Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: antiepileptics, other antiepileptics, ATC code: N03AX23 
Mechanism of action

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.



Clinical efficacy and safety

The efficacy of brivaracetam for the adjunctive therapy of partial-onset seizures (POS) was established in 3 randomized, double-blind, placebo-controlled, fixed-dose, multi-center studies in subjects 16 years of age and older. The daily dose of brivaracetam ranged from 5 to 200 mg/day across these studies. All studies had an 8-week baseline period followed by a 12-week treatment period with no up- titration. 1,558 patients received study drug of which 1,099 received brivaracetam. Study enrollment criteria required that patients have uncontrolled POS despite treatment with either 1 or 2 concomitant AEDs. Patients were required to have at least 8 POS during the baseline period. The primary endpoints in the phase 3 studies were the percent reduction in POS frequency over placebo and the 50 % responder rate based on 50 % reduction in POS frequency from baseline.
The most commonly taken AEDs at the time of study entry were carbamazepine (40.6 %), lamotrigine (25.2 %), valproate (20.5 %), oxcarbazepine (16.0 %), topiramate (13.5 %), phenytoin (10.2 %) and levetiracetam (9.8 %). The median baseline seizure frequency across the 3 studies was 9 seizures per 28 days. Patients had a mean duration of epilepsy of approximately 23 years.
The efficacy outcomes are summarized in Table 2. Overall, brivaracetam was efficacious for the adjunctive treatment of partial onset seizures in patients 16 years of age and older between 50 mg/day and 200 mg/day.

Table 2: Key Efficacy Outcomes for Partial Onset Seizure Frequency per 28 Days Study                                        Placebo                   Brivaracetam * Statistically significant (p-value)

50 mg/day             100 mg/day                200 mg/day
Study N01253(1) n= 96       n= 101
50 % Responder rate                               16.7        32.7*                       ~                          ~ (p=0.008)

Percent reduction over placebo (%)                NA          22.0*                       ~                          ~ (p=0.004)

Study N01252(1) n = 100       n = 99                 n = 100
50 % Responder rate                               20.0         27.3                   36.0(2)                        ~ (p=0.372)               (p=0.023)

Percent reduction over placebo (%)                NA            9.2                   20.5(2)                        ~ (p=0.274)               (p=0.010)

Study N01358 n = 259                              n = 252                      n = 249 50% Responder rate                                21.6           ~                    38.9*                        37.8* (p<0.001)                   (p<0.001)
*
Percent reduction over placebo (%)                NA             ~                     22.8                        23.2* (p<0.001)                   (p<0.001)
 n = randomised patients who received at least 1 dose of study medication ~ Dose not studied
*
Statistically significant
(1)
Approximately 20 % of the patients were on concomitant levetiracetam
(2)
The primary outcome for N01252 did not achieve statistical significance based on the sequential testing procedure . The 100 mg/day dose was nominally significant.

In clinical studies, a reduction in seizure frequency over placebo was higher with the dose of 100 mg/day than with 50 mg/day. Apart from dose-dependent increases in incidences of somnolence and fatigue brivaracetam 50 mg/day and 100 mg/day had a similar safety profile including CNS- related AEs and with long-term use.

Figure 1 shows the percentage of patients (excluding patients with concomitant levetiracetam) by category of reduction from baseline in POS frequency per 28 days in all 3 studies. Patients with more than a 25 % increase in POS are shown at left as “worse”. Patients with an improvement in percent reduction in baseline POS frequency are shown in the 4 right-most categories. The percentages of patients with at least a 50 % reduction in seizure frequency were 20.3 %, 34.2 %, 39.5 %, and 37.8 % for placebo, 50 mg/day, 100 mg/day, and 200 mg/day, respectively.

Figure 1:   Proportion of patients by category of seizure response for brivaracetam and placebo over 12 weeks across all three double-blind pivotal trials



In a pooled analysis of the three pivotal trials, no differences in efficacy (measured as 50 % responder rate) was observed within the dose range of 50 mg/day to 200 mg/day when brivaracetam is combined with inducing or non-inducing AEDs. In clinical studies 2.5 % (4/161), 5.1 % (17/332) and 4.0% (10/249) of the patients on brivaracetam 50 mg/day, 100 mg/day and 200 mg/day respectively became seizure free during the 12-week treatment period compared with 0.5 % (2/418) on placebo.

