h p://www.jclinpha m.o g
Pha macology
The Jou nal o Clinical
DOI: 10.1177/0091270005279364
2005; 45; 1062 J. Clin. Pha macol.
Luis Almeida, Amílca Falcão, Joana Maia, Dago Mazu , Man ed Gelle and Pa ício Soa es-da-Sil a
Elde ly and Young Subjec s
Single-Dose and S eady-S a e Pha macokine ics o Eslica bazepine Ace a e (BIA 2-093) in Heal hy
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10.1177/0091270005279364ALMEIDA ET ALPHARMACOKINETI CS OF ESLICARBAZEPINE ACETATEBRIEF REPORTS/PHARMACOKIN ETICS
Single-Dose and S eady-S a e Pha macokine ics
o Eslica bazepine Ace a e (BIA 2-093)
in Heal hy Elde ly and Young Subjec s
Luis Almeida, MD, FFPM, Amílca Falcão, Pha mD, PhD, Joana Maia, Pha mD,
Dago Mazu , MD, Man ed Gelle , and Pa ício Soa es-da-Sil a, MD, PhD
Eslica bazepine ace a e (BIA 2-093, S-(-)-10-
ace oxy-10,11-dihyd o-5H-dibenz/b, /azepine-5-
ca boxamide) is a new d ug cu en ly in phase III o
he ea men o epilepsy and phase II o bipola diso -
de . I is chemically ela ed o ca bamazepine and
oxca bazepine bu has been speci ically designed o
a oid he p oduc ion o oxic me aboli es (such as
epoxides) and o o e come enan iome ic impu i y and
he unnecessa y p oduc ion o enan iome s o
dias e eoisome s o me aboli es and conjuga es, wi h-
ou losing pha macological ac i i y.1Eslica bazepine
ace a e is a ol age-ga ed sodium channel blocke ha
compe i i ely in e ac s wi h si e 2 o he inac i a ed
s a e o he channel. The a ini y o his s a e o he
channel is simila o ha o ca bamazepine, while he
a ini y o he es ing s a e o he channel is abou 3-
old lowe han ha o ca bamazepine. This p o ile
may sugges an enhanced inhibi o y selec i i y o
eslica bazepine ace a e o apidly i ing neu ons o e
hose displaying no mal ac i i y.2
S udies in humans ha e shown ha a e o al ad-
minis a ion, eslica bazepine ace a e is apidly and ex-
ensi ely me abolized o he ac i e me aboli e
eslica bazepine, he S(+) enan iome o lica bazepine
(S-lica bazepine, (S)-(+)-10,11-dihyd o-10-hyd oxy-
5H-dibenz/b, /azepine-5-ca boxamide).3The plasma
concen a ions o he pa en d ug (eslica bazepine ace-
a e) ha e been sys ema ically ound below he limi o
quan i ica ion o he assay (10 ng/mL).3-5 When a
nonchi al me hod is used, he assay does no dis in-
guish be ween eslica bazepine and i s R-enan iome , a
mino me aboli e, and he mix u e is epo ed as BIA 2-
005.4,5
En y-in o-man s udies in heal hy subjec s adminis-
e ed eslica bazepine ace a e single o al doses anging
om 20 mg o 1200 mg4and mul iple doses anging om
200 mg wice daily o 1200 mg once daily5showed ha
BIA 2-005 maximum obse ed plasma concen a ion
(Cmax)wasa aineda 1 o4hou spos dose( max), he ex-
en o sys emic exposu e o BIA 2-005 was app oxi-
ma ely dose p opo ional, ands eadys a e o BIA2-005
plasma concen a ions was a ained a 4 o 5 days, con-
sis en wi h an e ec i e hal -li e o 20 o 24 hou s. The
mean enal clea ance o BIA 2-005 om plasma was 20
o 30 mL/min, and he o al amoun o BIA 2-005 eco -
e ed in he u ine was app oxima ely 20% and 40%
wi hin 12 hou s and 24 hou s pos dose, espec i ely. In
a placebo-con olled he apeu ic explo a o y s udy in
epilep ic pa ien s e ac o y o s anda d an iepilep ic
