Brivaracetam in the treatment of epilepsy: a review of clinical trial data

Figures & data

Table 1 The pharmacokinetic properties of brivaracetam in comparison to levetiracetam

	Brivaracetam	Levetiracteam
Dosage formulations  Oral  Intravenous	25 mg, 50 mg, 75 mg, 100 mg 50 mg/5 mL	250 mg, 500 mg, 750 mg, 1000 mg 500 mg/5 mL; 500 mg/100 mL; 1500 mg/5 mL
Bioavailability	100%* (may be delayed with high-fat meal)	>95%
Time to peak, median (range)	2 hr (1–4 hrs)	1 hr (1–2 hrs)
Protein binding	15–20%	<10%
Metabolism	Hydrolysis-primary metabolism Hydroxylation (CYP2C19)-16% Unchanged-9%	34% metabolized (hydrolysis) 66%-unchanged
Involvement of CYP450 enzymes	Yes (CYP2C19)	No
Elimination half-life (t1/2)	7–8 hrs	6–8 hrs
Time for steady state	2 days of repeated dosing	24–48 hrs of repeated dosing
Clearance	95% via kidney (8–10% unchanged)	100% via kidney (66% unchanged)
Dose adjustment in renal failure/dialysis	Not required	Required (50% supplemental dose following HD)
Dosing adjustment in liver failure	Reduce dose by 1/3 may be needed	Not required
Relevant drug–drug interaction	Reduced by co-administration of rifampin Reduce combined OCPs by 20–30% at 400 mg/day	None

Abbreviations: CYP450, cytochrome P450; HD, hemodialysis; OCP, oral contraceptive pills.

Figure 1 Proposed mechanism of action of brivaracetam (BRV) and levetiracetam (LEV). BRV and LEV bind to the human SV2A protein at closely related sites. BRV has a 15–30-fold higher binding affinity than LEV. Unlike LEV, BRV does not Inhibit high-voltage-gated calcium currents or modulate inhibitory or excitatory postsynaptic ligand-gated receptors at therapeutic brain concentrations.

Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA, gamma-aminobutyric acid; GAD65, glutamate decarboxylase 65; SV2A, synaptic vesicle protein 2A.

Table 2 Summary of efficacy outcomes from the six regulatory RCTs of brivaracetam as adjunctive therapy in adult patient with drug-resistant seizures

Study	Study design	Population	N (ITT)	Treatment arms	Age mean (years)	Primary outcome focal- onset seizure frequency/week vs placebo)	Median % reduction from baseline	Secondary endpoints >50% responder rate	Complete seizure freedom
French et al, 2010 (study N01193)^Citation51	Phase IIb, double-blind RCT, 4-week prospective baseline, 7-week treatment period	Patients with uncontrolled focal seizures despite 1–2 ASDs	208	Placebo BRV 5 mg BRV 20 mg BRV 50 mg	33.6 32.7 35,3 30.9	NA 9.8% (p=0.240) 14.9% (p=0.062) 22.1% (p=0.004)	21.7% 29.9 (p=0.086) 42.6% (p=0.014) 53.1% (p<0.001)	16.7% 32.0% (p=0.047) 44.2% (p=0.002) 55.8% (p=0.001)	1 (1.9%) 4 (8.0%) 4 (7.7%) 4 (7.7%)
Van Paesschen et al, 2013 (study N01114)^Citation52	Phase IIb, double-blind RCT, 4-week prospective baseline, 10-week treatment period (3-week up-titration plus 7-week maintenance)	Patients with uncontrolled focal seizures despite 1–2 ASDs	157	Placebo BRV 50 mg BRV 150 mg	40 38.2 34.4	NA 14.7% (p=0.093) 13.6% (p=0.124)	18.9% 38.2 (p=0.017) 34.9 (p=0.111)	17.3% 35.8% (p=0.038) 30.8% (p=0.114)	1 (1.9%) 5 (9.4%) 3 (5.8%)
Ryvlin et al, 2014 (study N01252)^Citation53	Phase III, double-blind RCT, 8-week prospective baseline, 12-week treatment period	Patients with uncontrolled focal seizures despite 1–2 ASDs	398	Placebo BRV 20 mg BRV 50 mg BRV 100 mg	36.4 35.7 38.9 38.0	NA 6.8 (p=0.239) 6.5% (p=0.261) 11.7% (p=0.037)	17% 30.0% (p=0.019) 26.8% (p=092) 23.5% (p=0.004)	20% 27.3% (p=0.339) 27.3 (p=0.372) 36.0% (p=0.023)	None 2 (2%) None 4 (4%)
Biton et al, 2014 (study N01253)^Citation54	Phase III, double-blind RCT, 8-week prospective baseline, 12-week treatment period	Patients with uncontrolled focal seizures despite 1–2 ASDs	396	Placebo BRV 5 mg BRV 20 mg BRV 50 mg	37.5 38.9 37.3 38.9	NA -0.9% (p=0.885) 4.1 (p=0.492) 12.8% (p=0.025)	17.8% 20.0% (p=NS) 22.5% (p=NS) 30.5 (p=0.003)	16.7% 21.9% (p=NS) 23.2% (p=NS) 32.3% (p=NS)	None 1 (1.1%) 1 91%) 4 (4%)
Kwan et al, 2014 (study N01254)^Citation55	Phase III, double-blind RCT, 4-week prospective baseline, 16-week treatment period (8-week dose-finding plus 8-week stable dose maintenance)	Patients with uncontrolled focal (n=431) or generalized (n=49) seizures despite 1–3 ASDs	480	Placebo BRV titration up to 150 mg	36.5 35.6	NA 7.3% (p=0.125)	18.9% 26.9% (p=0.070)	16.7% 30.3 (p=0.006)	None 2 (1.5%)
Klein et al, 2015 (study N01358)^Citation56	Phase III, double-blind RCT, 8-week prospective baseline, 12-week treatment period	Patients with uncontrolled focal seizures despite 1–2 ASDs	760	Placebo BRV 100 mg BRV 200 mg	39.8 39.1 39.8	NA 22.8% (p<0.001) 23.2 (p<0.001)	17.6% 37.2% (p<0.001) 35.6% (p<0.001)	21.6% 38.9% (p<0.001) 37.8% (p<0.001)	0.8% 5.3% 4.0%