Improvement in the median percent reduction in seizure frequency per 28 days has been observed in patients with type IC seizure (secondary generalized tonic-clonic seizures) at baseline treated with brivaracetam (66.6 % (n=62), 61.2 % (n=100) and 82.1 % (n=75) of the patients on brivaracetam 50 mg/day, 100 mg/day and 200 mg/day respectively as compared to placebo 33.3 % (n=115)).

The efficacy of brivaracetam in monotherapy has not been established. Brivaracetam is not recommended for use in monotherapy.

Treatment with levetiracetam

In two phase 3 randomised placebo-controlled studies, levetiracetam was administered as concomitant AED in about 20 % of the patients. Although the number of subjects is limited, there was no observed benefit of brivaracetam versus placebo in patients taking levetiracetam concurrently which may reflect competition at the SV2A binding site. No additional safety or tolerability concerns were observed.

In a third study, a pre-specified analysis demonstrated efficacy over placebo for 100 mg/day and 200 mg/day in patients with prior exposure to levetiracetam. The lower efficacy observed in these patients compared to the leveticacetam-naïve patients was likely due to the higher number of prior AEDs used and higher baseline seizure frequency.

Elderly (65 years of age and above)
The three pivotal double-blind placebo-controlled studies included 38 elderly patients aged between 65 and 80 years. Although data are limited, the efficacy was comparable to younger subjects.



Open label extension studies
Across all studies, 81.7 % of the patients who completed randomized studies were enrolled in the long-term open-label extension studies. From entry into the randomized studies,5.3 % of the subjects exposed to brivaracetam for 6 months (n=1,500) were seizure free compared to 4.6 % and 3.7 % for subjects exposed for 12 months (n=1,188) and 24 months (n=847), respectively. However, as a high proportion of subjects (26%) discontinued from the open-label studies due to lack of efficacy, a selection bias may have occurred, as the subjects who stayed in the study responded better than those who have terminated prematurely.
In patients who were followed up in the open-label extension studies for up to 8 years, the safety profile was similar to that observed in the short-term, placebo-controlled studies.

Paediatric population

In children aged 4 years and older, partial onset seizures have a similar pathophysiology to those in adolescents and adults. Experience with epilepsy medicines suggests that the results of efficacy studies performed in adults can be extrapolated to children down to the age of 4 years provided the paediatric dose adaptations are established and safety has been demonstrated (see sections 5.2 and 4.8). Doses in patients from 4 years of age were defined by weight-based dose adaptations which have been established to achieve similar plasma concentrations to the ones observed in adults taking efficacious doses (section 5.2).

A long-term, uncontrolled, open-label safety study included children (1 month to 16 years) who continued treatment after completing the PK study (see section 5.2), children who continued treatment after completing the I.V. (intravenous) safety study and children directly enrolled into the safety study.
Children who directly enrolled received a brivaracetam starting dose of 1 mg/kg/day and depending on response and tolerability, the dose was increased up to 5 mg/kg/day by doubling the dose at weekly intervals. No child received a dose greater than 200 mg/day. For children weighing 50 kg or greater the brivaracetam starting dose was 50 mg/day and depending on response and tolerability, the dose was increased up to a maximum of 200 mg/day by weekly increments of 50 mg/day.

From the pooled open-label safety and PK studies in adjunctive therapy, 186 children with POS in ages <16 years have received brivaracetam, of whom 149 have been treated for > 3 months, 138 for ≥6 months, 123 for ≥12 months, 107 for ≥24 months, and 90 for ≥36 months.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

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 tmax for tablets taken without food is 1 hour (tmax range is 0.25 to 3 h).
Coadministration with a high-fat meal slowed down the absorption rate (median tmax 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 (t1/2) 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 P- glycoprotein (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, 2C8, 2C9, 2D6 and 3A4) inhibitors.

In vitro, brivaracetam was not an inhibitor of the CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 3A4, 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). (see section 4.2).

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 (see section 4.2).

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. (see section 4.2).

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 (see section 4.8).
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. The analysis indicated that doses for up to 50 kg body weight 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.