U.S. patent application number 11/248125 was filed with the patent office on 2006-11-09 for methods of preparing pharmaceutical compositions comprising eslicarbazepine acetate and methods of use.
This patent application is currently assigned to Portela & C.A., S.A.. Invention is credited to Jose Luis de Almeida, Patricio Manuel Vieira Ara jo Soares Da Silva.
Application Number | 20060252746 11/248125 |
Document ID | / |
Family ID | 37394802 |
Filed Date | 2006-11-09 |
United States Patent
Application |
20060252746 |
Kind Code |
A1 |
Almeida; Jose Luis de ; et
al. |
November 9, 2006 |
Methods of preparing pharmaceutical compositions comprising
eslicarbazepine acetate and methods of use
Abstract
The present disclosure relates to the treatment of various
diseases and conditions with eslicarbazepine acetate. The present
disclosure also relates to the use of eslicarbazepine acetate in a
method for reducing or decreasing epileptic seizures in a patient.
The present disclosure also relates to a method for increasing the
exposure to eslicarbazepine in a patient. The present disclosure
also relates to a method of preparing a pharmaceutical composition
comprising eslicarbazepine acetate.
Inventors: |
Almeida; Jose Luis de;
(Arouca, PT) ; Ara jo Soares Da Silva; Patricio Manuel
Vieira; (Porto, PT) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER;LLP
901 NEW YORK AVENUE, NW
WASHINGTON
DC
20001-4413
US
|
Assignee: |
Portela & C.A., S.A.
|
Family ID: |
37394802 |
Appl. No.: |
11/248125 |
Filed: |
October 13, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11123205 |
May 6, 2005 |
|
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11248125 |
Oct 13, 2005 |
|
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Current U.S.
Class: |
514/217 |
Current CPC
Class: |
A61P 25/06 20180101;
A61K 45/06 20130101; A61P 25/08 20180101; A61P 25/18 20180101; A61P
25/00 20180101; A61K 31/19 20130101; A61K 31/55 20130101; A61K
31/19 20130101; A61K 2300/00 20130101; A61K 31/55 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/217 |
International
Class: |
A61K 31/55 20060101
A61K031/55 |
Claims
1-29. (canceled)
30. A method for the treatment of at least one affective disorder
or at least one bipolar disorder in a patient in need thereof,
comprising administering to the patient a pharmacologically
effective amount of eslicarbazepine acetate.
31. The method according to claim 30, comprising administering to
said patient an amount of eslicarbazepine acetate ranging between
about 400 mg and about 2400 mg approximately every 24 hours.
32. A method for the treatment of at least one manic symptom in a
patient in need thereof, comprising administering to the patient a
pharmacologically effective amount of eslicarbazepine acetate.
33. A method for the maintenance treatment of at least one
affective disorder or at least one bipolar disorder in a patient in
need thereof, comprising administering to the patient a
pharmacologically effective amount of eslicarbazepine acetate.
34. The method according to claim 33, comprising administering to
said patient an amount of eslicarbazepine acetate ranging between
about 400 mg and about 2400 mg approximately every 24 hours.
Description
BACKGROUND
[0001] The present disclosure relates to a pharmaceutical
composition and a treatment method using eslicarbazepine
acetate.
[0002] Epilepsy, pain conditions such as trigeminal neuralgia, and
affective brain disorders such as bipolar disorder are commonly
treated with carbamazepine. Treatment with carbamazepine, however,
can lead to serious side effects due to the production of toxic
metabolites. Oxcarbazepine was developed to reduce the severity of
those side effects, but oxcarbazepine has a greatly reduced
potency. See, e.g., Almeida, L. & Soares-da-Silva, P., "Safety,
Tolerability, and Pharmacokinetic Profile of BIA 2-093, a Novel
Putative Antiepileptic, in a Rising Multiple-Dose Study in Young
Healthy Humans,"J. Clin. Pharmacol., 44, 906-918 (2004) (herein
referred to as "Almeida I").
[0003] Thus, there is a need for a pharmaceutical composition and
method for treating various conditions or diseases such as, for
example, epilepsy, trigeminal neuralgia, and affective brain
disorders, that has a high potency and a low occurrence of side
effects.
SUMMARY
[0004] Eslicarbazepine acetate,
(S)-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide
("BIA 2-093"), is a new drug currently being developed which is
useful for the treatment of various conditions, such as, for
example, epilepsy and affective brain disorders, as well as pain
conditions and nervous function alterations in degenerative and
post-ischemic diseases. Although chemically related to
carbamazepine and oxcarbazepine, eslicarbazepine acetate is
believed to avoid the production of certain toxic metabolites (such
as, for example, epoxides) and to avoid the unnecessary production
of enantiomers or diastereoisomers of metabolites and conjugates,
without losing pharmacological activity. See Benes et al.,
"Anticonvulsant and Sodium Channel-Blocking Properties of Novel
10,11-Dihydro-5H-dibenz[b,f]azepine-5-carboxamide Derivatives," J.
Med. Chem., 42, 2582-2587 (1999).
[0005] Like carbamazepine and oxcarbazepine, eslicarbazepine
acetate is believed to be a voltage-gated sodium channel (VGSC)
blocker that competitively interacts with site 2 of the inactivated
state of the sodium channel. The affinity for this state of the
channel is similar to that of carbamazepine, while the affinity for
the resting state of the channel is about 3-fold lower than that of
carbamazepine. This profile may suggest an enhanced inhibitory
selectivity of eslicarbazepine acetate for rapidly firing neurons
over those displaying normal activity. See Bonifacio et al.,
"Interaction of the Novel Anticonvulsant, BIA 2-093, with
Voltage-Gated Sodium Channels: Comparison with Carbamazepine,"
Epilepsia, 42, 600-608 (2001).
[0006] Evaluation of the metabolic profile of eslicarbazepine
acetate, following chiral analysis, in liver microsomes from rats,
dogs, monkeys and humans was found to give the S(+) enantiomer of
licarbazepine, (S)-(+)-10,11-dihydro-10-hydroxy-5H
dibenz/b,f/azepine-5-carboxamide (also known as "eslicarbazepine"),
and not the R(-) form of licarbazepine,
(R)-(-)-10,11-dihydro-10-hydroxy-5H
dibenz/b,f/azepine-5-carboxamide (also known as
"R-licarbazepine").
