AEDs
Martin del Campo MD
UHN
Toronto, Ont.
Disclosures
• Speakers Bureau
• Ad-boards:
– UCB Canada
– Boehringer-Ingelheim
Outline
• Review the new AEDs including
Lacosamide
• Canadian experience with Lacosamide
• Example cases
Old vs New
The Bad News
470 patients who never received treatment before
222 controlled on the 1st AED
(47%)
151 received old drug
71 received a new drug
248 not controlled
168 received an old drug
80 received a new drug
18 responded to a 3rd or multiple drugs
(4%)
61 responded to a 2nd AED
(13%)
•At the last visit
 423 patients were on a single AED (68% seizurefree)
 53 patients took 2 AED’s (23% seizure-free)
 5 patients were on 3 AED’s (none were seizure-free)
Kwan, P. and Brodie, M. NEJM 2000; 342: 314-319
Lamotrigine (Lamictal)
•
•
•
•
•
•
Good “broad spectrum” AED
BID dosing (soon to be OD)
Useful as mood stabilizer
Metabolism inhibited by VPA
Insomnia
Skin rash - SJS
Lamotrigine (Lamictal)
• 5/564 incidence of oral clefts (3 palate,
2 lip) in North American registry
• 4/1623 had oral cleft in other registries
• Non-teratogenic in doses <200 mg/day
(2.6% mono, 10.8% with VPA)
Holmes LB et al. Birth Defects Research (Part
A); 2006; v76:5
Gabapentin (Neurontin)
•
•
•
•
•
•
•
Structural analog of GABA
Weak AED (30% responder rate)
Mode of action unknown
Excreted unchanged in urine
No drug interactions
Quick titration
Dizziness, fatigue
Topiramate (Topamax)
•
•
•
•
•
Various mechanisms of action
Minimally protein-bound
Plasma levels ‘d by PHT, CBZ and VPA
Partial renal excretion
Responder rate 30-50% in partial onset or
primarily generalized convulsive Sz’s
• Useful in Lennox-Gastaut and infantile
spasms
• Weight loss, renal stones, oligohydrosis,
hallucinations, cognitive impairment
• Rare acute narrow-angle glaucoma.
Vigabatrin (Sabril)
•
•
•
•
Another GABA look-alike
Designed as a GABA transaminase inhibitor
Excreted unchanged in urine
GABA levels elevated 120 hrs after single
dose
• Responder rates inferior to CBZ
• Decreases PHT and CBZ levels
• 20-30% incidence of visual field constriction
Clobazam (Frisium)
•
•
•
•
•
1,5 benzodiazepine
Active metabolite: desmethylclobazam
GABAa agonist
Efficacy in myoclonic and absence status
Usually used as adjunct for partial Sz’s with
or without generalization
• Tachyphylaxis
• Sometimes difficult to taper down
Oxcarbazepine (Trileptal)
•
•
•
•
•
CBZ analogue
Converted to MHD, active metabolite
Renal excretion
Traditional AED’s induce its metabolism
25% of pts with CBZ hypersensitivity will react
to OXC
• No reports of aplastic anemia
• hypoNa especially in older pts
Oxcarbazepine (Trileptal)
•
•
•
•
50-60% responder rate
12% Sz-free
Indicated as monotherapy
Not on ODB or LU
Levetiracetam (Keppra)
• Plasma half-life: 6 to 8 hours in adults
• Steady state: after 2 days of BID dosing
• Renal elimination
– 66% eliminated as unchanged drug
– Correlated with creatinine clearance
Levetiracetam (Keppra)
• No interaction with other AEDs included
in placebo-controlled clinical studies in
patients with epilepsy1
• No interaction with phenytoin2 and valproic
acid3 confirmed by clinical pharmacokinetic
studies
1. Keppra® Product Monograph
2. Browne TR et al. J Clin Pharmacol 2000;40:590-5.
3. Coupez R et al. Epilepsia 2003;44(2):171-8.
Responder Rate
% of patients with 50% reduction in
Sz frequency
45
*p<0.001 vs. placebo
*
40
% of Patients
35
30
25
42.1
20
15
10
5
16.7
0
Placebo
(n=105)
Ben-Menachem et al. Epilepsia 2000;41:1276-83.
