What’s New In Antiepileptic Drugs
May 22, 2015
What’s New In Antiepileptic Drugs
C-Slide 2
ILAE Classification of Seizures
Seizures
Partial Generalized
Simple Partial
Complex Partial
Secondarily Generalized
Absence
Myoclonic
Atonic
Tonic
Tonic-Clonic
C-Slide 3
Complex Partial Seizures
Impaired consciousness
Clinical manifestations vary with site of origin and degree of spread
– Presence and nature of aura
– Automatisms
– Other motor activity
Duration typically < 2 minutes
Seizures
Partial Generalized
Complex Partial
Generalized
Partial
AED Choice by Seizure Type
Tonic-clonic
PHT, CBZ, PB, GBP, TGB, LVT,
OCBZACTHTPM?TGB?VGB?
Tonic Myoclonic AtonicInfantileSpasms
Absence
ESX
VPA, LTG, TPM, (FBM)ZNS
SimpleComplex
Secondarygeneralized
1st Generation AEDs
• Vast Clinical Experience
• Incomplete Efficacy• Unfavorable Kinetics (M-M, protein binding)• Narrow Therapeutic Range
– Small window between efficacy & toxicity
• Adverse CNS Effects• Adverse Non-CNS Effects• Drug-Interactions
P-Slide 6
Idiosyncratic Adverse Effects of AEDs
Hematologic damageHematologic damage – Marrow aplasia, agranulocytosis
– Early symptoms: abnormal bleeding, acute onset of fever,
symptoms of anemia
– Laboratory monitoring probably not helpful in early detection
– Felbamate aplastic anemia approx. 1:5,000 treated patients
– Patient education
P-Slide 7
Long-Term Adverse Effects of AEDs
Endocrine/Metabolic EffectsEndocrine/Metabolic Effects Osteomalacia, osteoporosis
Carbamazepine Phenobarbital Phenytoin Oxcarbazepine Valproate
Folate (anemia, teratogenesis) Phenobarbital Phenytoin Carbamazepine Valproate
Altered connective tissue metabolism or growth (facial coarsening, hirsutism, gingival hyperplasia or contractures)
Phenytoin Phenobarbital
NeurologicNeurologic Neuropathy
Cerebellar syndrome - phenytoin
Sexual Dysfunction - 30-Sexual Dysfunction - 30-60%60% Phenytoin Carbamazepine Phenobarbital Primidone
Stevens-Johnson Syndrome
P-Slide 9
Gingival Hyperplasia Induced by Phenytoin
New Eng J Med. 2000:342:325.
P-Slide 10
After Withdrawal of Phenytoin
New Eng J Med. 2000:342:325.
P-Slide 11
Trabecular Bone
http://www.merck.com
P-Slide 12
AED Hypersensitivity Syndrome
Characterized by rash, systemic involvement
Arene oxide intermediates - aromatic ring
Lack of epoxide hydrolase
Cross-reactivity– Phenytoin
– Carbamazepine
– Phenobarbital
– Oxcarbazepine
Influence on Hepatic Metabolism
• 1st Generation antiepileptic drugs– Inducers
• Phenobarbital
• Phenytoin
• Carbamazepine
– Inhibitor• Valproate
• Therefore, affect the kinetics and dynamics of non-CNS drugs as well…
DO WE NEED MORE NEW ANTIEPILEPTIC DRUGS?
• Problem with conventional AEDs:
– Seizure control
• Newly diagnosed well treated
• Still 40% with therapy resistance
• New AEDs over last 20 years are slowly
changing this equation!
The Ideal AED Therapy:
• Improved efficacy no seizures• Few side effects no new problems in
patient’s daily life• Easy dosing scheduling no chance for
dosing mistakes• Minimal drug interactions no need to
adjust other medicines• Expense not prohibitive cost will not
prevent taking the AED• Maximizing quality of life
New Versus Standard AEDs
• Equal efficacy
• Differentiated by– Adverse events– Drug interactions– Pharmacokinetics profiles
How do we make progress?
• Revolutionary Drugs– Drugs that work with new mechanisms never tried
before– Expectation: They will control seizures that
existing drugs can’t control
• Evolutionary Drugs– Improve on existing drugs– Expectation: We can eliminate some of the
problems/side effects of good drugs, without reducing their effect on seizures
ANTIEPILEPTIC DRUG DEVELOPMENT
1840 1860 1880 1900 1920 1940 1960 1980 20000
5
10
15
20
BromidePhenobarbital
Phenytoin Primidone
Ethosuximide
Sodium Valproate
Benzodiazepines
Carbamazepine
Zonisamide
Felbamate
Gabapentin
Topiramate Fosphenytoin
OxcarbazepineTiagabine
Levetiracetam
RufinamideLacosamideBrivaracetam
Pregabalin
Retigabine
?