[0007] Studies in humans have shown that, after oral
administration, eslicarbazepine acetate appears to be rapidly and
extensively metabolized to the active metabolite eslicarbazepine
and, in a minor extent, to R-licarbazepine. See Silveira et al.,
"BIA 2-093 Pharmacokinetics in Healthy Elderly Subjects,"
Epilepsia, 45 (suppl. 3), 157 (2004). For example, the plasma
concentrations of the parent drug (eslicarbazepine acetate) have
been systematically found below the limit of quantification (LOQ)
of the assay (10 ng/mL). See Almeida I; Almeida, L. &
Soares-da-Silva, P., "Safety, Tolerability and Pharmacokinetic
Profile of BIA 2-093, a Novel Putative Antiepileptic Agent, during
First Administration to Humans," Drugs R&D, 4, 269-284 (2003)
(herein referred to as "Almeida II"). When a non-chiral method is
used, the assay does not distinguish between eslicarbazepine and
the R-enantiomer, and the mixture was reported as "BIA 2-005" or
"racemic licarbazepine."
[0008] The inventors performed entry-into-man studies in healthy
subjects, the results of which they described in the Almeida I and
Almeida II articles, both of which are hereby incorporated by
reference. In these studies, the healthy subjects received a single
oral dose of eslicarbazepine acetate wherein the dose ranged from
20 mg to 1200 mg (see Almeida II), and multiple daily-doses of
eslicarbazepine acetate ranging from 200 mg twice-daily to 1200 mg
once-daily (see Almeida I). Further studies (not yet published) by
the inventors have investigated higher doses of eslicarbazepine
acetate, including, for example, doses ranging up to 2400 mg
once-daily. The studies showed that BIA 2-005 maximum observed
plasma concentration (C.sub.max) was attained at about 1 hour to
about 4 hours post-dose (t.sub.max), the extent of systemic
exposure to BIA 2-005 was approximately dose-proportional, and
steady-state of BIA 2-005 plasma concentrations was attained at
about 4 to 5 days. The mean renal clearance of BIA 2-005 from
plasma was about 20-30 mL/min, and the total amount of BIA 2-005
recovered in the urine was approximately 20% and 40% within 12
hours and 24 hours post-dose, respectively.
[0009] The studies also showed that the apparent terminal half-life
of BIA 2-005 ranged from about 8 hours to about 17 hours. See,
e.g., Almeida II.
[0010] U.S. Pat. No. 6,296,873 discloses a sustained release
delivery system for carbamazepine, which has a half-life ranging
from 25 hours to 85 hours. To avoid adverse effects, U.S. Pat. No.
6,296,873 teaches that the carbamazepine should be administered in
tablet form up to two or more times daily to slowly release the
compound to maintain concentration levels between 4-12 .mu.g/mL.
Such a delivery system requires a form that is capable of
delivering the compound over an extended period of time, such as a
tablet form.
[0011] In one aspect of the present disclosure, the inventors have
unexpectedly discovered an enhanced efficacy of eslicarbazepine
acetate in the treatment of various conditions, such as, for
example, the treatment of epilepsy, using once-daily administration
compared to twice-daily administration. This discovery is
particularly surprising because the apparent half-life of
eslicarbazepine acetate (t.sub.1/2=about 8 hours to about 17 hours)
is significantly shorter than the half-life of carbamazepine
(t.sub.1/2=25 hours to 85 hours), a compound typically administered
3-4 times daily.
[0012] In another aspect of the present disclosure, the inventors
have also unexpectedly discovered an enhanced exposure to
eslicarbazepine after once-daily administration of eslicarbazepine
acetate versus the twice-daily regimen in humans. Once-daily
administration of eslicarbazepine acetate surprisingly provides an
increase of exposure to eslicarbazepine than the same drug dosage
divided into twice-daily doses.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1: Percentage reduction in seizure number in each dose
period versus baseline (400 mg once-daily versus twice-daily and
placebo; 800 mg once-daily versus twice-daily and placebo; 1200 mg
once-daily versus twice-daily and placebo).
[0014] FIG. 2: Mean (95% Cl) trough plasma concentrations
(.mu.g/mL) of BIA 2-005 following a daily dose of 400 mg, 800 mg
and 1200 mg of BIA-2-093 administered once-daily (o.d.) or
twice-daily (b.i.d.).
DETAILED DESCRIPTION
[0015] The foregoing and following aspects and embodiments,
including the studies discussed herein, are described and
illustrated in a manner intending to be exemplary only, and should
not be construed as limiting in scope.
[0016] One aspect of the present disclosure relates to a method for
treating at least one disease or condition in a patient in need
thereof by administering a pharmaceutical composition comprising
eslicarbazepine acetate in a pharmacologically effective
amount.
[0017] In one exemplary embodiment of the present disclosure, the
pharmaceutical composition comprising eslicarbazepine acetate is
administered in a once-daily dosing regimen.
[0018] In another exemplary embodiment of the present disclosure,
the pharmaceutical composition is administered in a dosage intended
to maximize the total exposure to eslicarbazepine, as measured by
the rate of exposure and extent of exposure (C.sub.max and
AUC.sub.0-.tau.).
[0019] In an exemplary embodiment of the present disclosure, the at
least one disease or condition treated may be chosen from, for
example, epilepsy, central and peripheric nervous system disorders,
affective disorders, schizoaffective disorders, bipolar disorders,
attention disorders, anxiety disorders, neuropathic pain and
neurophratic pain-related disorders, sensorimotor disorders,
vestibular disorders, and nervous function alterations in
degenerative and post-ischemic diseases.
[0020] Examples of affective disorders include depression,
pre-menstrual dysphoric disorder, post-partum depression,
post-menopausal depression, anorexia nervosa, bulimia nervosa, and
neurodegeneration-related depressive symptoms.
[0021] The methods disclosed in the present disclosure may be used
to treat schizoaffective disorders such as, for example,
schizodepressive syndromes, schizophrenia, extreme psychotic
states, schizomanic syndromes, dysphoric and aggressive behavior,
episodic dyscontrol or intermittent explosive disorder, and
borderline personality disorder.
[0022] Bipolar disorders that may be treated according to the
methods of the present disclosure include, for example, bipolar
disorder and unstable bipolar disorder with rapid fluctuations
(rapid cyclers), manic-depressive disorders, acute mania, mood
episodes, and manic and hypomanic episodes
[0023] Examples of attention disorders include attention deficit
hyperactivity disorders and other attention disorders, such as, for
example, autism.