d ug he apy, eslica bazepine ace a e in daily doses
anging om 400 mg o 1200 mg adminis e ed in a
once-daily o wice-daily egimen was shown o be e -
ec i e and well- ole a ed.6
T ea men o elde ly pa ien s o en equi esin o ma-
ion on whe he dose adjus men s a e needed. Mos o
he ecognized impo an di e ences be ween younge
and olde pa ien s a e pha macokine ic di e ences, o -
en ela ed o impai men o exc e o y unc ion o o
1062 •J Clin Pha macol 2005;45:1062-1066
Keywo ds: Eslica bazepine ace a e; eslica bazepine; BIA
2-093; age e ec ; elde ly; pha macokine ics
Jou nal o Clinical Pha macology, 2005;45:1062-1066
©2005 he Ame ican College o Clinical Pha macology
F om he Depa men o Resea ch and De elopmen , BIAL (Po ela & Ca
SA), S Mamede do Co onado, Po ugal (D Almeida, D Falcão, D Maia,
D Soa es-da-Sil a), and Scope In e na ional Li e Sciences AG, Hambu g,
Ge many (D Mazu , M Gelle ). Submi ed o publica ion Ma ch 5,
2005; e ised e sion accep ed June 1, 2005. Add ess o ep in s:
Pa icio Soa es-da-Sil a, Depa men o Resea ch and De elopmen , BIAL
(Po ela & CaSA), 4745-457 S Mamede do Co onado, Po ugal.
DOI: 10.1177/0091270005279364
© 2005 Ame ican College o Clinical Pha macology. All igh s ese ed. No o comme cial use o unau ho ized dis ibu ion.
a Uni e sidade Do Po o on Ap il 11, 2007 h p://www.jclinpha m.o gDownloaded om
d ug-d ug in e ac ions. The p ima y objec i e o his
s udy was o answe ha ques ion by compa ing he
pha macokine ic p o ile o eslica bazepine ace a e in
young and elde ly subjec s.
METHODS
S udy Design
This was a single-cen e , open-label, non andomized
s udy pe o med a Scope In e na ional Li e Sciences
AG (Hambu g, Ge many) in 12 heal hy elde ly and 12
heal hy young subjec s. The s udy consis edo asingle-
dose phase (phase A) ollowed by a 8-day mul iple-
dose phase (phase B). Subjec s we e adminis e ed
eslica bazepine ace a e 600 mg single dose in phase A
and 600 mg once daily in phase B.
In phase A, subjec s we e admi ed o he uni on he
day be o e dosing (day 0) and emained unde clinical
supe ision un il a leas 24 hou s pos dose (day 2);
hen, hey le and we e eques ed o a end he uni a
36, 48, 72, and 96 hou s pos dose. Phase B s a ed ol-
lowing he 96-hou pos dose p ocedu es o phase A
(day 5). On days 5 o 11, subjec s we e eques ed o a -
end he uni ea ly in he mo ning o p edose blood
sampling o he assay o ough plasma concen a ions
and s udy p oduc adminis a ion. On he e ening o
day 11, subjec s we e admi ed o he uni , and on he
mo ning o day 12, he las dose o s udy medica ion
was adminis e ed. Subjec s emained unde clinical
supe ision un il he 24-hou pos dose p ocedu es
(day 13); hen, hey le and we e eques ed o a end
he uni in he e ening o day 13 and in he mo ning o
days 14, 15, 16,and 17 o he 36-, 48-,72-, 96-, and 120-
hou pos –las dose p ocedu es, espec i ely.
The s udy was conduc ed acco ding o he p inci-
ples o he Decla a ion o Helsinki and he Good Clini-
cal P ac ice ecommenda ions, and an Independen
E hics Commi ee (E hik-Kommission de
Ä z ekamme Hambu g,Hambu g,Ge many) e iewed
and app o ed he s udy p o ocol and he subjec in o -
ma ion. W i en in o med consen was ob ained o
each subjec p io o en olmen in he s udy.