Calendar Year
Nu
mb
er o
f L
icen
sed
An
tiep
ilep
tic
Dru
gs
Lamotrigine
SINCE 1998
20000
5
10
20
Zonisamide
Felbamate
Gabapentin
Topiramate Fosphenytoin
OxcarbazepineTiagabineLevetiracetam
Pregabalin
Calendar Year
Nu
mb
er o
f L
icen
sed
An
tiep
ilep
tic
Dru
gs
Lamotrigine
1990
Generalized
Partial
AED Choice by Seizure Type
Tonic-clonic
PHT, CBZ, PB, GBP, TGB, LVT,
OCBZACTHTPM?TGB?VGB?
Tonic Myoclonic AtonicInfantileSpasms
Absence
ESX
VPA, LTG, TPM, (FBM)ZNS
SimpleComplex
Secondarygeneralized
Gabapentin
• Mechanism– designed, yet unknown
• Dose (900 to 4800 mg/day [TID to QID])• Side Effects
– fatigue, dizziness, ataxia
• Drug Interactions– None with AEDs [only Antacids]
• Renal Elimination - CrCl• Clinical Pearl
– non-Epilepsy uses
Lamotrigine
• Mechanism– Na+ Channels, Glutamate
• Dose (100 to 500 mg/day [QD or BID])• Side Effects
– Sedation, Diplopia, Ataxia, Nausea - Rash
• Drug Interactions• “one way street”• Contraceptives
• Clinical Pearl• Slow taper - (esp. VPA)• Incidence of severe rash may by overestimated• Pediatric approval
Topiramate
• Mechanisms - many– Na+ Channels, Glutamate, GABA, CAI
• Dose (200 to 400 mg/day [BID - QDrenal])• Side Effects
• Sedation, Difficulty Concentrating, Kidney Stones, Glaucoma
• Drug Interactions– “one way street”
• Clinical Pearl– ceiling dose, fluids, visual changes, use outside of
epilepsy
Tiagabine
• Mechanism– Blocks re-uptake of pre-synaptic GABA
• Dose (32 to 56 mg/day [BID to QID])• Side Effects
– Fatigue, Dizziness, Weakness
• Drug Interactions– “one-way street”
• Clinical Pearl• different mechanism of action• take with food to decrease side effects (same AUC)
Oxcarbazepine • Mechanism - Na+ Channels• Dose
• Adjunctive (600 to 1,200 mg/day [BID])• Mono (up to 2,400 mg/day)
• Side Effects• Dizziness, Somnolence, Diplopia, N/V, Ataxia
• Drug Interactions• Inhibit/Induce - OCs, PHT
• Clinical Pearl• Prodrug (OCBZ to MHD)
Levetiracetam
• Mechanism– SV 2 inhibitor
• Dose: (1,000 to 3,000 mg/day [BID])• Side Effects
– Somnolence, Asthenia, Infection, Dizziness
• Drug Interactions– PK
• None with AEDs, probenecid - metabolite
– PD ?
• Clinical Pearl– Adjust dose for renal function
Zonisamide
• Mechanism– Na+ and T-calcium channels, CAI
• Dose: 100 to 600 mg/day (BID or QD)• Side Effects:
– somnolence, dizziness, nausea, headache, agitation/irritation, kidney stones, weight loss
• Drug Interactions• No effect on others
• Clinical Pearl• Appr. Japan & Korea ‘89, Sulfonamide• Use outside of epilepsy
What’s really new
• Two new drugs – Revolutionary
• lacosamide• rufinamide
• Four drugs in late trials– Evolutionary
• brivaracetam• Eslicarbazepine
– Revolutionary:• Carisbamate• Retigabine
Lacosamide
• Works on sodium channels, like Carbamazepine and Phenytoin
• However, It selectively enhances slow inactivation of sodium channels, whereas the older drugs work on fast inactivation
• Approved in Europe and USA
Double-Blind Placebo-Controlled Add-on Trial of Lacosamide (LCS) in Refractory Partial Epilepsy: 50% Responder Rates (n=418)
Double-Blind Placebo-Controlled Add-on Trial of Lacosamide (LCS) in Refractory Partial Epilepsy: 50% Responder Rates (n=418)
22%
41%*38%*
% P
atie
nts
33%
Placebo LCS 200mg LCS 400mg LCS 600mg
(* P<0.05 vs PL)
Ben-Menachem, E et al Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures Epilepsia. 2007
RUFINAMIDE
• Also works on sodium channels with new mechanism
• Approved in Europe for treatment of a severe form of epilepsy (Lennox-Gastaut syndrome)– “Orphan drug”
• In Front of FDA for Lennox-Gastaut and Partial seizures
Rufinamide AEs With Incidence ≥3% vs Placebo: All Treated
Subjects With Epilepsy (Double-blind Only)
RufinamideN (%)
PlaceboN (%)
Subjects 1465 635
