Use of the New Antiepileptic Agents

Anthony Murro, M.D.

Research Support

• I currently received support for research involving biravacetam from UCB

New Antiepileptic Agents

• Lacosamide (Vimpat)

• Rufinamide (Banzel)

• Vigabatrin (Sabril)

• Clobazam (Onfi)

• Ezogabine (Potiga)

Lacosamide• Adjunctive therapy in the treatment of

partial-onset seizures• Functionalized amino acid

Lacosamide - Mechanism• Lacosamide facilitates slow inactivation of

voltage gated sodium ion channels

Lacosamide - Slow inactivation

• Membrane depolarization occurs

• A relatively slower & more sustained ion channel conformation occurs at a intra-membrane channel site

• This conformation blocks sodium ion flow

• Lacosamide enhances slow inactivation

• (Goldin, 2011)

Sodium Ion Channel Fast Inactivation

• Voltage gated sodium ion channel conformation occurs post-depolarization

• An intracellular protein segment (inactivating particle) binds to a docking site & blocks sodium ion flow

• Carbamazepine, felbamate, lamotrigine, phenytoin, oxcarbazepine, topiramate enhance fast inactivation

• (Goldin, 2011)

Slow inactivationIntra-membrane sites S5 & S6 block ion

channel

Fast Inactivation

Intracellular loop between domains III & IV blocks ion channel

CRMP-2 Binding• Lacosamide also binds to a collapsin

response mediator protein-2 (CRMP-2)

CRMP-2 Binding• This protein performs important roles that

include cytoskeletal, vesicle, and synaptic functions in the developing brain.

• The significance of this binding is an area of current research (Hensley et al., 2011)

Lacosamide Dosing

• Adult: 50 mg twice daily; may be increased at weekly intervals by 100 mg/day

• Maintenance dose: 200-400 mg/day

Lacosamide Metabolism

• Linear kinetics 100-800 mg/d dose

• Metabolism (CYP2C19) by de-methylation to form O-desmethyl-lacosamide (inactive)

• No significant induction/inhibition or P450 mediated interaction

(Chu et al, 2010)

Lacosamide Effectiveness• Multi-center randomized prospective

controlled trials

• > 400 patients per trial

• Age 16 years and older

• Adjunctive therapy with 1-3 anti-epileptic medications

Lacosamide Median Sz ReductionGroup Ben-Menachem Halasz

Placebo 10% 20.5%

200 mg/d 26% 35.3%

400 mg/d 39% 36.4%

600 mg/d 40% ---

(Ben-Menachem et al, 2007, Halasz et al, 2009)

Lacosamide Effectiveness

• Dose of 600 mg/day not more effective but did have increased side effect risk

• Events leading to discontinuation: Dizziness, nausea, ataxia, vomiting, nystagmus

• (Ben-Menachem et al, 2007)

Effect of Sodium Channel Blocker

Retrospective analysis suggests:

• Lacosamide will reduce seizure frequency even when combined with a fast sodium channel blocker (Sake et al., 2010, Stephen et al., 2011)

Effect of Sodium Channel Blocker

Retrospective analysis suggests:

• Lacosamide with a sodium channel blocker (e.g. phenytoin) will lead to less seizure reduction & increased side effects

• Caution: Post-hoc analysis, small samples, multiple comparisons, and potential confounding factors.

(Sake et al., 2010, Stephen et al., 2011)

Lacosamide Pooled Analysis

Median Seizure Reduction

Sodium Channel Blocker

Group Present Absent

Placebo 18.9% 28%

200 mg/d 33.3% 38%

400 mg/d 39% 62.5%

600 mg/d 42.7% 79%

Lacosamide Case Reports• Intravenous lacosamide has been used to

treat status epilepticus & seizure clusters. Bolus of 200 mg IV at rate of 60 mg/min (Höfler et al., 2011)

• Lacosamide has been used in primary generalized epilepsy (Afra et al., 2012)

• A single report described worsening of seizures in Lennox Gastaut syndrome with lacosamide (Cuzzola et al., 2010)

Lacosamide SummaryPositive

• No significant drug interactions

• Common side effects are dose dependent & easily managed with dose reduction

• Infrequent need for serum drug levels

• Low protein binding

Negative

• High cost

Role of Lacosamide

• The favorable profile makes lacosamide a likely early choice for adjuvant drug therapy of partial seizures

• Future research might confirm effectiveness for primary generalized epilepsy & status epilepticus.

