Brivaracetam

Brivaracetam displays a high and selective affinity for synaptic vesicle protein 2A (SV2A), a transmembrane glycoprotein found at presynaptic level in neurons and in endocrine cells. Although the exact role of this protein remains to be elucidated it has been shown to modulate exocytosis of neurotransmitters. Binding to SV2A is believed to be the primary mechanism for brivaracetam anticonvulsant activity.

Brivaracetam film-coated tablets, oral solution and solution for intravenous injection show the same AUC, while the maximum plasma concentration is slightly higher after intravenous administration. Brivaracetam exhibits linear and time-independent pharmacokinetics with low intra- and inter-subject variability, and features complete absorption, very low protein binding, renal excretion following extensive biotransformation, and pharmacologically inactive metabolites.

Absorption

Brivaracetam is rapidly and completely absorbed after oral administration and the absolute bioavailablity is approximately 100%. The median t_max for tablets taken without food is 1 hour (t_max range is 0.25 to 3 h).

Coadministration with a high-fat meal slowed down the absorption rate (median t_max 3 h) and decreased the maximum plasma concentration (37% lower) of brivaracetam, while the extent of absorption remained unchanged.

Distribution

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 lipophylicity (Log P) brivaracetam has high cell membrane permeability.

Biotransformation

Brivaracetam is primarily metabolized by hydrolysis of the amide moiety to form the corresponding carboxylic acid (approximately 60% the elimination), and secondarily by hydroxylation on the propyl side chain (approximately 30% the elimination). 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 of brivaracetam is mediated primarily by CYP2C19. Both metabolites, are further metabolised forming a common hydroxylated acid formed predominantly by hydroxylation of the propyl side chain on the carboxylic acid metabolite (mainly by CYP2C9). In vivo, in human subjects possessing ineffective mutations of CYP2C19, production of the hydroxy metabolite is decreased 10-fold while brivaracetam itself is increased by 22% or 42% in individuals with one or both mutated alleles. The three metabolites are not pharmacologically active.

Elimination

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. Less than 1% of the dose is excreted in faeces and less than 10% of brivaracetam is excreted unchanged in urine. The terminal plasma half-life (t_1/2) is approximately 9 hours. The total plasma clearance in patients was estimated to 3.6 L/h.

Linearity

Pharmacokinetics is dose-proportional from 10 to at least 600 mg.

Interactions with medicinal products

Brivaracetam is cleared by multiple pathways including renal excretion, non-CYP-mediated hydrolysis and CYP-mediated oxidations. In vitro, brivaracetam is not a substrate of human Pglycoprotein (P-gp), multidrug resistance proteins (MRP) 1 and 2, and likely not organic anion transporter polypeptide 1B1 (OATP1B1) and OATP1B3. In vitro assays showed that brivaracetam disposition should not be significantly affected by CYP (eg. CYP1A, CYP2C8, CYP2C9, CYP2D6 and CYP3A4) inhibitors.

In vitro, brivaracetam was not an inhibitor of the CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP3A4, or the transporters P-gp, BCRP, BSEP MRP2, MATE-K, MATE-1, OATP1B1, OATP1B3, OAT1 and OCT1 at clinically relevant concentrations. In vitro, brivaracetam did not induce CYP1A2.

Pharmacokinetics in special patient groups

Elderly (65 years of age and above)

In a study in elderly subjects (65 to79 years old; with creatinine clearance 53 to 98 ml/min/1.73 m²) receiving brivaracetam 400 mg/day in bid administration, the plasma half-life of brivaracetam was 7.9 hours and 9.3 hours in the 65 to 75 and >75 years groups, respectively. The steady-state plasma clearance of brivaracetam was similar (0.76 ml/min/kg) to young healthy male subjects (0.83 ml/min/kg).

Renal impairment

A study in subjects with severe renal impairment (creatinine clearance <30 ml/min/1.73 m² and not requiring dialysis) revealed that the plasma AUC of brivaracetam 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 non active metabolites was decreased 10-fold. The hydroxyacid metabolite did not reveal any safety concerns in non clinical studies. Brivaracetam has not been studied in patients undergoing hemodialysis.