Subjects with an AE 1180 (80.5) 497 (78.3)
Somnolence 36 (17) 16 (8.1)
Vomiting 35 (16.5) 14 (7.1)
Headache 34 (16.0) 16 (8.1)
Nausea 16 (7.5) 7 (3.6)
Ataxia 10 (4.7) 1 (0.5)
Diplopia 10 (4.7) 1 (0.5
BRIVARACETAM
• Similar mechanism to Levetiracetam but much stronger in animal models
• Also has sodium channel blocking activity
• FDA trials underway
Efficacy of Brivaracetam (5, 20 and 50 mg/day) Add-on Treatment in Refractory
Partial-Onset Epilepsy SEIZURE-FREEDOM RATESRESPONDER RATES
ITT population: n=208; 110M, 98F; age range 16–65 yITT population: n=208; 110M, 98F; age range 16–65 y
PBO(n=54)
BRV5(n=50)
BRV20(n=52)
BRV50(n=52)
0
10
20
30
40
50
60
16.7%
p = 0.04732.0%
p = 0.00244.2%
p = 0.00155.8%
% R
esp
on
den
ts
PBO(n=54)
BRV5(n=50)
BRV20(n=52)
BRV50(n=52)
0
10
% P
atie
nts
1.9%1/54
8.0%4/50
7.7%4/52
7.7%4/52
Eslicarbazepine
• A “third generation” Carbamazepine• Improves on second generation
– Less effect on sodium– Smoother release may produce less side effects
• Hopefully will work equally as well• Ready to submit to FDA
Summary of 2nd Generation AEDs• Safer
• More expensive
• May help with intractable partial seizures
• Less drug interactions
• Not profoundly more potent
Seizure type or epilepsy syndrome
Class I Studies
Class II Studies
Class III Studies
Level of efficacy and effectiveness evidence (in alphabetic order)
Adults with partial-onsetseizures
2 1 30 Level A: CBZ, PHTLevel B: VPALevel C: GBP, LTG, OXC, PB, TPM, VGB
Children with partial-onsetSeizures
1 0 17 Level A: OXCLevel B: NoneLevel C: CBZ, PB, PHT, TPM, VPA
Elderly adults with partial-onset seizures
1 1 2 Level A: GBP, LTGLevel B: NoneLevel C: CBZ
Adults with generalizedonset tonic–clonic seizures
0 0 23 Level A: NoneLevel B: NoneLevel C: CBZ, LTG, OXC, PB, PHT, TPM, VPA
Children with generalizedonset tonic–clonic seizures
0 0 14 Level A: NoneLevel B: NoneLevel C: CBZ, PB, PHT, TPM, VPA
Children with absenceSeizures
0 0 6 Level A: NoneLevel B: NoneLevel C: ESM, LTG, VPA
BECTS 0 0 2 Level A: NoneLevel B: NoneLevel C: CBZ, VPA
JME 0 0 0 Levels A, B, C: None
ILAE Summary Guidelines
Reference: Epilepsia 2006:47; 1094-1120.
C-Slide 38
Summary of AAN evidence-based guidelines level A or B
recommendations
AEDNewly Diagnosed
Monotherapy
Partial/mixed
Newly Diagnosed Absence
Gabapentin Yes* No
Lamotrigine Yes* Yes*
Topiramate Yes No
Tiagabine No No
*Not FDA approved for this indication
Reference: Neurology 2004, 62:1252-1260.
C-Slide 39
Summary of AAN evidence-based guidelines level A or B
recommendations
AEDNewly Diagnosed
Monotherapy
Partial/mixed
Newly Diagnosed Absence
Oxcarbazepine Yes No
Levetiracetam No No
Zonisamide NoNo
*Not FDA approved for this indication
Reference: Neurology 2004, 62:1252-1260.
C-Slide 40
Summary of AAN evidence-based guidelines level A or B
recommendation
AEDPartial
adjunctive adult
Partial Monotherapy
Primary generalized
Symptomatic generalized
Pediatric partial
Gabapentin Yes No No No Yes
LamotrigineYes Yes
Yes*(only absence) Yes Yes
Levetiracetam Yes No No No No
* Not FDA approved for this indication
References: Neurology 2004, 62:1252-1260. | Neurology 2004, 62:1261-1273.
C-Slide 41
Summary of AAN evidence-based guidelines level A or B
recommendation
AEDPartial
adjunctive adult
Partial Monotherapy
Primary generalized
Symptomatic generalized
Pediatric partial
Oxcarbazepine
Yes Yes No No Yes
Tiagabine Yes No No No No
Topiramate Yes Yes* Yes Yes Yes
Zonisamide Yes No No No No
* Not FDA approved for this indication
References: Neurology 2004, 62:1252-1260. | Neurology 2004, 62:1261-1273.
C-Slide 42
Summary of ILAE guidelines on therapeutic drug levels
What we don’t know
What we know
LEVEL OF KNOWLEDGE AT TIME OF APPROVAL
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