• Future research might confirm greater benefit among patients not using sodium channel blockers

Rufinamide• Adjunctive therapy in the treatment of

generalized seizures of Lennox-Gastaut syndrome (LGS)

Rufinamide Mechanism• Rufinamide slows sodium ion channel

recovery from the inactivated state & limits repetitive neuronal firing

Rufinamide Dosing• Children: Initial: 10 mg/kg/day in 2 equally

divided doses; increase dose by ~10 mg/kg every other day to a target dose of 45 mg/kg/day or 3200 mg/day (whichever is lower) in 2 equally divided doses

• Adults: Initial: 400-800 mg/day in 2 equally divided doses; increase dose by 400-800 mg/day every other day to a maximum dose of 3200 mg/day in 2 equally divided doses.

Rufinamide Oral Absorption• Oral absorption increases with food due to

increased solubility (33% increase overall absorption & 50% increase in peak concentration).

• Keep relationship with meals constant.

Rufinamide Metabolism

• Carboxylesterase metabolism to inactive metabolite

• Rufinamide is a weak CYP3A4 inducer

• Non-linear drug kinetics

Rufinamide Drug Levels

• Drug levels correlate with effectiveness and frequency of adverse effects

• Mean plasma level causing a 50% decrease of seizure frequency was 30 mg/l; range in studies: 5-55 mg/l.

Rufinamide Drug Interactions

• Mild increased clearance of oral contraceptives (CYP3A4 induction)

• Phenobarbital, primidone, phenytoin, carbamazepine induce carboxyesterase & significantly increase rufinamide clearance

• Valproate significantly increases rufinamide levels by 60-70%

Rufinamide Lennox Gastaut Median Seizure Reduction

Group All Seizures Tonic-atonic

Placebo 11.7% -1.4%

45 mg/kg-d 32.7% 42.5%

(Glauser et al., 2007)

Rufinamide Partial Seizures Median Seizure Reduction

Group Seizure Reduction

Placebo -1.6%

Rufinamide* 20.4%

Dose: 1200-3200 mg/d (mean 2800 mg/d)

(Brodie et al, 2007)

Adverse Effects• Most common: Dizziness, fatigue,

somnolence, nausea, headache

• AED hypersensitivity syndrome (rash & fever) has occurred 1-4 weeks after therapy & more likely in children

• No significant effects on working memory, psychomotor speed, or attention

• (Wheles et al. 2010)

Rufinamide QT shortening

• > 20 msec reduction in QT can occur but in in study population had < 300 msec

• Rufinamide should not be given to those with familial short QT syndrome potassium channelopathy

• Do not administer in situations with reduced QT interval: digoxin, hpercalcemia, hyperkalemia, acidosis

Myoclonic-astatic epilepsy (Doose syndrome)

• Onset age 1-6 years of age

• Myoclonic, astatic, & myoclonic-astatic Sz

• Normal development prior to seizures

• Prognosis variable: spontaneous resolution in some; prolonged non-convulsive status epilepticus, cognitive impairments & evolution to Lennox-Gastaut in others

• EEG: 2-3 Hz generalized spike wave

• MRI normal

Myoclonic-astatic epilepsy & Rufinamide

• In a case series, rufinamide adjunctive therapy reduced seizure frequency by >75% in 6 of 7 cases

• Seizure reduction decreased for patients followed over longer time intervals of 6-18 months (von Stülpnagela et al. 2012)

Rufinamide SummaryPositive

• Most side effects are dose dependent & easily managed with dose reduction

• Infrequent need for serum drug levels

• Low protein binding

Negative

• Significant drug interactions are possible

• High cost

Role of Rufinamide

• Rufinamide has features similar to many of the approved drugs for Lennox-Gastaut (e.g. lamotrigine, topiramate).

• Future research might confirm the beneficial effect of rufinamide for treatment of myoclonic-astatic epilepsy.