Hepatic impairment

A pharmacokinetic study in subjects with hepatic cirrhosis (Child-Pugh classes A, B, and C) showed similar increases in exposure to brivaracetam irrespective of disease severity (50%, 57% and 59%), relative to matched healthy controls.

Body weight

A 40% decrease in steady-state plasma concentration has been estimated across a body weight range from 46 kg to 115 kg. However, this is not considered to be a clinically relevant difference.

Gender

There are no clinically relevant differences in the pharmacokinetics of brivaracetam by gender.

Race

The pharmacokinetics of brivaracetam was not significantly affected by race (Caucasian, Asian) in a population pharmacokinetic modeling from epilepsy patients. The number of patients with other ethnic background was limited.

Pharmacokinetic/pharmacodynamics relationship

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 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.

Paediatric population

In a pharmacokinetic study with a 3-week evaluation period and weekly fixed 3-step up-titration using the brivaracetam oral solution, 99 subjects aged 1 month to <16 years were evaluated. Brivaracetam 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. At the end of the evaluation period, subjects may have been eligible for entry into a long-term follow-up study continuing on their last received dose. Plasma concentrations were shown to be dose-proportional in all age groups. Population pharmacokinetics modeling was performed based on sparse plasma concentration data collected in the 3-week PK study and the ongoing long-term follow-up study. 232 paediatric patients with epilepsy, aged 2 months to 17 years, were included in the analysis. The analysis indicated that doses of 5.0 (body weights 10-20 kg) and 4.0 mg/kg/day (body weights 20-50 kg) provide the same steady-state average plasma concentration as in adults receiving 200 mg/day. The estimated plasma clearance was 0.96 L/h, 1.61 L/h, 2.18 L/h and 3.19 L/h for children weighing 10 kg, 20 kg, 30 kg and 50 kg, respectively. In comparison, plasma clearance was estimated at 3.58 L/h in adult patients (70 kg body weight). Currently, no clinical data are available in neonates.

In safety pharmacology studies, the predominant effects were CNS related (mainly transient CNS depression and decreased spontaneous locomotor activity) seen at multiples (greater than 50 fold) of the pharmacologically active dose of brivaracetam, 2 mg/kg. Learning and memory function were not affected.

Findings not observed in clinical studies, but seen in the repeated-dose toxicology dog studies at exposure similar to the clinical plasma AUC, were hepatotoxic effects (mainly porphyria). However, toxicological data accumulated on brivaracetam and on a structurally-related compound indicate that the dog liver changes have developed through mechanisms not relevant for humans. No adverse liver changes were seen in rats and monkeys following chronic administration of brivaracetam at 5- and 42- fold the clinical AUC exposure. In monkeys, CNS signs (prostrate, loss of balance, clumsy movements) occurred at 64 fold the clinical C_max, these effects being less apparent over time.

Genotoxicity studies have not detected any mutagenic or clastogenic activity. Carcinogenicity studies did not indicate any oncogenic potential in rats, whereas increased incidences of hepatocellular tumors in male mice are considered to result of a non-genotoxic, mode of action linked to a phenobarbitonelike liver enzyme induction, which is a known rodent specific phenomenon.

Brivaracetam did not affect male or female fertility and has demonstrated no teratogenic potential in either rat or rabbit. Embryotoxicity was observed in rabbits at a maternal toxic dose of brivaracetam with an exposure level 8-fold the clinical AUC exposure at the maximum recommended dose. In rats, brivaracetam was shown to readily cross the placenta and to be excreted in milk of lactating rats with concentrations similar to maternal plasma levels. Brivaracetam did not show any dependence potential in rats.

Juvenile animals studies

In juvenile rats, brivaracetam exposure levels 6- to 15-fold the clinical AUC exposure at the maximum recommended dose induced developmental adverse effects (i.e. mortality, clinical signs, decreased body weight and lower brain weight). There were no adverse effects on CNS function, neuropathological and brain histopathological examination. In juvenile dogs, the brivaracetam-induced changes at the exposure level 6-fold the clinical AUC were similar to those observed in adult animals. There were no adverse effects in any of the standard developmental or maturation endpoints.