[0024] Anxiety disorders may include conditions such as, for
example, social anxiety disorders, post traumatic stress disorder,
panic, obsessive-compulsive disorder, alcoholism, drug withdrawal
syndromes, and cravings.
[0025] The neuropathic pain and neurophratic pain-related disorders
that may be treated according to the methods of the present
disclosure include, by way of example, neuropathic pain and
associated hyperalgesia, including trigeminal, herpetic,
post-herpetic and tabetic neuralgia, diabetic neuropathic pain,
migraines, tension-type headaches, causalgia, and deafferentation
syndromes such as, for example, brachial plexus avulsion.
[0026] Examples of sensorimotor disorders include Restless legs
syndrome, spasticity, hemifacial spasm, nocturnal paroxysmal
dystonia, brain ischemia associated motor and sensitive deficits,
Parkinson's disease and parkinsonian disorders,
antipsychotic-induced motor deficits, tardive dyskinesia, episodic
nocturnal wandering, and myotonia.
[0027] Exemplary vestibular disorders include Tinnitus or other
inner ear/cochlear excitability related diseases, such as, for
example, neuronal loss, hearing loss, sudden deafness, vertigo, and
Meniere's disease.
[0028] In other exemplary embodiments, the at least one disease or
condition may be chosen from epilepsy, bipolar disorder, and
trigeminal neuralgia. In yet another embodiment, the disease may be
refractory partial epilepsy.
[0029] One skilled in the art will understand that these conditions
are exemplary only, and will understand from the disclosure what
other diseases and conditions would be considered to be within the
scope of the present disclosure.
[0030] Another aspect of the present disclosure relates to a
pharmaceutical composition comprising eslicarbazepine acetate and
at least one pharmaceutical excipient, at least one auxiliary
substance, at least one carrier material, or combinations
thereof.
[0031] A further aspect of the present disclosure relates to a
method of preparing a pharmaceutical composition comprising
combining eslicarbazepine acetate with at least one excipient, at
least one auxiliary substance, at least one carrier material, or
combinations thereof. Suitable excipients, carrier materials, and
other auxiliary substances which would be useful in the present
invention are known to those skilled in the art, and would be
readily determined. Methods for preparing pharmaceutical
compositions are also known to those skilled in the art.
[0032] In one exemplary embodiment of the present disclosure, the
pharmaceutical composition may be in tablet form and may comprise
at least one excipient, auxiliary substance, and/or carrier
material. The at least one excipient, auxiliary substance, and/or
carrier material may be chosen from, for example, povidone,
croscarmellose sodium, magnesium stearate, saccharin sodium,
dibasic calcium phosphate dihydrate, sodium lauryl sulphate,
flavorings, and combinations thereof. Exemplary tablets may be
formed using granulation liquids, such as, for example, purified
water and ethanol.
[0033] In another exemplary embodiment of the present disclosure,
the pharmaceutical composition may be in oral suspension form and
may comprise at least one excipient, auxiliary substance, and/or
carrier material. The at least one excipient, auxiliary substance,
and/or carrier material may be chosen from, for example, xantham
gum, macrogol stearate (such as, for example, Myrj 59 P, produced
by UNIQEMA), methylparaben, propylparaben, saccharin sodium,
sorbitol, buffers, flavorings, and combinations thereof.
[0034] Another aspect of the present disclosure relates to a method
for reducing or decreasing the number, duration, or frequency of
epileptic seizures in a patient by administering to the patient a
dose of a pharmaceutical composition comprising eslicarbazepine
acetate in a pharmacologically effective amount. In one exemplary
embodiment of the present disclosure, the method for reducing
epileptic seizures in patients comprises administering a once-daily
dose of the pharmaceutical composition comprising a
pharmacologically effective amount of eslicarbazepine acetate.
[0035] The present disclosure also relates to a method for
increasing the exposure to eslicarbazepine in a patient by
administering to the patient a pharmaceutical composition
comprising eslicarbazepine acetate in an amount effective to
increase the plasma concentration of eslicarbazepine over the
dosage interval. In one exemplary embodiment, the exposure to
eslicarbazepine may be increased by delivering the pharmaceutical
composition in a manner that minimizes the number of daily doses.
In a further exemplary embodiment of the present disclosure, the
method for increasing the exposure to eslicarbazepine in the
patient comprises administering to a patient a once-daily dose of a
pharmaceutical composition comprising an amount of eslicarbazepine
acetate effective to increase the plasma concentration of
eslicarbazepine over the dosage interval.
[0036] In a further exemplary embodiment of the present disclosure,
the active ingredient of the pharmaceutical composition may consist
essentially of eslicarbazepine acetate.
[0037] In a further aspect of the present disclosure,
eslicarbazepine acetate may be administered to a patient in an
amount resulting in a maximum plasma concentration (C.sub.max) of
eslicarbzepine greater than about 7,400 ng/mL. In other exemplary
embodiments, eslicarbazepine acetate may be administered to a
patient in an amount resulting in a C.sub.max of eslicarbazepine
greater than about 12,000 ng/mL or greater than about 16,100 ng/mL.
In further exemplary embodiments, eslicarbazepine acetate may be
administered to a patient in an amount resulting in a C.sub.max of
eslicarbazepine greater than about 22,700 ng/mL, such as greater
than about 36,500 ng/ml, greater than about 45,200 ng/mL, or
more.
[0038] In a further exemplary embodiment, eslicarbazepine acetate
may be administered to a patient in an amount resulting in a
maximum plasma concentration (C.sub.max) of eslicarbzepine up to
about 58,800 ng/mL or up to about 67,800 ng/mL. In a further
exemplary embodiment, eslicarbazepine acetate may be administered
to a patient in an amount resulting in a maximum plasma
concentration (C.sub.max) of eslicarbzepine up to about 885,000
ng/mL or up to about 1,000,000 ng/mL.
[0039] For example, a once-daily dose of about 400 mg may be
administered to a patient resulting in a maximum plasma
concentration (C.sub.max) of eslicarbazepine greater than about
7,400 ng/mL. As a further example, a once-daily dose of about 800
mg or about 1200 mg may be administered to a patient resulting in a
C.sub.max of eslicarbazepine greater than about 16,100 ng/mL or
greater than about 22,700 ng/mL, respectively. In other examples,
eslicarbazepine acetate may be administered in a once-daily dose
greater than about 1200 mg, such as about 1800 mg or about 2400 mg,
to result in a C.sub.max of eslicarbazepine greater than about
36,500 ng/mL, about 45,200 ng/mL, respectively.