Subjec s
Subjec s sa is ied he ollowing main inclusion c i e-
ia: aged be ween 18 and 40 yea s (young g oup) o 65
yea s o olde (elde ly g oup); wi hin 15% (i young) o
20% (i elde ly) o ideal body weigh ; “heal hy” as de-
e mined by p es udy medical his o y, physical exami-
na ion, neu ological examina ion, 12-lead elec oca -
diog am, and clinical labo a o y es s; nonsmoke s o
smoke s o less han 10 ciga e es pe day; i emale, no
o childbea ing po en ial o , i o childbea ing po en-
ial, using double-ba ie o in au e ine de ice
me hods and ha ing a nega i e p egnancy es .
Eslica bazepine ace a e adminis a ion occu ed be-
ween 8:00 AM and 9:00 AM ollowing an o e nigh as -
ing o a leas 8 hou s on day 1 (single dose o phase A)
and day 12 (las dose o phase B). On days 5 o 11,
dosing occu ed wi hou ega d o meals because a p e-
ious ood-in e ac ion s udy showed ha p esence
o ood has no e ec on he pha macokine ics o
eslica bazepine ace a e.7On days 1 and 12, meals we e
se ed abou 4, 7, and 11 hou s ollowing p oduc ad-
minis a ion. Wa e d inking as desi ed was allowed.
Blood Sampling
Blood samples (7 mL) o d ug plasma assays we e
aken a he ollowing imes: phase A: p edose and 0.5,
1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, and 96 hou s
pos dose; phase B: om day 5 o day 11 inclusi e, be-
o e hedailydose ( o ough concen a ion assay);day
12: p edose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72,
96, and 120 hou s pos dose. Blood samples we e
d awn in o li hium hepa in ubes and cen i uged a
app oxima ely 1500 g o 10 minu es a 4°C. The esul -
ing plasma was sepa a ed in o 2 equal aliquo s o 1 mL
and s o ed a –20°C un il equi ed o analysis.
Sample Analysis
Eslica bazepine ace a e, eslica bazepine, and R-
lica bazepine concen a ions in plasma we e analyzed
using alida ed isoc a ic liquid ch oma og aphy wi h
single quad upole mass spec ome ic de ec ion (MS).
The MS de ec o was ope a ed in posi i e ion mode
wi h mass ansi ions o eslica bazepine ace a e,
eslica bazepine,R-lica bazepine,and hein e nal s an-
da d (10,11-dihyd oca bamazepine) o 319.16 amu
(200 ms), 277.08 amu (200 ms), 277.08 amu (200 ms),
and 261.05 amu (200 ms), espec i ely. The o e all im-
p ecision o he me hod, measu ed by he coe icien o
a ia ion, anged om 6.7% o 7.4% o
eslica bazepine ace a e, om 6.7% o 9.6% o
eslica bazepine, and om 7.8% o 9.4% o R-
lica bazepine. The mean accu acy anged om 98.8%
o 99.0% o eslica bazepine ace a e, om 98.1% o
102.8% o eslica bazepine, and om 96.9% o 98.8%
o R-lica bazepine. The limi o quan i ica ion o he
assaywas 50ng/mL o eslica bazepineace a e and 100
ng/mL o eslica bazepine and R-lica bazepine.