LEV 3000 mg/day
(n=181)
AEDs: Molecular and
Cellular Mechanisms
 Phenytoin, Carbamazepine
– Block voltage-dependent sodium channels at high
firing frequencies
 Barbiturates
– Prolong GABA-mediated chloride channel
openings
– Some blockade of voltage-dependent sodium
channels
 Benzodiazepines
– Increase frequency of GABA-mediated chloride
channel openings
AEDs: Molecular and
Cellular Mechanisms
 Gabapentin
– Increases neuronal GABA concentration
– Enhances GABA mediated inhibition
 Lamotrigine
– Blocks voltage-dependent sodium channels at
high firing frequencies
– May interfere with pathologic glutamate
release
AEDs: Molecular and
Cellular Mechanisms
 Ethosuximide
– Blocks low threshold, “transient” (T-type) calcium
channels in thalamic neurons
 Valproate
– May enhance GABA transmission in specific
circuits
– Blocks voltage-dependent sodium channels
 Vigabatrin
– Irreversibly inhibits GABA-transaminase
AEDs: Molecular and
Cellular Mechanisms
 Topiramate
– Blocks voltage-dependent sodium channels at
high firing frequencies
– Increases frequency at which GABA opens Clchannels (different site than benzodiazepines)
– Antagonizes glutamate action at
AMPA/kainate receptor subtype
– Inhibition of carbonic anydrase
AEDs: Molecular and
Cellular Mechanisms
 Levetiracetam
– Binding of reversible saturable specific binding site
– Reduces high-voltage- activated Ca2+ currents
– Reverses inhibition of GABA and glycine gated
currents induced by negative allosteric modulators
 Oxcarbazepine
– Blocks voltage-dependent sodium channels at
high firing frequencies
– Exerts effect on K+ channels
Lacosamide:
Metabolism and Elimination
 About 95% of dose excreted in urine
 40% as unchanged lacosamide
 ~30% as O-desmethyl metabolite (no known pharmacological
activity)
 CYP2C19 enzyme responsible for O-desmethyl
metabolite
 No clinical difference in pharmacokinetics in poor vs. extensive
metabolizers for CYP2C19
 No clinical relevant changes in pharmacokinetics with
omeprazole (CYP2C19 inhibitor)
 t½: ~13 hours (steady-state achieved in 3 days)
 Low intra- and inter-subject variability
EU SmPC; Doty 2007
Pharmacokinetics of Lacosamide:
Special Patient Populations and Drug-Drug Interaction
• Mild and moderate renal impairment: No dose adjustment needed
– Maximum dose of 300mg/day recommended for patients with severe renal
impairment (CLCR ≤30 mL/min) or end-stage renal disease.
– Supplement of up to 50% of the divided daily dose directly after the end of
hemodialysis is recommended.
– In all patients with renal and/or hepatic impairment, dose titration should be
performed with caution.
• Low potential for drug-drug interactions
– No clinical relevant changes in the plasma concentrations of concomitant AED’s
(carbamazepine, valproic acid, phenytoin, gabapentin, lamotrigine, levetiracetam,
oxcarbazepine or zonisamide).
– No clinical relevant interaction with digoxin, metformin, omeprazole (CYP2C19
inhibitor), or ethinyl estradiol + levonorgestrel-containing oral contraceptives.
– Caution should be exercised when VIMPAT is given with other drugs that prolong the
PR interval (eg. carbamazepine, pregabalin, lamotrigine or beta-blockers), and in
patients treated with class I anti-arrhythmic drugs as further PR prolongation is
possible.
UCB data on file; Canadian Product Monograph.
Pivotal trials: Patient demographics and baseline
characteristics (ITT)
• 1294 patients received trial medication and had ≥1 post-baseline
efficacy assessment (ITT)
– Mean age: 38.6 years
– 51.1% female
– 91.7% Caucasian
– BMI: 26.8 kg/m2
– Time since diagnosis 23.7 years
– Lifetime use of AEDs
• 32.2% tried 4 to 6
• 45.2% tried 7 or more
– Number of concomitant AEDs
• 1 AED: 15.5%
• 2 AEDs: 62.4%
• 3 AEDs: 22.0%
AED=antiepileptic drug; BMI=body mass index
ITT= all patients with ≥1 post-baseline efficacy
assessment
24
UCB data on file
Pivotal trials: Seizure freedom during maintenance
(Pooled data)
Seizure-free rates for completers
14
14
12
12
Median change in percentage of seizurefree days during maintenance phase
10
8
6
4.8%
4
2
2.7%
3.3%
Median increase (%)
Seizure-free patients (%)
12.1%
9.3%
10
7.4%
8
6
5.4%
4
2
0.9%
0
0
PBO
n=326
200 mg
n=225
400 mg
n=366
Lacosamide
600 mg
n=124
PBO
n=337
200 mg
n=244
400 mg
n=393
Lacosamide
600 mg
n=142
Rosenfeld study: ≥50% responder rate
N=370
Patients responding (%)
70
65.5
60
60.7
57.7
55.4
50
48.3
40
47.4
44.2
30
20
10
0
n=370
>0−6
n=326
>6−12
n=284
n=248
>12−18
>18−24
Months
n=224
>24−30
n=206
>30
n=370
Treatment
period
Percentages were based on the number of patients in each modal dose group with an evaluable responder
status during the relative time interval. Responders were defined as patients who experienced ≥50%
reduction in seizure frequency during the time interval from baseline (where baseline was from the previous
trial). A month was defined as 28 days.
