Use of AEDs in 2011 and beyond:

optimizing clinical management

December 3, 2011

David M. Treiman, M.D.

Director, Epilepsy Center,
Newsome Chair in Epileptology,
Barrow Neurological Institute;
Professor of Bioengineering and Neuroscience,
Arizona State University;
Clinical Professor of Neurology,
University of Arizona College of Medicine;
Professor of Neurology,
Creighton University School of Medicine
American Epilepsy Society | Annual Meeting
 Learning Objectives
Strategies for optimal use of AEDs in the
treatment of epilepsy.
Some thoughts on how AED use will evolve in
the 21th century.

American Epilepsy Society | Annual Meeting

 Guiding principle

We obtain our data from

population statistics; we treat
individual patients.

Treiman
 AEDs are the mainstay
of epilepsy management.

(2011: 14 1st-line AEDs in US)

Shhhh, Zog! . . . Here
comes one now!
 Strategies for use of AEDs
be sure of the diagnosis, etiology, classification
& seizure type(s)
match AED to sz type & patient characteristics
monotherapy if possible; polytherapy if
necessary
push to maximum tolerated dose
change timing of dosing to reduce toxicity
use pharmacokinetic principles to fine tune dose
adjust for drug-drug interactions
dont give up
Treiman Neuropsychiat Dis Treat 6:297308, 2010.
 Diagnosis
When in doubt, check it out!
Does patient have epilepsy? Differentiate
epileptic seizures
syncope
psychogenic events (15 - 30 % of referrals to
epilepsy centers (Clin Neurol Neurosurg 111:1-9, 2009))
Identify the seizure type(s)
Choose AED by:
Efficacy for control of specific seizure type
Toxicity
side effects profile
modified by individual patient considerations
Treiman Neuropsychiat Dis Treat 6:297308, 2010.
 Effect of accurate Dx & Rx
25 pharmaco-resistant patients

25 patients referred for poor sz. control

11 M, 14F; 19 LRE, 6 PGE all followed for 1 year
Outcome:
17 (68%) > 50% reduction of sz frequency; 7 (28%) sz free;
6 (24%) no change; 2 (8%) worse.

SUCCESSFUL STRATEGIES:
All patients Responders
in sz dx. 14/25 (56%) 13/17 (76 %
of AED 19/25 (74%) 15/17 (88%)
of AED dose 6/25 (24%) 2/17 (12%)

Norton & Treiman, Epilepsia 28(5):582-3), 1987

 Seizure type and AED choice
All current AEDs except ethosuximide are
effective against partial onset seizures.
Individual studies may favor one drug, but
there is no consistent evidence for superiority
of one drug over another.
Five are broad spectrum, and effective against
both partial onset and primarily generalized
seizures:
valproate
lamotrigine
topiramate
zonisamide
levetiracetam
Wilby et al. Health Technol Assess. 9:1157, 2005.
 Importance of Accurate Dx.
Exacerbation of szs

Drug Seizure type(s) exacerbated

_____________________________________
CBZ, OXC absence, myoclonic
GPN, PGB myoclonic
LTG myoclonic
TIA, VGB absence

Panayiotopoulos Clinical Guide to Epileptic Syndromes & their Rx., 2nd ed., 2010
True, Mr. Bascomb, thats not listed as one of the side effects.
 Choice of AEDs
Individualize to patients
ADVERSE REACTIONS AED(s)
hirsuitism, gum hyperplasia PHT
alopecia, tremor VPA
weight gain VPA, GBP, PGB
weight loss TPM, FBM, ZNS
hyponatremia CBZ, OXC
teratogenicity VPA
cognitive impairment TPM

COMPLIANCE ISSUES
qd dosing possible PHT, PB,TPM, ZNS
extended rel. AEDs
Modified from Treiman Neuropsychiat Dis Treat 6:297308, 2010.
 Example: VPA & wt. gain
Heavier children at greater risk

Novak et al. (J Child Neurol 14:490-5, 1999)

55 Children 1.8-16.9 y.o.
Increase in weight Z-score and BMI significantly
correlated with initial weight Z-score and BMI.
Wirrell (Ped Neurol 28:236-9, 2003)
72 children 10-17 y.o.
Overweight or potentially overweight at onset predicted
overweight at end.
Higher BMI at initiation of VPA tended to have greater
increase in BMI at end.
 Monotherapy

Variable percent (10 50%) get better sz

control with polyRx; return to monoRx may
improve seizure control.
Easier to manage balance between efficacy
and toxicity.
No potential drug-drug interactions.
May be more cost effective.
Improved compliance and more convenient.
ARs in monoRx half as frequent as w/ polyRx

Treiman Neuropsychiat Dis Treat 6:297308, 2010.

 Adding a 2nd AED
Existing AED should be in mid-therapeutic range.
Add new AED using smallest pill (tablet or
capsule) appropriate to patient.
Start with one pill h.s.
Increase daily dose by one pill each week, spacing
as indicated.
Monitor ARs and sz control by phone during
titration.
Re-evaluate when low maintenance dose is reached
Adjust dose as indicated.
Slowly withdraw first AED.

Treiman Neuropsychiat Dis Treat 6:297308, 2010.

 Management philosophy
Why add 2nd AED before stopping 1st AED?

Risk of increased seizures >> risk of new

dose-related ARs.
Important principle in patient management:
Make only one change at a time, so you
know what the effect of that change is.

Treiman Neuropsychiat Dis Treat 6:297308, 2010.

 Start low
Go slow
Push the dose
 Reason to push dose:
Response is proportional to dose
(e.g. levetiracetam RCCT responder rate)

50% Reduction in Weekly Seizure Frequency

40
35
39.5
% of Patients

30
35.2
25
20 28.6
15
10
5 9.4
0
Placebo LEV LEV LEV
1000 mg/day 2000 mg/day 3000 mg/day

Pooled data of responding patients by

randomized dose. Data on file. UCB Pharma Inc.
 Push dose
Push the dose sufficiently to either
achieve seizure control or produce
dose-related side effects, using the
therapeutic range as a guide.