BRIEF REPORTS/PHARMACOKINETICS 1063
PHARMACOKINETICS OF ESLICARBAZEPINE ACETATE
© 2005 Ame ican College o Clinical Pha macology. All igh s ese ed. No o comme cial use o unau ho ized dis ibu ion.
a Uni e sidade Do Po o on Ap il 11, 2007 h p://www.jclinpha m.o gDownloaded om
Pha macokine ic Analysis
The ollowing pha macokine ic pa ame e s we e cal-
cula ed by he s anda d me hod o noncompa men al
analysis using he WinNonlin p og am ( e sion 4.0;
Pha sigh Co po a ion, Moun ain View, Cali ): peak
plasma concen a ion (Cmax); ime o each Cmax ( max);
a ea unde he plasma concen a ion- ime cu e (AUC)
om ime 0 o he las quan i iable concen a ion
(AUC0- ), calcula ed by he linea apezoidal me hod;
AUC o e he dosing in e al (AUC0-24); AUC om ime
0 o in ini y (AUC0-∞), calcula ed om AUC0- +(C
las /λz),
whe e Clas is he las quan i iable concen a ion; appa -
en e minal a e cons an (λz) calcula ed by log-linea
eg ession o he e minal segmen o he plasma con-
cen a ion- ime p o ile; appa en e minal elimina ion
hal -li e ( 1/2), calcula ed om ln 2/λz; and obse ed
deg ee o accumula ion (R0) calcula ed om AUC0-∞
(day 12)/AUC0-∞(day 1).
Compa isons be ween age g oups we e pe o med
by 1-way analysis o a iance o he loga i hmic ans-
o med pa ame e s (Cmax, AUC0-24,andAUC
0-∞). Poin
es ima es and 95% con idence in e als (95% CIs)
we e calcula ed o he elde ly/young a io o hese
pha macokine ic pa ame e s o single and mul iple
dose. The s a is ical package SAS ( e sion 8.2; SAS
Ins i u e Inc, Ca y, NC) was used.
RESULTS
Subjec s
Twel e young subjec s (6 males and 6 emales; mean ±
SD age = 29.8 ±7.03 yea s, ange = 18-38 yea s; heigh
175 ±9 cm, ange = 158-188 cm; weigh 70.1 ±13.3 kg,
ange = 48-98 kg) and 12 elde ly subjec s (6 males and 6
emales; mean ±SD age = 69.9 ±5.38 yea s, ange = 65-
80 yea s; heigh 171 ±11 cm, ange = 149-187 cm;
weigh 76.8 ±13.1 kg, ange = 55-104 kg) comple ed he
s udy acco ding o he p o ocol and we e a ailable o
pha macokine ic analysis. All subjec s we e
Caucasian.
Pha macokine ic Resul s
Plasma concen a ions o pa en d ug (eslica bazepine
ace a e) we e sys ema ically ound o be below he
limi o quan i ica ion, and he e o e he concen a-
ion- ime p o iles and pha macokine ic pa ame e s
could no be de e mined. Figu e 1 displays he mean
eslica bazepine and R-lica bazepine concen a ion-
ime p o iles ollowing a 600-mg single dose (phase A),
mean p edose ( ough) alues du ing adminis a ion o
1064 •J Clin Pha macol 2005;45:1062-1066
ALMEIDA ET AL
A - Pos single-dose, phase A
012 24 36 48 60 72 84 96
0
2000
4000
6000
8000
10000
12000
14000
16000 Elde ly
Young
Eslica bazepine
R-lica bazepine
Time (h)
Plasma concen a ion
(ng/mL)
B - T ough concen a ions, phase B
5 6 7 8 9 10 11 12
0
2000
4000
6000
8000
10000
12000
14000
16000
Eslica bazepine
R-lica bazepine
Elde ly
Young
Time (days)
Plasma concen a ion
(ng/mL)
C - Pos las -dose, phase B
012 24 36 48 60 72 84 96
0
2000
4000
6000
8000
10000
12000
14000
16000 Eslica bazepine
R-lica bazepine
Elde ly
Young
Time (h)
Plasma concen a ion
(ng/mL)
Figu e 1. Mean eslica bazepine and R-lica bazepine plasma con-
cen a ion- ime p o iles ollowing adminis a ion o eslica bazepine
ace a e in heal hy young and elde ly subjec s. (a) Following a 600-mg
single dose (phase A); (b) ough (p edose) plasma concen a ions ol-
lowing a 600-mg once-daily dose o 8 days (phase B); (c) ollowing
he las dose o phase B (n = 12 in each age g oup).