26
Pivotal Trials Pooled Results:
≥ 50% Responder Rate During Maintenance By Dose (ITT)
45%
Patients Responding (%)
40%
35%
*P <.05; ** P <.001 versus placebo
N = 1294
*
**
**
40%
40%
LCM 400 mg/day
LCM 600 mg/day §
34%
30%
25%
20%
23%
15%
10%
5%
0%
Placebo
n = 359
LCM 200 mg/day
n = 267
n = 466
n = 202
ITT = all randomized patients receiving ≥1 dose of trial medication with ≥1 post-baseline efficacy assessment,;
§ Lacosamide is approved up to a dose of 400 mg/day
Chung AES 2008
Pooled Pivotal Trials:
Most Common AEs During Titration and Maintenance*
Titration
Maintenance
Placebo
n = 364
%
Lacosamide
n = 944
%
Placebo
n = 337
%
Lacosamide
n = 781
%
Dizziness
7
25
2
8
Headache
6
9
5
6
Nausea
4
9
1
3
Diplopia
1
9
1
3
Vomiting
2
8
1
4
Fatigue
5
8
1
2
Coordination Abnormal
1
7
<1
3
Vision Blurred
2
7
1
2
Tremor
3
5
1
2
Nystagmus
3
4
1
1
Adverse Event,
MedDRA Preferred Term
* Safety population, N = 1308.
Lacosamide in Canada
Patient characteristics
Age (yrs)
19-63, avg. 32.5, med. 19.5
Gender
46 F, 38 M
Duration of
epilepsy (yrs)
1-46, avg. 19.5, med. 18.5
Sz’s/ mo. baseline
1-315, avg. 67.5, med. 25
Co-AEDs #
1:17, 2:34, 3:26, 4:7
Surgery
11 lobectomy/cortical resection, 2 CCS.
Devices
16 VNS, 2 DBS
Imaging
39 normal, 9 conformational disorders, 7 FCD,
7 encephalomalacia, 7 neoplasm/AVM. 5 MTS,
4 other
Lacosamide in Canada
LCM Total daily dose (mg)
300
35
Number of patients
30
25
400
20
15
10
200
5
0
100
50
75
150
450
250
350
500
600
Lacosamide in Canada
Responder rate (N=83)
18
14
10
7
21%
16%
12%
>30
8%
>50
>75
Sz-free
Lacosamide in Canada
Reasons for discontinuation
SE's (nausea,
dizziness,
discoordination,
blurred vision), 4
Psychiatric SE's
(paranoia, panic
attacks), 2
increased
seizures, 2
no improvement, 5
rash, 4
Lacosamide in Canada
Case 1
•22 y.o. woman with 6 month h/o episodes of
unresponsiveness, associated with lip smacking, lasting 2-3
min., occurring 2-4/month.
•Lives with boyfriend.
•No consistent contraception
•EEG shows left temporal spikes
•MRI shows left mesial temporal sclerosis
Mesial Temporal Sclerosis
Case 1
Issues
• Young female in childbearing age
• Compliance
• Cosmetic side effects
• Weight control
– Long-term side effects
– Birth control
– Risk to baby
Case 1
options
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•
•
•
•
Lamictal
Tegretol
Trileptal
Surgery
Nothing
Case 2
• 65 y.o. man with high blood pressure,
irregular heart beat, high cholesterol
and a recent stroke.
– Reports 3 episodes of head turning to the
left and involuntary jerking of the left arm
and face lasting 1 min.
– On several drugs for control of his various
conditions including warfarin
Case 2
issues
• Multiple drugs
– Compliance
– Side effects
– Interactions
– Organ failure
Case 2
options
•
•
•
•
Neurontin
Keppra
Lacosamide
Surgery?
Case 3
• Twenty-one y.o. man, obese, with a 6
year history of several Grand Mal
seizures per year. On Epival but does
not always take it (drowsy, hand tremor)
– Sister has seizures too
Case 3
issues
• Non-compliance
– Side effects
• Strong potential for social issues
– Depression
– Inability to buy drugs
Case 3
options
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•
•
•
•
•
Tegretol
Dilantin
Lamictal
Topamax
Keppra
Surgery?
Case 4
• 45 y.o lady, single, works as a town librarian
in St. Joseph’s Island, gives a history of
temporal lobe seizures since mid-teens. They
used to occur every week but as she got
older, they happen 3-4 times/ y.
• Has always been on Tegretol, 4 pills/day.
Higher doses make her see double and get
dizzy
Case 4
issues
• Social and geographic isolation
– Can’t drive
– Can’t find a job in the city
– Can’t access specialty care easily
• Has read about other drugs but local
GP says “this is as good as she’ll ever
be”
Case 4
options
•
•
•
•
•
•
•
Lacosamide
Tegretol CR
Trileptal
Lamictal
Keppra
Topamax
Surgery?
Summary
• Numerous pharmacological choices
• Newer AEDs have less potential for drugdrug interaction
• Choose AED according to patient profile
• If no success, consider surgery