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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