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 intramembrane 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 inactivation
Intra-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 Reduction

Group Ben-Menachem Placebo 10% 200 mg/d 26% 400 mg/d 39% 600 mg/d 40% Halasz 20.5% 35.3% 36.4% ---

(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 (Hfler 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 Summary
Positive 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 Placebo 45 mg/kg-d All Seizures 11.7% 32.7% Tonic-atonic -1.4% 42.5%

(Glauser et al., 2007)

Rufinamide Partial Seizures Median Seizure Reduction

Group Placebo Rufinamide* Seizure Reduction -1.6% 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 Stlpnagela et al. 2012)

Rufinamide Summary
Positive 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 Spasms Tuberous Sclerosis Responds Best

Group % Spasm Free day 14 Vigabatrin 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 Cases

Group Hormonal Vigabatrin Percent Spasm Free 2 wks* 12-14 months 73% 75% 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 Number Age Duration Dose With Lesions 8 subjects 11 months 3 months 170 mg/kg-d Without Lesions 15 subjects 5 years 12 months 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 binding Negative 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

Clobazam
Adjunctive 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 Dosing
CYP2C19 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 [Ndesmethyl] 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 Summary
Positive 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 Summary
Negative 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, Nglucoside) 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 Effectiveness
Group 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 Effectiveness
Group Seizure Reduction Placebo 15.9% 600 mg/d 27.9% 900 mg/d 39.9% (Brodie et al., 2010)

Ezogabine Effectiveness
Group 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 Summary
Positive Minimal drug interactions Common side effects are dose dependent & easily managed with dose reduction Ezogabine Infrequent need for serum drug levels Unique drug mechanism Negative High cost

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 Summary
Lacosamide, & 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 Summary
Vigabatrin 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 Summary
Rufinamide 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 Properties
Drug 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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References
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