Compounds which are second or third generation derivatives of AEDs

introduced before 1970

O
NH CH 3CH2CH 2
N
O CHCOOH
C
O NH 2 NH CH 3CH2 CH 2
O

1 Generation Carbamazepinee
st Valproic Acid
AED Phenobarbital Depakote TM
Tegretol TM
O
O CH 2 OCH 3
CH 3CH2CH2
N
N O CHCONHCH2CONH 2
2nd Generation O
C
NH 2
N
CH3CH2CH2

AED
O CH 2 OCH 3

Oxcarbazepine Valrocemide CH CH
T2000 3 2

(SPD–493) CH CH CH* CHCONH

3 2
2

CH3
H3 C
O
O

3rd Generation * Valnoctamide

AED N
C
O NH 2

Eslicarbazepine Acetate Perucca et al, Lancet Neurol, 2007

(BIA 2-093)
 Eslicarbazepine acetate

• CHEMICAL STRUCTURE

• PHARMACOKINETICS

• PHARMAKODYNAMICS

• CLINICAL TRIALS

• DOSAGE AND ADMINSTRATION

 Eslicarbazepine acetate
chemical structure

Vol. 4, 88–96, January 2007 c The American Society for Experimental

NeuroTherapeutics, Inc
 Eslicarbazepine acetate
ESL was developed with the expectation that S-
licarbazepine would be

• More effective than R-licarbazepine.

• Better tolerated than R-licarbazepine.

• Cross the blood brain barrier more efficiently

than R-licarbazepine.
Firing Sequence of Voltage-gated Sodium Channels
(VGSC)
Resting/normal
(channel recovering)

Inactive Active
(channel closed) (channel open)

• ESL, CBZ and OXC competitively inhibit the VGSC by binding with
the receptor in its inactive state, prolonging the period between
successive firings.

1.Bonifacio MJ, et al. Epilepsia 2001;42(5):600-608

 Eslicarbazepine acetate
Mechanism of action
ESL stabilizes the inactive form of the sodium
channel, preventing its return to the active state, and
sustains repetitive neuronal firing.
ESL has a much higher affinity for the inactivated
state of the channel compared with the resting state.
The affinity of ESL for resting channels is about
threefold lower than that of CBZ.
This profile suggests that ESL has an enhanced
inhibitory selectivity for rapidly firing neurons over
those displaying normal activity.
Firing Sequence of Voltage-gated Sodium Channels
(VGSC)
 Pharmacokinetics
• Bioavailability complete
• Peak plasma conc. 1-4 h
• Plasma protein binding <40%
• Half life 13-20h
• Serum conc. 5-9 mcg/ml
• Therapeutic range not established
• Plasma clearance 20-30 ml/min
• Elimination renal excretion
 Pharmacokinetics
• The pharmacokinetics of eslicarbazepine
is linear and dose-proportional in the dose
range of 400 mg to 1600 mg once daily,
both in healthy subjects and patients. The
apparent half-life of eslicarbazepine in
plasma was 13 -20 hours in epilepsy
patients. Steady-state plasma
concentrations are attained after 4 to 5
days of once daily dosing.
 Pharmacokinetics
• ESL acetate is a pro-drug, it undergoes
hydrolysis into S-licarbazepine the
biologically active drug.
• Its bioavailability is 16% higher than
equivalent dose of OXC.
• Steady state plasma levels are attained
after 4-5 days.
• ESL displays linear kinetics.
Undesirable effects
• Hyponatremia is 0.6-1.3%, incidence
increases if used with CB2, or those with
pre-existing renal-damage.
• Skin rash in 3% of cases, less than that
reported with both CB2 and OXC (SANAD
trial).
• Mild prolongation of P-R interval.
 Safety

• No specific concerns with respect to

safety of ESL.
• Psychiatric events are rare; skin rash 1%;
No changes of concern regarding lab.
parameters; no clinically relevant
differences in vital signs, body weight or
 Absorption
• Peak plasma concentrations (Cmax) of
eslicarbazepine are attained at 1-4 hours
post-dose. Eslicarbazepine is highly
bioavailable, because the amount of
eslicarbazepine and glucuronide
metabolites recovered in urine
corresponded to more than 90% of an
eslicarbazepine dose. Food has no effect
on the pharmacokinetics of
eslicarbazepine after oral administration
 INDICATIONS AND USAGE
• indicated for the treatment of partial-onset seizures as
monotherapy or adjunctive therapy.

• General Dosing Recommendations

• The recommended initial dosage of eslicarbazepine is 400 mg once
daily. For some patients, treatment may be initiated at 800 mg once
daily if the need for seizure reduction outweighs an increased risk of
adverse reactions during initiation . Dosage should be increased in
weekly increments of 400 mg to 600 mg, based on clinical response
and tolerability, to a recommended maintenance dosage of 800 mg to
1600 mg once daily. For patients on eslicarbazepine monotherapy, the
800 mg once daily maintenance dose should generally be considered
in patients who are unable to tolerate a 1200 mg daily dose. For
patients on eslicarbazepine adjunctive therapy, the 1600 mg daily dose
should generally be considered in patients who did not achieve a
satisfactory response with a 1200 mg daily dose.
 CONTRAINDICATIONS

is contraindicated in patients with a hypersensitivity to

eslicarbazepine acetate or oxcarbazepine

Drug-drug interactions
• Carbamezapine
– Need dose adjustment to Carb. “40%”
• Phenytoin
• Phenobarbitol
– May need higher doses of Eslicarbazepine
Drug-drug interactions

• No significant effect on the

pharmacokinetic of metformin,
digoxin or warfarin.
 Oral Contraceptives
• Because concomitant use of
Eslicarbazepine and ethinylestradiol and
levonorgestrel is associated with lower
plasma levels of these hormones, females
of reproductive potential should use
additional or alternative non-hormonal
birth control.
 USE IN SPECIFIC POPULATIONS
Pregnancy Category C
There are no adequate and well-controlled studies in
pregnant women. Eslicarbazepine should be used
during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Nursing Mothers
Eslicarbazepine is excreted in human milk.
Pediatric Use
Safety and effectiveness in patients below 18 years of
age have not been established.
Thaks