[0040] In a further aspect of the present disclosure,
eslicarbazepine acetate may be administered to a patient in an
amount resulting in an area under the concentration curve (which
corresponds to the extent of systemic exposure) over the dosing
interval (AUC.sub.0-.tau.) of eslicarbazepine greater than about
110,000 ngh/mL. In other exemplary embodiments, eslicarbazepine
acetate may be administered to a patient in an amount resulting in
an AUC.sub.0-.tau. of eslicarbazepine greater than about 240,000
ngh/mL or greater than about 375,000 ngh/mL, respectively. In other
examples, eslicarbazepine acetate may be administered to a patient
in an amount resulting in an AUC.sub.0-.tau. of eslicarbazepine
greater than about 595,000 ngh/mL, greater than about 790,000
ngh/mL, or more.
[0041] For example, a once-daily dose of about 400 mg may be
administered resulting in an area under the concentration curve
(which corresponds to the extent of systemic exposure) over the
dosing interval (AUC.sub.0-.tau.) of eslicarbazepine greater than
about 110,000 ngh/mL. In other exemplary embodiments, a once-daily
dose of about 800 mg or about 1200 mg may be administered resulting
in an AUC.sub.0-.tau. of eslicarbazepine greater than about 240,000
ngh/mL or greater than about 375,000 ngh/mL, respectively. In other
examples, eslicarbazepine acetate may be administered in a
once-daily dose greater than about 1200 mg, such as about 1800 mg,
about 2400 mg, or more, to result in a respective AUC.sub.0-.tau.
of eslicarbazepine greater than about 595,000 ngh/mL, greater than
about 790,000 ngh/mL, or more.
[0042] In one exemplary embodiment of the present disclosure, a
once-daily dose may be administered in a dosage comprising at least
about 400 mg of eslicarbazepine acetate. In another exemplary
embodiment, a once-daily dose may be administered in a dosage
comprising an amount of eslicarbazepine acetate ranging from about
800 mg to about 1200 mg. In further exemplary embodiments, a
once-daily dose may be administered in a dosage comprising an
amount of eslicarbazepine greater than about 1200 mg, such as about
1800 mg, about 2400 mg, or more.
[0043] The pharmaceutical composition comprising eslicarbazepine
acetate may optionally be administered by any route known to those
skilled in the art, and may be in a form chosen from, for example,
tablets or oral suspensions, or other forms.
[0044] The term "about" as used herein is meant to signify that the
number modified by the term may be considered an approximation that
may vary depending upon the desired properties or effect sought by
the particular application, and thus should be considered to
encompass the range that one of skill in the art would understand
to achieve the desired or recited properties or effect.
[0045] A "method of treating" as described herein refers to
administering to a patient the compound described in any amount
effective to reduce the effects of, counteract, or eliminate the
disease or condition being treated, or the symptoms thereof.
[0046] A "method for increasing the exposure to eslicarbazepine in
a patient" as described herein refers to administering to a patient
the compound described in any amount effective to increase the
plasma concentration of eslicarbazepine in the patient over the
dosage interval. This may, for example, be an increase due to
once-daily dosing relative to twice-daily dosing.
[0047] "Reducing epileptic seizures in a patient" as described
herein refers to any decrease in the number, duration, or frequency
of epileptic seizures in a patient relative to the number,
duration, or frequency of epileptic seizures experienced by the
patient without treatment.
[0048] A "pharmacologically effective amount" of eslicarbazepine
acetate in a pharmaceutical composition as described herein refers
to any amount sufficient to have the desired pharmacological
activity.
[0049] All effective amounts as described herein will vary
according to various well-known and understood factors, such as,
for example, the condition being treated and the physiological
characteristics of the patient being treated. Accordingly, the
effective amount will be well within the ability of one skilled in
the art to determine.
Study Materials and Methods
[0050] The following demonstrates, as one example of the present
disclosure, the determination and administration of an effective
amount of a pharmaceutical composition comprising eslicarbazepine
acetate to treat epilepsy in patients in need thereof. The
effective amount of a pharmaceutical composition to treat other
diseases and/or conditions would be determinable by one skilled in
the art based on the techniques and concepts disclosed herein and
known in the art.
[0051] The effects of eslicarbazepine acetate in humans was studied
in at least the following clinical studies. In the first study, a
placebo-controlled therapeutic exploratory study, once-daily and
twice-daily dosing was compared in epileptic patients refractory to
standard anti-epileptic drug therapy. In the second study, healthy
subjects received either a once-daily (o.d.) oral dose of 900 mg of
eslicarbazepine acetate or a twice-daily (b.i.d.) dose of 450 mg of
eslicarbazepine acetate. In the third study, healthy subjects
received single oral doses of eslicarbazepine acetate ranging from
20 mg to 2400 mg, and repeated once-daily (o.d.) oral doses ranging
from 400 mg to 2400 mg of eslicarbazepine acetate.
[0052] The bioequivalence of tablets and oral suspensions was
proven in a relative bioavailability study.
Study in Epileptic Patients
[0053] This clinical trial was a double-blind, randomized,
placebo-controlled study performed by 20 centers in Croatia, Czech
Republic, Germany, Lithuania and Poland. The stated objectives of
the study were to assess the efficacy and safety of BIA 2-093 as
adjunctive therapy in patients with refractory partial epilepsy. In
total, 143 patients aged 18-65 years with at least 4 partial-onset
seizures per month in spite of treatment with 1 or 2 antiepileptic
drugs (AEDs) (e.g., phenytoin, valproate, primidone, phenobarbital,
lamotrigine, gabapentin, topiramate or clonazepam) were randomly
assigned to one of three groups: treatment with placebo (n=47), BIA
2-093 once-daily (n=50), or BIA 2-093 twice-daily (n=46), during 12
weeks (plus 1 week of tapering off). For the first 4 weeks, daily
dose was 400 mg. Then, daily doses were increased to 800 mg (weeks
5-8), and finally to 1200 mg (weeks 9-12). Tablets with strengths
of 200 mg, 400 mg, and 600 mg eslicarbazepine acetate and placebo
tablets were manufactured by BIAL (S. Mamede do Coronado, Portugal)
in accordance with Good Manufacturing Practice. The assay plasma to
determine the concentration of BIA 2-005 was performed with a
non-chiral method using isocratic liquid chromatography (LC) with
single quadrupole mass spectrometric detection (MS), as described
herein. See, e.g., Almeida I and Almeida II.