© 2005 Ame ican College o Clinical Pha macology. All igh s ese ed. No o comme cial use o unau ho ized dis ibu ion.
a Uni e sidade Do Po o on Ap il 11, 2007 h p://www.jclinpha m.o gDownloaded om
600 mg once daily o 8 days (phase B), and mean con-
cen a ion- ime p o iles ollowing he las dose o
phase B.
The a i hme ic mean ±SD o he main
eslica bazepine pha macokine ic pa ame e s in he
young and elde ly g oups ollowing a 600-mg single
dose (phase A) and he las dose o phase B a e p e-
sen ed in Table I. Eslica bazepine was shown o be he
majo me aboli e, ep esen ing app oxima ely 97%
and 98% o o al sys emic exposu e (as assessed by
AUC0-24) ollowing a 600-mg single dose o
eslica bazepine in elde ly and young subjec s, espec-
i ely. Following mul iple adminis a ion, he s eady
s a e o eslica bazepine plasma concen a ions was a -
ained a 4 o 5 days o adminis a ion in bo h age
g oups, consis en wi h an e ec i e hal -li e in he o -
de o 17.8 hou s (young g oup) and 16.8 hou s (elde ly
g oup), calcula ed om he heo e ical deg ee o accu-
mula ion (RT), whe e λzis he key alue o i s de e mi-
na ion ( 1/2e . =ln2/λz) in acco dance wi h Boxenbaum
and Ba le.8In he young and elde ly g oups, an ob-
se ed accumula ion ac o (R0) o , espec i ely, 1.64
and 1.59 was es ima ed. Following mul iple adminis-
a ion o eslica bazepine ace a e o 8 days,
eslica bazepine wasshown o ep esen app oxima ely
95% and 96% o o al sys emic d ug exposu e in
elde ly and young subjec s, espec i ely.
In phase A, he geome ic means o Cmax, AUC0-24,
and AUC0-∞we e, espec i ely, 9743 ng/mL, 135 253
ng•h/mL, and 177 298 ng•h/mL in he young g oup
and 9232 ng/mL, 137313 ng•h/mL, and 187793 ng•h/
mL in he elde ly g oup. Following epea ed adminis-
a ion (phase B), he geome ic means o hose
pha macokine ic pa ame e s we e, espec i ely, 16990
ng/mL, 209997 ng•h/mL, and 289233 ng•h/mL in he
young g oup and 14942 ng/mL, 206628 ng•h/mL, and
291723ng•h/mLin he elde lyg oup.The co espond-
ing poin es ima es and 95% CIs we e calcula ed and
a e included in Table I. No s a is ically signi ican di -
e ence appea ed in any pha macokine ic pa ame e ,
ollowing single o epea ed adminis a ion o
eslica bazepine ace a e.
The di e ence in eslica bazepine max be ween he
elde ly and young g oups was –0.0417 hou s (95% CI,
–1.68, 1.60) ollowing a single dose and 0.000 hou s
(95% CI, –1.07, 1.07) ollowing epea ed adminis a-
ion. No s a is ical di e ences we e ound be ween age
g oups.
DISCUSSION AND CONCLUSIONS
The p ima y objec i e o he s udy was o in es iga e he
e ec o age on he pha macokine ics o eslica bazepine
ace a e in young (18-40 yea s) and elde ly (65 yea s o
olde ) subjec s. Eslica bazepine ace a e was shown o
be ex ensi ely me abolized o eslica bazepine (S-
lica bazepine) and, in a mino ex en , o R-
lica bazepine. Eslica bazepine ep esen ed be ween
95% and 98% o o al sys emic d ug exposu e (as as-
sessed by AUC0-24, ie, AUC o e he dosing in e al)
and he e o e is expec ed o be mainly esponsible o
pha macological ac i i y ollowing adminis a ion o
eslica bazepine ace a e. Wi h mul iple dosing, s eady-
s a e plasma concen a ions we e a ained a 4 o 5 days
o adminis a ion in bo h age g oups, consis en wi h
an e ec i e hal -li e on he o de o 17 o 18 hou s.
