies of epilepsy.
BRIVLERA has not been studied in patients with end-stage renal disease undergoing hemodialysis (see 7 WARNINGS AND PRECAUTIONS, Renal and 4.2 Recommended Dose and Dosage Adjustment, Patients with Renal Impairment).
No microbiological information is required for this drug product.
After acute administration, the maximum non-lethal oral dose in the rat was ≥1000 mg/kg, since 2000 mg/kg was not considered tolerable and a no-effect level of 500 mg/kg (both sexes) was identified based on the absence of clinical signs.
The toxicity potential of brivaracetam was investigated in the following repeated administration for 3 months in mice, up to 6 months in rats and dogs and 9 months in monkeys by the oral route and for up to 4 weeks in rats and dogs by i.v. infusion.
The liver was the main target organ with different sensitivity across species. The dog was the most sensitive species with no safety margin identified based on systemic exposure to brivaracetam. In dogs, the adverse changes in the liver were characterized by porphyrin deposits in hepatocytes, bile canaliculi, and Kupffer cells (i.e. porphyria) accompanied by increases in plasma biomarkers (increased ALT, AST, alkaline phosphatase, GGT, SDH, 5' nucleotidase, and bile acids) and histopathologic findings of centrilobular fibrosis and hyperplasia of oval cells/bile ducts, single hepatocyte necrosis, and centrilobular inflammation, as well as concretions in the lumen of the gall bladder. The high sensitivity of the dog for hepatotoxicity may be related to the relatively species-specific formation of a reactive metabolite, based mainly on data for an analog compound that causes similar hepatic effects.
Liver changes were also evident in mice in which hepatocellular hypertrophy, with, in males, single cell necrosis of hepatocytes and increased plasma aminotransferases and glutamate dehydrogenase activities occurred at 675 and 1000 mg/kg/day with the 450 mg/kg/day dose considered a no observed adverse effect level (NOAEL) at which systemic exposure to brivaracetam was approximately double that at the maximum recommended human dose (MRHD). These histopathological findings, along with lipofuscin pigment in hepatocytes and Kupffer cells, were also seen mainly in male mice chronically exposed for two years at all dose levels (carcinogenicity study).
In rats, centrilobular hepatocellular hypertrophy occurred at all dose levels; however no adverse liver changes were seen following chronic administration of brivaracetam at exposures up to 8 times (6 months) that at the MRHD of 200 mg/day. Lipofuscin, bile, and porphyrin pigment deposits in bile ducts, minimal bile duct hyperplasia, and peribiliary inflammation were observed in rats, but only after short term administration (4 weeks) with brivaracetam doses at or above a maximum tolerated dose (≥1000 mg/kg/day).
No adverse liver changes were seen in monkeys following administration of brivaracetam at exposures up to 42 times the mean human exposure at the clinical dose of 200 mg/day.
Carcinogenicity studies were conducted in the mouse at dose levels of 400, 550, and 700 mg/kg/day for 104 weeks and in the rat at 150, 230, 450, and 700 mg/kg/day for 104 weeks. In mice, there were higher incidences of liver tumours (hepatocellular adenoma and carcinoma) in males at the mid and high dose levels with systemic exposures (AUC) to brivaracetam at the no effect level (400 mg/kg/day) approximately equal to those at the MRHD of 200 mg/day. The liver tumours are considered to be the result of pleiotrophic effects on the liver that includes hepatocellular hypertrophy and induction of microsomal enzymes, a mode of action comparable to phenobarbitone that is not likely relevant for humans. In rats, there were higher incidences of thyroid tumours at ≥230 mg/kg/day, that were considered secondary to hepatic enzyme induction and not relevant for humans, and benign thymomas (thymic tumours) in high dose females. Systemic exposure at the no-effect dose level (450 mg/kg/day) for thymomas was about 9 times that at the MRHD.
Brivaracetam is not considered genotoxic based on evaluations in in vitro assays in bacterial (Ames test) and mammalian cells (mouse lymphoma assay, chromosomal aberration test in CHO cells) and in vivo in rats (bone marrow micronucleus assay) and mice (Muta mice).
In male and female rats administered brivaracetam (oral doses of 100, 200 or 400 mg/kg/day) prior to and throughout mating and continuing in females until gestation day 6, there were no effects on fertility. Based on toxicokinetic data from a repeated dose study in rats, the exposure margins are considered to be at least 6 and 13 times that at the MRHD, in male and female rats, respectively.
In embryo-fetal development studies, brivaracetam was administered to rats at oral dose levels of 150, 300 and 600 mg/kg/day and rabbits at 30, 60, 120, and 240 mg/kg/day during the period of organogenesis. Brivaracetam showed no evidence of teratogenicity. Brivaracetam caused maternal toxicity at 600 mg/kg/day, but no embryo-fetal toxicity in rats up to the maximum dose tested, 600 mg/kg/day, at which plasma exposure (AUC) was 32 times that at the MRHD of 200 mg/day. Brivaracetam caused developmental toxicity consisting of increased post-implantation loss, reduced fetal weight, and increased incidences of fetal minor abnormalities and variants related to the extent of ossification in the rabbit at 240 mg/kg/day, a maternal toxic dose, with systemic exposure at the no-effect dose (120 mg/kg/day) 8 times the AUC at the MRHD of 200 mg/day.
When brivaracetam (150, 300, or 600 mg/kg/day) was orally administered to rats throughout gestation, parturition, and lactation, lower body weight gains were observed in the offspring at the highest dose, with associated slight increase in age of attainment of vaginal patency and lower locomotor activity. The no-effect dose for pre- and post-natal developmental toxicity in rats (300 mg/kg/day) was associated with a maternal plasma brivaracetam AUC approximately 7 times that in humans at the MRHD.
After [14C]-brivaracetam administration to rats, brivaracetam and/or its metabolites readily crossed the placental barrier with maternal blood radioactivity levels similar to those in the fetus, placenta and amniotic fluid. Brivaracetam and/or its metabolites were excreted into milk of lactating female rats following a single radioactive dose, with mean milk/plasma ratio close to unity.
The potential adverse effects of long-term oral administration of brivaracetam on neonatal growth and development was investigated in juvenile rats and dogs with dosing starting on post natal day (PND) 4. In juvenile rats, the highest dose tested, 600 mg/kg/day, resulted in mortality, clinical signs, decreased body weight, delayed sexual maturation of males, hepatocellular hypertrophy, and lower brain weight. The no effect level for all effects except lower brain weight was 300 mg/kg/day, at which exposure to brivaracetam was 3-9 times that at the MRHD. A no-effect dose for lower brain weight was not identified; however, the differences from controls at the low and mid dose levels were small (≤6.5%) and there were no adverse effects at any dose level on behaviour, learning, and memory or no microscopic findings, which included a comprehensive histopathologic evaluation of the brain. In juvenile dogs, the dose of 100 mg/kg/day induced hepatotoxicity similar to those observed in adult animals. There were no adverse effects on growth, bone density or strength, brain (including brain weight) and neurobehavioral assessments and neuropathology evaluation. Similar exposure to brivaracetam was achieved in adult and juvenile animals at the NOAEL, except at post-natal day 4 where higher exposure was achieved in juvenile animals compared to adults. Based on hepatic toxicity at 100 mg/kg/day, 30 mg/kg/day was considered a NOAEL at which systemic exposure to brivaracetam was slightly higher than that at the MRHD.
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