Study in Healthy Human Volunteers
Trial A
[0054] This human pharmacology trial was a study to investigate the
steady-state pharmacokinetics of once-daily and twice-daily
regimens of eslicarbazepine acetate in healthy subjects. The study
was a single center, open-label, randomized, two-way crossover
study in 12 healthy volunteers (6 males and 6 females) that
consisted of two 8-day treatment periods separated by a washout
period of 10-15 days. On each of the treatment periods the
volunteers received either a daily oral dose of eslicarbazepine
acetate 900 mg once-daily (o.d.) or eslicarbazepine acetate 450 mg
twice-daily (b.i.d.). Tablets with a strength of 450 mg of
eslicarbazepine acetate, manufactured by BIAL (S. Mamede do
Coronado, Portugal) in accordance with Good Manufacturing Practice,
were used.
[0055] Blood samples for drug plasma assays were taken at the
following times:
[0056] Phase A: [0057] pre-dose, and 1/2, 1, 11/2, 2, 3, 4, 6, 8,
12, 24, 36,48, 72, and 96 hours post-dose;
[0058] Phase B: [0059] day 5 to day 11 (inclusive): before the
daily dose (for "trough" concentrations assay); [0060] day 12:
pre-dose, and 1/2, 1, 11/2, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96,
and 120 hours post-dose. Blood samples were drawn either by direct
venipuncture or via an intravenous catheter into lithium heparin
tubes and centrifuged at approximately 1500 g for 10 minutes at
4.degree. C. The resulting plasma was separated into 2 equal
aliquots of 1 mL and stored at -20.degree. C. until required for
analysis.
[0061] Plasma concentrations of eslicarbazepine acetate,
eslicarbazepine, and R-licarbazepine were determined using
isocratic liquid chromatography (LC) with single quadrupole mass
spectrometric detection (MS).
[0062] The method involved the addition of 500 .mu.L of
approximately 0.5 .mu.g/mL of 10,11-dihydrocarbamazepine (internal
standard prepared in acetonitrile:water, 3:97, v:v) to 250 .mu.L of
plasma (centrifuged at 1800 rpm, prior to analysis) in a
polypropylene tube. After vortex mixing for 10 seconds, the mixture
was transferred to a Schleicher and Schuell C18/100 mg 96 well
solid phase extraction plate. Each well was preconditioned with 800
.mu.L methanol, followed by 800 .mu.L acetonitrile and 800 .mu.L
acetonitrile:water (3:97, v:v) prior to application of the total
sample volume. Each polypropylene tube was then washed with 500
.mu.L acetonitrile:water (3:97, v:v) and the washings transferred
to the respective well. The compounds were eluted into a collection
plate with 750 .mu.L acetonitrile and the extract evaporated to
dryness under oxygen-free nitrogen, at 40.degree. C. All solid
phase extraction manipulations were undertaken using the Tomtec
QUADRA 96.RTM. Model 320 system and a vacuum was applied at each
elution step. The final extract was reconstituted in 100 .mu.L of
water:methanol (90:10, v:v) and mixed. The collection plate was
then centrifuged at approximately 3000 rpm (at approximately
4.degree. C., for approximately 10 minutes) prior to analysis. An
aliquot of the final extract (10 .mu.L) was injected onto the LC-MS
system.
[0063] The LC-MS system used in the analysis consisted of a Perkin
Elmer series 200 micro pump, a Perkin Elmer series 200 autosampler,
and a Perkin Elmer/Sciex API 150EX single quadrupole mass
spectrometer fitted with a Turbo IonSpray.RTM. source. Separation
was achieved using a LichroCART 250-4 ChiraDex column
(.beta.-cyclodextrin, 5 .mu.m), a LichroCART 4-4 ChiraDex column
guard column (.beta.-cyclodextrin, 5 .mu.m), a Jones Chromatography
7971 column heater at 50.degree. C., a mobile phase A (0.2 mM
sodium acetate, aq) and a mobile phase B (0.2 mM sodium acetate,
MeOH). The MS detector was operated in positive ion mode with mass
transitions for BIA 2-093, eslicarbazepine, R-licarbazepine, and
the internal standard of 319.16 amu (200 ms), 277.08 amu (200 ms),
277.08 amu (200 ms) and 261.05 amu (200 ms), respectively. The
limit of quantification of the assay was 10 ng/mL for
eslicarbazepine acetate and 100 ng/mL for eslicarbazepine and
R-licarbazepine.
[0064] Eslicarbazepine acetate, (S)-(-)-10-acetoxy-10,11
-dihydro-5H-dibenz/b,f/azepine-5-carboxamide; eslicarbazepine,
(S)-(+)-10,11-dihydro-10-hydroxy-5H
dibenz/b,f/azepine-5-carboxamide; and R-licarbazepine,
(R)-(-)-10,11-dihydro-10-hydroxy-5H
dibenz/b,f/azepine-5-carboxamide, were synthesized in the
Laboratory of Chemistry, BIAL, with purities >99.5%. The
internal standard, 10,11-dihydrocarbamazepine was supplied by
Sigma-Aldrich (St. Louis, Mo.).
[0065] The pharmacokinetic parameters were derived from
non-compartmental analysis using WinNonlin (Version 4.0, Pharsight
Corporation, Mountain View, Calif.). The following parameters were
derived, where appropriate, from the individual plasma
concentration-time profiles: maximum observed plasma concentration
(C.sub.max); time of occurrence of C.sub.max (t.sub.max); area
under the plasma concentration versus time curve (AUC) from time
zero to the last sampling time (t) at which concentrations were at
or above the limit of quantification (AUC.sub.0-t), calculated by
the linear trapezoidal rule; AUC over the dosing interval
(AUC.sub..tau.), i.e., 24 hours and 12 hours in the once-daily and
the twice-daily group, respectively; AUC from time zero to infinity
(AUC.sub.0-.infin.), calculated from AUC.sub.0-t
+(C.sub.last/.lamda..sub.z), where C.sub.last is the last
quantifiable concentration; apparent terminal rate constant
(.lamda..sub.z) calculated by log-linear regression of the terminal
segment of the plasma concentration versus time curve; apparent
terminal half-life (t.sub.1/2), calculated from ln
2/.lamda..sub.z.