Vigabatrin• Adjunctive treatment for infantile spasms and

adult refractory complex partial seizure

Vigabatrin Mechanism

• Irreversible & competitive binding to GABA transaminase (Chu-Shore et al., 2010)

Vigabatrin Mechanism

• Possibly also might stimulate GABA release

• Brain GABA increases by 40% at 2 hours post-dose

• (Chu-Shore et al., 2010)

Vigabatrin

• Linear dose relationship

• Reduces phenytoin level by 20%

• Dosage adjustment for decreased renal clearance

• (Chu-Shore et al., 2010)

Vigabatrin Dosing Complex Partial Seizures

• Adults: Initial: 500 mg twice daily; increase daily dose by 500 mg at weekly intervals based on response and tolerability. Recommended dose: 3 g/day

• Children: Oral: Initial: 40 mg/kg/day divided twice daily; maintenance dosages based on patient weight

Vigabatrin Dosing Infantile Spasm

• Initial dosing: 50 mg/kg/day divided twice daily; may titrate upwards by 25-50 mg/kg/day every 3 days to a maximum of 150 mg/kg/day

Vigabatrin Effectiveness Complex Partial Seizures

(Dean et al., 1999)

Vigabatrin Effectiveness Complex Partial Seizures

(French et al., 1996)

Vigabatrin Treats Infantile SpasmsTuberous Sclerosis Responds Best

Group % Spasm Free day 14Vigabatrin low dose 11%Vigabatrin high dose 36%• Tuberous sclerosis 52%• Cryptogenic 27%• Symptomatic 10%Low: 18-36 mg/kg-d; High: 100-148 mg/kg-d(Elterman et al., 2001)

Hormonal Therapy Better Early Response For Non-Tuberous

Sclerosis CasesPercent Spasm Free

Group 2 wks* 12-14 months

Hormonal 73% 75%

Vigabatrin 54% 76%

• Significant difference (Lux et al., 2005)

Tuberous sclerosis cases were excluded

Better Cognitive Outcome: Hormonal Treatment Cryptogenic Cases

Outcome at 12-14 months Following Treatment

Symptomatic Vineland Adaptive Behavior Scale

Hormonal 70.8

Vigabatrin 75.9

Cryptogenic* Vineland Adaptive Behavior Scale

Hormonal 88.2**

Vigabatrin 78.9**• Significant difference (Lux et al., 2005)

Tuberous sclerosis cases were excluded

Better Cognitive Outcome: Hormonal Treatment Cryptogenic Cases

Outcome at 4 years Following Treatment

Symptomatic Vineland Adaptive Behavior Scale

Hormonal 45

Vigabatrin 50

Cryptogenic* Vineland Adaptive Behavior Scale

Hormonal 96

Vigabatrin 63

* Significant difference (Darke et al., 2005)

Tuberous sclerosis cases were excluded

Vigabatrin Effectively Treats Tuberous Sclerosis

Practice Parameter: Medical Treatment of Infantile Spasms:

“Overall cessation of spasms was seen in 41 of 45 (91%) of children treated with vigabatrin, with a 100% response rate seen in five studies.”

(Mackay et al. 2004)

Vigabatrin Visual Adverse Effects

• Bilateral irreversible concentric peripheral field defects occur in 30-50% of cases

• Most with defects were treated for at least 6 months; often stable after 2 years

• Defects often asymptomatic but might impair driving (Chu-Shore et al., 2010)

Vigabatrin Visual Adverse Effects

• Adults: visual testing done at baseline & each 6 months

• Infants: visual testing done at baseline & test each 3 months for 18 months, then each 6 months (sedate for electroretinogram)

(Chu-Shore et al., 2010)

Vigabatrin Visual Effects• Common approach is treatment for a

duration under 3 months; consider discontinuation after 6 months, if seizures are effectively controlled (Kossoff EH, 2010).