However, do not be inhibited by the

therapeutic range which is only a
statistical probability statement that
has been determined empirically.
 Therapeutic ranges of common AEDs
Drug Total concentration Usual adult dose
g/mL mg/day
carbamazepine 4-12 800-2400
ethosuximide 40-100 750-1000
gabapentin 4-16 1800-3600
lacosamide 200-400
lamotrigine 2-20 300-500
levetiracetam 20-60 1000-3000
oxcarbazepine 10-15 1200-3600
phenobarbital 15-45 180-240
phenytoin 8-25 300-400
pregabalin 150-600
tiagabine 5-70 16-64
topiramate 2-25 200-600
valproate 50-150 1000-3000
zonisamide 10-40 100-400
Modified from Treiman, 1995
I owe my reputation to the fact
that I use digitalis in doses the
text books say are dangerous
and in cases the text books
say are unsuitable.

- Karel Frederick Wenckebach

(1844 - 1940)
 Caveats
1. Drugs that can be rapidly titrated to therapeutic
dose (e.g., GPN, LEV) generally are better than
drugs that require 6-12 weeks to achieve therapeutic
dose (e.g., LTG).
2. The best dose is the lowest one that achieves
complete seizure control without ARs but allow
margin of protection for lowering of seizure
threshold (lack of sleep, intercurrent infection, etc.)
3. In general, the largest dose should be at bedtime,
except if AED induces insomnia (e.g. LTG).
4. Allow patient to slow rate of AED titration if they
wish, but not increase rate of titration (esp. LTG).
 Change timing of AED
administration
Sometimes toxicity can be reduced or seizure
control improved simply by altering the timing
of AED dosing.
Tmax = Time to peak concentration after drug
administration
For most IR drugs, the Tmax is 60-90 minutes
If ARs occur 1-2 hours after oral administration,
divide administration into smaller, more frequent
doses.
Caveat: adults have a difficult time with compliance if
dosing > bid.
 Compliance rates and
AED dosage regimen
100
87
C 81
o 77
R 80
m
a
p
t 60
l
e
i 39
a 40
n
%
c 20
e
0
QD BID TID QID
Dosing Regimen
Cramer et al., JAMA 1989; 261:3273-3277
 Half-lives of common AEDs
1/2 day ~1-2 days 3-6 days
carbamazepine ethosuximide lamotrigine***
gabapentin felbamate phenobarbital
lacosamide lamotrigine**
lamotrigine* oxcarbazepine
levetiracetam (phenytoin)
primidone topiramate
rufinamide zonisamide
tiagabine
valproate
vigabatrin
*as polytherapy with enzyme-inducing AEDs
**as monotherapy
***as polytherapy with enzyme-inhibiting AEDs

Modified from Treiman, 1995

 Treatment administered by 12 physicians
to King Charles II after a violent
convulsion in 1685
Bled one pint from right arm, 1/2 pint from right shoulder
Emetic and two purgatives
Enema containing 13 ingredients
Sneezing powder to strengthen the brain
Soothing drinks of barley water, licorice and almond,
extract of mint, thistle leaves, rue and angelica
Plaster of burgundy pitch and pigeon dung to chest
As the king died, Raleighs antidote, pearl julep and
ammonia was forced down his throat
 Drug interactions

Pharmacokinetic Pharmacodynamic
Absorption Efficacy
Stability
Complexation
Dissolution
Physiology
Distribution Toxicity
Binding
Elimination
Metabolism
Excretion
 Effects on AED elimination
Antiepileptic Drugs
Microsomal P450 enzyme:
Inducers Inhibitors No effect
CBZ FBM GPN
PB VPA LCM
PHT ZNS (min.PHT) LTG
PRIM LEV
OXC (estrogens, DHPs) PGB
VGB TIA
ZNS (min.CBZ) TPM

Modified from Treiman, 1995

 Effects on AED elimination
Non-antiepileptic drugs

Microsomal P450 enzyme:

__Inducers___ _______Inhibitors________

alcohol allopurinol erythromycin

nicotine chloramphenicol isoniazid, PAS
oral contraceptives cimetidine phenylbutazone
other steroids coumarin propranolol
phenothiazines diltiazem, propoxyphene
rifampin other Ca blockers sulfonamides
disulfiman

Modified from Treiman, 1995

 Dont give up!
Many AEDs abandoned before they have been pushed to
maximum tolerated doses, because:
titration too fast and thus avoidable ARs occur
physician fearful of high doses/serum concentrations

14 classical or new AEDs approved for partial onset szs

and some primarily generalized szs (excluding niche
AEDs). Thus there are 91 pairs and 364 triplets possible.

Although probability of success decreases with number

of combinations that fail, in the patient with uncontrolled
seizures for whom surgical intervention is not a
consideration, keep trying.
 Future developments
in AED use
Identification of new AEDs
Development of true rational polypharmacy
Development of strategies for improving AED
efficacy in drug-resistant patients
Development of antiepileptogenic strategies
Personalized medicine: strategies to predict
Which patients will develop ARs (e.g. HLA typing to
predict Stevens-Johnson syndrome and toxic
epidermal necrolysis)
Which patients will respond to which AEDs.
 Impact on Clinical Care and Practice

To use AEDs in the most effective way possible:

Treat the patient as an individual, based on data
from population statistics.
Get the diagnosis right, pick the right drug.
Push the dose to full control but w/o ARs
Know your drugs well (PKs, interactions, ARs)
Keep trying there are many possible
combinations.