[0066] Actual sampling times were used for the pharmacokinetic
analysis. Where an AUC was extrapolated to infinity, the percentage
of the extrapolated area to the total area was assessed; if greater
than 20%, the AUC value was flagged as unreliable. Plasma
concentrations below the limit of quantification of the assay (BLQ)
were taken as zero for all calculations. All calculations were made
using raw data. Values for t.sub.max were displayed as nominal
times.
[0067] Summary statistics for each group and schedule sampling time
were reported, as appropriate, using the geometric mean, arithmetic
mean, standard deviation (SD), coefficient of variation (CV),
median, minimum, and maximum. Comparisons between elderly versus
young groups for the single-dose and multiple-dose data were based
on analysis of variance (one-way ANOVA) of the logarithmic
transformed C.sub.max, AUC.sub..tau. and AUC.sub.0-.infin.
parameters. A t.sub.max comparison between age groups was performed
assuming a non-parametric approach using the Wilcoxon signed rank
test. In addition, differences in logarithmic transformed
parameters (C.sub.max, AUC.sub..tau. and AUC.sub.0-.infin.) and
their associated 95% confidence intervals (95% Cl) were estimated
between age groups to take the form of ratios on a linear scale.
The median values and differences of t.sub.max between age groups
and 95% Cl were reported. All tests of significance were performed
at the p=0.05 level. The statistical package SAS (Version 8.2, SAS
Institute Inc, Cary, N.C.) was used.
Trial B
[0068] This human pharmacology trial was a study to determine the
pharmacokinetics of eslicarbazepine acetate following single and
repeated doses. The study integrated the results of three
double-blind, randomized, placebo-controlled trials. To measure the
pharmacokinetics of eslicarbazepine acetate following single doses,
oral single doses of eslicarbazepine acetate ranging from 20 mg to
2400 mg were administered to healthy young male subjects (6
subjects per dose). The pharmacokinetics of eslicarbazepine acetate
following repeated doses were measured by administering repeated
oral doses ranging from 400 mg to 2400 mg of eslicarbazepine
acetate to healthy young male subjects (6 subjects per dose) over a
period of 8 days. Analytical test methods and experimental
procedures were similar to those described for Trial A above.
Study Results
Study in Epileptic Patients
Baseline Characteristics
[0069] At baseline, the treatment groups were homogenous with
regard to age, height, weight, and body mass index. All 143
patients were Caucasian. With respect to gender, there were
relatively more female patients in the twice-daily group than in
the once-daily and placebo groups (65.2%, 56.0% and 57.4%,
respectively); this difference did not significantly affect the
results. No significant differences were found in the number of
AEDs used: respectively 30.0%, 34.8% and 29.8% of patients in the
once-daily, twice-daily, and placebo groups were treated with 1
AED; the remaining patients were treated with 2 AEDs. The most
frequently used concomitant AEDs were valproic acid (68.0%, 60.9%
and 66.0% of patients in the once-daily, twice-daily, and placebo
groups, respectively), topiramate (36.0%, 34.8%, and 21.3%,
respectively) and lamotrigine (30.0%, 28.3%, and 31.9%,
respectively).
[0070] At baseline, mean duration of epilepsy was 16.7, 19.5, and
20.0 years in the once-daily, twice-daily, and placebo groups,
respectively. With respect to seizure type frequency, IA simple
partial, IB complex partial, and IC partial evolving to secondarily
generalized were present in, respectively, 34.0%, 72.0%, and 80.0%,
in the once-daily group; 37.0%, 71.7%, and 80.4%, in the
twice-daily group; and 27.7%, 80.9%, and 72.3%, in the placebo
group. The mean of total number of seizures per month prior to the
study was 14.1, 13.6, and 11.8, in the once-daily, twice-daily, and
placebo groups, respectively.
Efficacy Results
[0071] The proportion of patients with a 50% or greater reduction
in seizure frequency in the treatment period compared to the
baseline period in the intention-to-treat (ITT) population (n=143)
was the primary efficacy endpoint. At the dose of 1200 mg/day
(weeks 9-12), the proportion of responders in the once-daily group
(54%) was significantly higher (p=0.008) than in the placebo group
(28%). The proportion of responders in the once-daily group (54%)
was also higher than in the twice-daily (41%) group. At the dose of
800 mg/day (weeks 5-8), the proportion of responders in the
once-daily group (58%) was significantly higher (p<0.05) than in
the twice-daily (33%) and placebo (38%) groups. At this dose level,
no significant difference was found between the twice-daily and the
placebo groups.
[0072] Secondary endpoints include the reduction in total seizure
frequency, proportion of seizure-free patients, distribution of
responders, comparison of once and twice daily regimens, and
investigator's and patient's global evaluation.
[0073] The greatest decrease in the number of seizures was achieved
with 1200 mg and 800 mg once-daily doses, and the results with the
once-daily group were better than those obtained in the twice-daily
group (FIG. 1). For all dosages (400 mg, 800 mg, and 1200 mg),
patients receiving once-daily doses of eslicarbazepine acetate had
a substantially greater reduction in the number of seizures
compared to patients in the twice-daily and placebo groups.
[0074] The number of seizures in patients receiving 1200 mg and 800
mg once-daily doses of eslicarbazepine acetate was reduced by 59.5%
and 55.8%, respectively. In comparison, seizures in patients
receiving 1200 mg and 800 mg twice-daily doses reduced by 47.5% and
38.1%, respectively. Patients receiving a 400 mg once-daily dose of
eslicarbazepine acetate experienced a 38.9% reduction in the number
of seizures, almost twice the reduction in seizures observed in
patients receiving 400 mg twice-daily doses of eslicarbazepine
acetate (20.2%).
[0075] At the end of the 12-week treatment phase, 27.9% of the
patients in the once-daily dosing group became seizure-free.
[0076] In addition, the assessment of efficacy by the investigator
(CGI--Clinical Global Impression) and of acceptability by patient
was rated best in the once-daily group.
