Transcript Use of the New Antiepileptic Agents

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
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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
(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 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%
(Glauser et al., 2007)
Tonic-atonic
-1.4%
42.5%
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)
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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 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
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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
(Pearl et al., 2009)
Without Lesions
15 subjects
5 years
12 months
87 mg/kg-d
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
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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
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Somnolence
Fatigue
Confusion
Dizziness
Headache
Dysarthria
Ataxia
Blurred vision
Ezogabine Summary
Positive
• Minimal drug interactions
• Common side effects are dose dependent
& easily managedEzogabine
with dose reduction
• 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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