The kine ic p o ile o eslica bazepine was simila in
young and elde ly subjec s, and no s a is ical di e -
BRIEF REPORTS/PHARMACOKINETICS 1065
PHARMACOKINETICS OF ESLICARBAZEPINE ACETATE
Table I A i hme ic Mean ±SD Eslica bazepine Pha macokine ic Pa ame e s and Poin Es ima es (95% CI) o
he Elde ly/Young Ra ios o he Geome ic Means o Cmax,AUC
0-24,andAUC
0-∞
Following Single- and Mul iple-Dose Adminis a ion o 600 mg
Eslica bazepine Ace a e in Young and Elde ly Subjec s (n = 12 in Each Age G oup)
Single Dose Mul iple Dose
Young Elde ly Poin Young Elde ly Poin
Pa ame e G oup G oup Es ima e (95% CI) G oup G oup Es ima e (95% CI)
Cmax, ng/mL 9867 ±1714 9469 ±2284 0.95 (0.81, 1.14) 17309 ±3430 15067 ±2126 0.88 (0.77, 1.03)
max,h 3.0±1.8 3.0 ±1.3 — 2.0 ±1.6 2.0 ±0.9 —
AUC0- , ng•h/mL 174713 ±37062 190521 ±69082 — 290630 ±68649 288364 ±40878 —
AUC0-24, ng•h/mL 137354 ±24742 141245 ±38438 1.02 (0.86, 1.24) 213815 ±41889 208432 ±28561 0.98 (0.90, 1.09)
AUC0-∞, ng•h/mL 180899 ±37624 196030 ±69152 1.06 (0.88, 1.32) 296702 ±67577 294290 ±40356 1.01 (0.89, 1.18)
1/2, h 10.1 ±1.0 10.9 ±0.9 — 10.5 ±1.4 11.1 ±1.6
R0———1.64±0.21 1.59 ±0.32 —
© 2005 Ame ican College o Clinical Pha macology. All igh s ese ed. No o comme cial use o unau ho ized dis ibu ion.
a Uni e sidade Do Po o on Ap il 11, 2007 h p://www.jclinpha m.o gDownloaded om

ences we e ound o any o he pha macokine ic pa-
ame e s assessed (Cmax,
max,AUC
0-24, and AUC0-∞) ol
-
lowing bo h single and epea ed adminis a ion o
eslica bazepine ace a e. In his ega d, he
pha macokine ic beha io o eslica bazepine ace a e is
di e en om ha o oxca bazepine, in which an age-
ela ed di e ence in sys emic exposu e was epo ed.9
Oxca bazepine is apidly and ex ensi ely me abolized
o a mix u e o he S- and R-lica bazepine,10 bo h ap-
pea ing in plasma and u ine in he p opo ion o ap-
p oxima ely 4:1.11-13 Subs an ial di e ences in he dis-
posi ion o oxca bazepine be ween young and elde ly
olun ee s we e ound bo h o Cmax and AUC pa ame-
e s. Cmax and AUC o he mix u e o he S- and R-
lica bazepine, he ac i e me aboli e o oxca bazepine
(also know as MHD), we e 30% o 60% highe in el-
de ly subjec s (60-82 yea s o age) han in younge sub-
jec s (18-32 yea s o age). Di e ences we e judged o be
p esumably due o age- ela ed educ ions in c ea inine
clea ance and slowe plasma elimina ion o MHD.14 I
emains o be de e mined whe he R-lica bazepine has
a majo ole in he nega i e impac o oxca bazepine
pha macokine ic p o ile in elde ly subjec s.
In conclusion, he pha macokine ics o
eslica bazepine ace a e was essen ially simila in
young and elde ly subjec s.
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