Pharmacokinetic Results
[0077] Plasma/serum samples for the "trough" (pre-dose) levels of
BIA 2-005 and concomitant AEDs were collected at all visits but V5
(post-study visit). The objective was to characterize the influence
of eslicarbazepine acetate on the pharmacokinetic behavior of the
concomitant AEDs (e.g., phenytoin, valproate, primidone,
phenobarbital, lamotrigine, gabapentin, topiramate, and
clonazepam). The mean trough plasma concentrations of BIA 2-005 are
displayed in Table 1. As shown in FIG. 2, no significant
differences in the BIA 2-005 trough (pre-dose) values between the
once-daily and twice-daily groups were found. TABLE-US-00001 TABLE
1 Trough plasma concentrations of BIA 2-005 following oral
administration of eslicarbazepine acetate once-daily (o.d.) and
twice-daily (b.i.d) 400 mg/day 800 mg/day 1200 mg/day o.d. b.i.d.
o.d. b.i.d. o.d. b.i.d. group group group group group group Mean
4.0 (3.2) 4.9 (2.3) 10.7 13.5 14.6 (8.8) 15.5 (8.8) (.mu.g/mL)
(7.0) (9.6) Results expressed as arithmetic means with the
correspondent standard deviations (sd) in parenthesis.
[0078] The relatively small number of patients being administered
phenytoin, primidone, phenobarbital, gabapentin, and clonazepam
precluded the appropriate characterization of the eventual effect
of eslicarbazepine acetate on the pharmacokinetic behavior of these
concomitant AEDs. For valproate, lamotrigine and topiramate, the
number of patients was also small, but an exploratory analysis of
the effect of eslicarbazepine acetate on the trough blood values of
these concomitant AEDs was performed. The mean trough serum
concentrations of valproate were not significantly changed by
concomitant administration of eslicarbazepine acetate once-daily
(7.0%; 95% IC: -7.6, 36.2) or twice-daily (6.3%; 95% IC: -7.5,
20.1). In the placebo group, a significant increase in the serum
levels of valproate was noticed (25.4%; 95% IC: 5.1, 45.8). With
respect to lamotrigine, its serum levels were not significantly
changed when eslicarbazepine acetate once-daily (-10.0%; 95% IC:
-46.2, 26.2) or placebo (12.6%; 95% IC: -12.6, 37.8) were added to
therapy. With eslicarbazepine acetate twice-daily, the serum levels
of lamotrigine decreased significantly (-46.7%; 95% IC: -69.7;
-23.8). With respect to topiramate, its serum levels were not
significantly changed when eslicarbazepine acetate once-daily
(-15.2%; 95% IC: -34.8, 4.4) was added to the therapy. With
eslicarbazepine acetate twice-daily, the serum levels of topiramate
decreased significantly (-32.4%; 95% IC: -49.5; -15.3). One skilled
in the art will know whether a change in serum levels is
significant.
Study in Healthy Human Volunteers
Trial A
Pharmacokinetic Results
[0079] Eslicarbazepine acetate was shown to be extensively
metabolized to eslicarbazepine and, in a minor extent, to
R-licarbazepine. The steady-state of eslicarbazepine plasma
concentrations was attained at 4 to 5 days of administration in
both groups.
[0080] Following the last dose, in the once-daily group, mean
C.sub.max of eslicarbazepine and R-licarbazepine was, respectively,
22,210 ng/mL and 674 ng/mL and occurred at (median t.sub.max) 2.45
hours and 9.42 hours post-dose, respectively. Mean AUC.sub.0-t of
eslicarbazepine and R-licarbazepine was 381,601 ngh/mL and 19,600
ngh/mL, respectively. In the twice-daily group, mean C.sub.max of
eslicarbazepine and R-licarbazepine was 16,667 ng/mL and 718 ng/mL,
respectively, and occurred (median t.sub.max) at 2.09 hours and
6.40 hours post-dose, respectively. Mean AUC.sub.0-t of
eslicarbazepine and R-licarbazepine was 283,014 ngh/mL and 19,661
ngh/mL, respectively. Following multiple administration of
eslicarbazepine acetate for 8 days, eslicarbazepine was shown to be
the major metabolite, representing approximately 95% and 96% of
total systemic drug exposure (as assessed by AUC.sub.0-24) in
once-daily and twice-daily subjects, respectively. Tables 2 and 3
depict the eslicarbazepine and R-licarbazepine pharmacokinetic
parameters in the once-daily and twice-daily groups following the
last dose of eslicarbazepine acetate. The total exposure of healthy
volunteers to eslicarbazepine in the once-daily group was
unexpectedly at least 26% higher than in the twice-daily group.
TABLE-US-00002 TABLE 2 Mean pharmacokinetic parameters of
eslicarbazepine and R-licarbazepine following a multiple oral dose
of 900 mg eslicarbazepine acetate once-daily. AUC.sub.0-t C.sub.max
t.sub.max (ng AUC.sub.0-.tau. AUC.sub.0-.infin. t.sub.1/2 (ng/mL)
(h) h/mL) (ng h/mL) (ng h/mL) (h) Eslicarbazepine n 11 11 11 11 11
11 A.sub.mean 22210 2.45 381601 294019 389344 9.12 SD 7257 0.879
95368 58364 97383 1.19 R-licarbazepine n 12 12 12 12 12 12
A.sub.mean 674 9.42 19600 13397 23989 15.0 SD 184 6.48 6763 3187
7144 3.41 n = Number of subjects; A.sub.mean = Arithmetic mean; SD
= Standard deviation.
[0081] TABLE-US-00003 TABLE 3 Mean pharmacokinetic parameters of
eslicarbazepine and R-licarbazepine following a multiple oral dose
of 900 mg eslicarbazepine acetate twice-daily. AUC.sub.0-.tau.
C.sub.max t.sub.max AUC.sub.0-t (ng AUC.sub.0-.infin. t.sub.1/2
(ng/mL) (h) (ng h/mL) h/mL) (ng h/mL) (h) Eslicarbazepine n 11 11
11 11 11 11 A.sub.mean 16667 2.09 283014 142080 289792 9.17 SD 3981
0.664 74203 25933 74346 1.49 R-licarbazepine n 10 10 10 10 10 10
A.sub.mean 718 6.40 19661 7783 23807 14.8 SD 184 3.06 6049 2083
7150 4.09 n = Number of subjects; A.sub.mean = Arithmetic mean; SD
= Standard deviation.
Trial B Pharmacokinetic Results
[0082] As in Trial A, eslicarbazepine acetate was extensively
metabolized to eslicarbazepine and, in a minor extent, to
R-licarbazepine. The steady-state of eslicarbazepine plasma
concentrations was attained at 4 to 5 days of once-daily
dosing.