Note: The p-values are bold where they are significant.

Abbreviations: ASDs, antiseizure drugs; BRV, brivaracetam; N (ITT), number of patients in intention to treat population; NA, not applicable; NS, non-significant; RCT, randomized controlled trial.

Table 3 Rate of TEAEs (%) reported by ≥5% of patients in any treatment group in the six regulatory RCTs of brivaracetam

Side effect	Brivaracetam 20 mg		Brivaracetam 50 mg		Brivaracetam 100 mg		Brivaracetam 150 mg		Brivaracetam 200 mg		Overall incidence rate
	RR	p	RR	p	RR	p	RR	p	RR	p
At least one TEAE	1.06 (0.86–1.30)	0.59	1.07 (0.91–1.25)	0.42	1.16 (1.04–1.30)	0.818	0.95 (0.73–1.22)	0.67	1.13 (0.99–1.29)	0.08	NA
Headache	0.82 (0.48–1.40)	0.46	1.28 (0.82–1.99)	0.27	0.86 (0.52–1.41)	0.545	1.00 (0.26–3.79)	1.00	0.95 (0.53–1.70)	0.86	10.4%
Dizziness	1.11 (0.60–2.06)	0.74	1.44 (0.83–2.48)	0.19	1.77 (1.01–3.09)	0.047	1.67 (0.42–6.62)	0.46	2.89 (1.57–5.32)	0.001	9.6%
Somnolence	1.47 (0.81–2.66)	0.20	1.54 (0.90–2.64)	0.12	2.25 (1.45–3.49)	<0.001	1.00 (0.21–4.73)	1.00	2.19 (1.33–3.63)	0.002	12.4%
Fatigue	3.00 (1.21–7.47)	0.02	2.38 (1.16–4.89)	0.02	2.31 (1.19–4.48)	0.014	0.75 (0.18–3.19)	0.69	3.03 (1.51–6.08)	0.002	7.7%
Nasopharyngitis	5.99 (1.36–26.35)	0.02	2.16 (0.77–6.08)	0.15	2.00 (0.18–21.7)	0.569	1.33 (0.31–5.67)	0.69	NA	NA	4.2%
Nausea	0.99 (0.36–2.69)	0.98	0.83 (0.38–1.82)	0.64	1.50 (0.44–5.16)	0.520	0.67 (0.20–2.23)	0.51	NA	NA	4.9%
Insomnia	1.47 (0.25–8.61)	0.67	2.59 (0.70–9.60)	0.15	NA	NA	3.00 (0.32–27.91	0.33	NA	NA	2.5%
Irritability	1.96 (0.37–10.46)	0.43	2.95 (1.03–8.44)	0.04	6.48 (1.17–35.9)	0.033	0.50 (0.05–5.35)	0.56	7.31 (0.91–58.97)	0.062	2.8%

Notes: Data from Lattanzi et al.²³ The p-values are bold where they are significant.

Abbreviations: RR, Mantel-Haenszel risk ratios; TEAEs, treatment-emergent adverse events; NA, not applicable.

Table 4 Comparisons of pharmacological properties of brivaracetam and levetiracetam

	Brivaracetam	Levetiracetam
Discovery	Target-based rational drug discovery program	Screening in audiogenic seizure susceptible mice
Available formulations	Oral and intravenous	Oral and intravenous
Approval status (FDA) Focal-onset seizures Generalized onset seizures	First time approval in 2016 Yes (for age >4 years old) No	First time approval in 1999 Yes (for age >1 month old) Yes Primary generalized GTCs (age >6 years old) Myoclonic seizures (>12 years old)
Mechanism of action	Selective binding to SV2A	Binding to SV2A Inhibition of AMPA receptors Inhibition of high-voltage-gated calcium currents
Binding affinity to SVA2	15–30 times higher than LEV	-
Drug entry to the brain	Fast speed of entry (within minutes)	Longer than BRV (1 hr)
Clinically relevant drug interactions	With rifampin and combined oral contraceptives	None
Involvement of CYP450 enzymes	Yes	No
Dosing adjustments in liver failure	Required in severe cases	Not required
Dosing adjustments in renal failure	Not required	Required
Behavioral and psychiatric adverse events	3%	10–15%
Effect on cognition	Suspected to be similar to LEV	Neutral^Citation86 or positive^Citation87,Citation88 effect on cognition First-line therapy for dementia-related epilepsy
Switching from LEV to BRV	10:1–15:1 without titration	–

Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BRV, brivaracetam; CYP450, Cytochrome P450; FDA, Food and Drug Administration; GTCs, generalized tonic-clonic seizures; LEV, levetiracetam; SV2A, synaptic vesicle glycoprotein 2A.

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