• An experimental animal study found that taurine prevented the visual adverse effect (Firas et al, 2009)

Vigabatrin White Matter Changes

• Lesions were asymptomatic & reversible

• Age: 9 months - 18 years (median 5.4 yrs)

• 8 of 23 (34%) subjects were affected

• T2/DWI scans show lesions in basal ganglia, thalamus, brainstem, & dentate nucleus (Pearl et al., 2009)

Vigabatrin White Matter Changes

Feature With Lesions Without Lesions

Number 8 subjects 15 subjects

Age 11 months 5 years

Duration 3 months 12 months

Dose 170 mg/kg-d 87 mg/kg-d

(Pearl et al., 2009)

Vigabatrin White Matter Changes

Vigabatrin Summary

Positive• High effectiveness for infantile spasms• Few significant drug interactions; exception is

phenytoin• Infrequent need for serum drug levels• Low protein bindingNegative• Irreversible visual field defects• White matter lesions • High cost

Role of Vigabatrin

• Vigabatrin is likely to be among the last choices for adjuvant treatment of partial seizures

• Vigabatrin is a good 1st choice for infantile spasms from tuberous sclerosis (TS)

• Hormonal therapy might provide more effective early control for non-TS cases & better cognitive outcome for cryptogenic infantile spasms

ClobazamAdjunctive treatment of seizures associated

with Lennox-Gastaut syndrome

Clobazam Mechanism• Allosteric activation of GABAa receptor

Clobazam Mechanism• Allosteric activation of GABAa receptor

• Up-regulation GABA transporters 1 to 3 (GAT1 to GAT3)

• Clobazam has decreased affinity for GABAa subunits that mediate sedative effects

Clobazam Dosing• ≤30 kg: Initial: 5 mg once daily for ≥1

week, then increase to 5 mg twice daily for ≥1 week, then increase to 10 mg twice daily thereafter

• >30 kg: Initial: 5 mg twice daily for ≥1 week, then increase to 10 mg twice daily for ≥1 week, then increase to 20 mg twice daily thereafter

Clobazam DosingCYP2C19 poor metabolizers:

• ≤30 kg: Initial: 5 mg once daily for ≥2 weeks, then increase to 5 mg twice daily; after ≥1 week may increase to 10 mg twice daily

• >30 kg: Initial: 5 mg once daily for ≥1 week, then increase to 5 mg twice daily for ≥1 week, then increase to 10 mg twice daily; after ≥1 week may increase to 20 mg twice daily

Clobazam Metabolism• Hepatic via CYP3A4 and to a lesser extent via

CYP2C19 and 2B6

• N-demethylation to active metabolite [N-desmethyl] with ~20% activity of clobazam.

• CYP2C19 primarily mediates subsequent hydroxylation of the N-desmethyl metabolite.

• Carbamazepine reduces clobazam level, & clobazam decreases valproate (Riss et al, 2008)

• Many other potential drug interactions

Clobazam• Placebo controlled trial in 238 cases

(age 2-60 years) with Lennox-Gastaut syndrome (Ng YT et al, 2011)

• Treatment groups: placebo, 0.25 mg/kg-d, 0.5 mg/kg-d, 1.0 mg/kg-d.

• Weekly seizure rate reduction showed a dose response effect

• Side effects: somnolence, pyrexia, respiratory infections, lethargy, behavioral problems.

Clobazam Treatment Response

Group Drop Attack Reduction

Placebo 12.1%

0.25 mg/kg-d (max 10 mg/d) 41.2%

0.5 mg/kg-d (max 20 mg/d)49.4%

1.0 mg/kg-d (max 40 mg/d)68.3%

(Ng YT et al, 2011)

Clobazam Side Effects

• Somnolence

• Fever

• Lethargy

• Drooling

• Constipation

Clobazam Other Studies• Retrospective studies involving refractory

partial seizures reported an early improvement in seizure reduction.

• Many could not tolerate the drug due to somnolence.

• Tolerance occurred; seizures re-occurred in subjects that had improved initially (Shimizu et al., 2003, da Silveira et al., 2006)

Clobazam SummaryPositive

• High level of effectiveness for a difficult to treat seizure disorder

• Common side effects are dose dependent & easily managed with dose reduction

• Parent compound & metabolite have long half life

Clobazam SummaryNegative

• High cost

• High protein binding

• Active metabolite & potentially significant drug interactions

Role of Clobazam• Clobazam is likely to be a useful drug for

adjuvant therapy of Lennox Gastaut

• Limiting factors are likely to be cost and occurrence of drug related side effects

• Research might confirm the benefit of this drug for refractory partial seizures.