[0083] Following the last dose, in the repeated once daily group,
mean C.sub.max of eslicarbazepine ranged from 8,800 ng/ML(16.0%
coefficient of variation, CV) for 400 mg doses of eslicarbazepine
acetate to 56,500 ng/ML(20.0% CV) for 2400 mg doses of
eslicarbazepine acetate. The maximum plasma concentration for all
dosages occurred (median t.sub.max) at 2 hours to 3.5 hours. The
mean area under the concentration for the dosing interval of 24
hours, AUC.sub.0-24h, ranged from 126,300 ng/ML for 400 mg
once-daily doses of eslicarbazepine acetate to 905,900 ng/ML for
2400 mg once-daily doses of eslicarbazepine acetate. Tables 4 and 5
depict the eslicarbazepine and R-licarbazepine pharmacokinetic
parameters following the single dose of eslicarbazepine acetate and
the pharmacokinetic parameters following the last of the repeated
doses of eslicarbazepine acetate. TABLE-US-00004 TABLE 4 Mean
pharmacokinetic parameters of eslicarbazepine and R-licarbazepine
following single doses of eslicarbazepine acetate (n = 6 subjects
per dose group). Mean C.sub.max Median t.sub.max Mean AUC.sub.0-24
h Mean apparent t.sub.1/2 Dose ng/mL (% CV) h (range) ng h/mL (%
CV) h (% CV) 20 mg 300 (18.7) 0.8 (0.5-0.8) 2,400 (16.2) 9.1 (15.9)
50 mg 900 (24.7) 0.8 (0.5-2) 6,700 (12.7) 8.1 (9.1) 100 mg 1,500
(13.8) 1.5 (0.5-2) 16,400 (11.7) 9.3 (8.7) 200 mg 2,900 (16.2) 1.5
(0.8-2.5) 30,500 (23.7) 8.4 (18.8) 400 mg 5,200 (11.6) 4 (4-5)
81,500 (10.8) 11.7 (18.6) 600 mg 8,500 (20.0) 4 (0.5-5) 119,700
(17.4) 12.3 (14.8) 900 mg 15,000 (18.2) 2.3 (0.8-4) 210,300 (10.6)
16.3 (31.9) 1200 mg 18,600 (16.3) 4 (2-6) 285,700 (16.7) 16.5 (6.8)
1800 mg 34,600 (16.3) 3.5 (3-6) 507,600 (17.0) 11.8 (11.7) 2400 mg
35,900 (42.6) 3 (1.5-6) 445.6 (26.1) 11.1 (21.1) CV = Coefficient
of variation (%); C.sub.max = Maximum plasma concentration;
AUC.sub.0-24 h = Area under the curve of plasma concentration-time
over 24 h; t.sub.max = Time to C.sub.max; t.sub.1/2 = Elimination
half-life
[0084] TABLE-US-00005 TABLE 5 Mean pharmacokinetic parameters of
eslicarbazepine and R-licarbazepine following the last dose of an
8-day repeated dose regimen of eslicarbazepine acetate (n = 6
subjects per dose group). Mean Mean AUC.sub.0-24 h apparent Mean
C.sub.max Median t.sub.max ng h/mL t.sub.1/2 Dose ng/mL (% CV) h
(range) (% CV) h (% CV) 400 8,800 (16.0) 3 (0.5-7) 126,300 (11.7)
9.50 (18.8) mg o.d. 800 18,700 (14.0) 3.5 (1-7) 268,400 (10.3) 12.3
(22.9) mg o.d. 1200 25,500 (10.8) 3 (0.5-6) 423,000 (10.9) 13.1
(20.1) mg o.d. 1800 47,700 (23.3) 2 (0.5-4) 740,300 (19.6) 11.3
(28.8) mg o.d. 2400 56,500 (20.0) 2 (1.5-8) 905,900 (12.8) 10.4
(24.1) mg o.d. CV = Coefficient of variation (%); C.sub.max =
Maximum plasma concentration; AUC.sub.0-24 h = Area under the curve
of plasma concentration-time over 24 h; t.sub.max = Time to
C.sub.max; t.sub.1/2 = Elimination half-life
Study Discussion
[0085] Once-daily administration of eslicarbazepine acetate was
found to be more efficacious than the same total dosage divided
into twice-daily doses, and is clearly more efficacious in reducing
epileptic seizures than placebo. 800 mg and 1200 mg once-daily
doses of eslicarbazepine acetate were shown to be noticeably more
efficacious in reducing epileptic seizures than twice-daily doses
achieving the same total daily dosage.
[0086] Eslicarbazepine acetate was shown to be extensively
metabolized to eslicarbazepine and, in a minor extent, to
R-licarbazepine. Eslicarbazepine represented between 95% and 98% of
total systemic drug exposure (as assessed by AUC.sub.0-.tau., i.e.,
AUC over the dosing interval) and, therefore, is believed to be
mainly responsible for pharmacological activity following
administration of eslicarbazepine acetate. Plasma concentrations of
parent drug (eslicarbazepine acetate) were systematically found to
be below the limit of quantification. With multiple-dosing,
steady-state plasma concentrations were attained at 4 to 5 days of
administration in both groups, consistent with an effective
half-life on the order of about 20-24 hours.
[0087] The kinetic profile of eslicarbazepine in the once-daily
group was markedly different from the twice-daily group with
statistical differences found for some of the pharmacokinetic
parameters assessed (C.sub.max, AUC.sub.0-t and AUC.sub.0-.infin.)
following multiple oral dosing of eslicarbazepine acetate. In fact,
the total exposure of healthy volunteers to eslicarbazepine in the
once-daily group was unexpectedly at least 26% higher than in the
twice-daily group. This unexpected result is in line with finding
in epileptic patients that once-daily administration of
eslicarbazepine acetate was more efficacious than the same total
daily dosage divided into twice-daily doses. Though this result
might imply that the enhanced clinical efficacy would result from
an increase in the rate (C.sub.max) and extent (AUC) of exposure to
eslicarbazepine, the reasons for such an enhanced extent of
exposure after once-daily versus twice-daily administration remain
unexplained.
[0088] In addition to the exemplary aspects and embodiments
described above, further aspects and embodiments will become
apparent to those skilled in the art by study of the foregoing
description. Those skilled in the art will recognize that certain
modifications of the above description are possible, and such
modifications are considered to be within the scope of the
invention. It is therefore intended that the following appended
claims (including any amendments thereto) and any claims hereafter
introduced should be interpreted to include all such aspects,
embodiments, and modifications.
* * * * *