Ezogabine (Retigabine)Adjuvant treatment of partial-onset seizures

Ezogabine

• Binds to KCNQ2/3 KCNQ3/5 potassium channels

Ezogabine• Ezogabine binds to KCNQ2/3 & KCNQ3/5

potassium channels at a hydrophobic pocket near channel gate

• This binding stabilizes the open KCNQ2/3 & KCNQ3/5 potassium channels

• This causes membrane hyperpolarization (Gunthorpe et al. 2012)

Ezogabine• At high concentrations: blocks sodium

voltage gated sodium & calcium channels and increases GABA synthesis (Czuczwar et al., 2010)

Autosomal Dominant Neonatal Epilepsy

• Loss of function mutation KCNQ2/3

• Focal or generalized tonic-clonic seizures on day 3; seizures remit by 1 month

• 10-15% develop epilepsy

• Therapy resistant epileptic encephalopathy might occur (Kurahashi et al., 2009)

Ezogabine Dosing

• Initial: 100 mg 3 times/day; may increase at weekly intervals in increments of ≤150 mg/day to a maintenance dose of 200-400 mg 3 times/day (maximum: 1200 mg/day)

Ezogabine Metabolism

• No P450 metabolism• Glucuronidation via UGT1A4, UGT1A1,

UGT1A3, and UGT1A9• Acetylation via NAT2 to an N-acetyl active

metabolite (NAMR) and other inactive metabolites (eg, N-glucuronides, N-glucoside)

• Linear drug kinetics (Weisenberg et al,, 2011)

Ezogabine Drug Interactions

• No effect on oral contraceptive clearance

• Lamotrigine decreases ezogabine clearance slightly; ezogabine increases lamotrigine clearance slightly

Ezogabine EffectivenessGroup Seizure Reduction

Placebo 13.1%

600 mg/d 23.4%

900 mg/d 29.3%

1200 mg/d 35.2%

(Porter et al., 2007)

Ezogabine EffectivenessGroup Seizure Reduction

Placebo 15.9%

600 mg/d 27.9%

900 mg/d 39.9%

(Brodie et al., 2010)

Ezogabine EffectivenessGroup Seizure Reduction

Placebo 17.5%

1200 mg/d 44.3%

(French et al., 2011)

Ezogabine Side Effectts

• Somnolence• Fatigue• Confusion• Dizziness• Headache• Dysarthria• Ataxia• Blurred vision

Ezogabine SummaryPositive

• Minimal drug interactions

• Common side effects are dose dependent & easily managed with dose reduction

• Infrequent need for serum drug levels

• Unique drug mechanism

Negative

• High cost

Ezogabine

Role of Ezogabine

• Ezogabine is likely to be a useful drug for adjuvant therapy for refractory partial seizures

• Limiting factors are likely to be cost and occurrence of drug related side effects

Cumulative SummaryLacosamide, & ezogabine are likely to be

considered early choices for adjuvant drug therapy of partial seizure because:

• Minimal drug interactions

• Novel mechanisms of action

• Relatively safe side effect profile.

Cumulative SummaryVigabatrin has a specialized role:• First choice therapy for infantile spasms

among those with tuberous sclerosis• Adjuvant therapy in otherwise refractory

infantile spasm cases.• ACTH may be a better choice in select

infantile cases. • Vigabatrin is likely to be among the later

choices for refractory partial seizures due to its risk of visual loss.

Cumulative SummaryRufinamide and clobazam have a

specialized role as adjuvant therapy for Lennox-Gastaut.

• Drug interactions are more complex with these medications.

• Side effects might limit the use of these medications in some cases

Pharmacokinetic PropertiesDrug Tmax T1/2 %PB

Lacosamide 1-2 hr 13 hr <19%

Rufinamide 4-6 hr 6-10 hr 34%

Vigabatrin 2 hr 5-8 hr 0%

Clobazam 1-2 hr 10-30 hr 82-90%

Clobazam ** --- 36-46 hr ---

Ezogabine 1-2 hr 8-10 hr <80%

** desmethylclobazam active metabolite

(Chu et al, 2010)

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