Single-dose and steady-state pharmacokinetics of eslicarbazepine acetate (BIA 2-093) in healthy elderly and young subjects

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 h p://www.jclinpha m.o g The online e sion o his a icle can be ound a : Published by: h p://www.sagepublica ions.com On behal o : Ame ican College o Clinical Pha macology can be ound a :The Jou nal o Clinical Pha macology Addi ional se ices and in o ma ion o h p://www.jclinpha m.o g/cgi/ale s Email Ale s: h p://www.jclinpha m.o g/subsc ip ions Subsc ip ions: h p://www.sagepub.com/jou nalsRep in s.na Rep in s: h p://www.sagepub.com/jou nalsPe missions.na Pe missions: © 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 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. REFERENCES 1. Benes J, Pa ada A, Figuei edo AA, e al. An icon ulsan and so- dium channel-blocking p ope ies o no el 10,11- dihyd o-5H- dibenz[b, ]azepine-5-ca boxamide de i a i es. J Med Chem. 1999;42:2582-2587. 2. Boni acio MJ, She idan RD, Pa ada A, Cunha RA, Pa mo e L, Soa es-da-Sil a P. In e ac ion o he no el an icon ulsan , BIA 2-093, wi h ol age-ga ed sodium channels: compa ison wi h ca bamazepine. Epilepsia. 2001;42:600-608. 3. Sil ei a P, Falcão A, Almeida L, Maia J, Soa es-da-Sil a P. BIA 2- 093 pha macokine ics in heal hy elde ly subjec s. Epilepsia. 2004;45(suppl 3):157. 4. Almeida L, Soa es-da-Sil a P. Sa e y, ole abili y and pha ma- cokine ic p o ile o BIA 2-093, a no el pu a i e an iepilep ic agen , du ing i s adminis a ion o humans. D ugs R D. 2003;4:269-284. 5. Almeida L, Soa es-da-Sil a P. Sa e y, ole abili y, and pha macokine ic p o ile o BIA 2-093, a no el pu a i e an iepilep ic, in a ising mul iple-dose s udy in young heal hy humans. J Clin Pha macol. 2004;44:906-918. 6. Maia J, Almeida L, Soa es-da-Sil a P. BIA 2-093 as add-on he apy o e ac o y pa ial epilepsy in adul s. Epilepsia. 2004;45(suppl 3):158. 7. Vaz-da-Sil a M, Almeida L, Falcão A, Maia J, Sil ei a P, Soa es-da- Sil a P. In luence o ood on he pha macokine ics o he an iepilep ic agen BIA 2-093. Epilepsia. 2004;45(suppl 3):157. 8. Boxenbaum H, Ba le M. E ec i e hal -li e in clinical pha macol- ogy. J Clin Pha macol. 1995;35:763-766. 9. Van Heiningen PNM, E e MD, Oos e huis B, e al. The in luence o age on he pha macokine ics o he an iepilep ic agen oxca bazepine. Clin Pha macol The . 1991;50:410-419. 10. Faigle JW, Menge GP. Me abolic cha ac e is ics o oxca bazepine and hei clinical signi icance: compa ison wi h ca bamazepine. Beha Neu ol. 1990;3(suppl 1):21-30. 11. Schu z H, Feldmann KF, Faigle JW, K iemle HP, Winkle T. The me abolism o 14C-oxca bazepine in man. Xenobio ica. 1986;16:769- 778. 12. Flesch G, F anco e E, Hell F, Degen PH. De e mina ion o he R-(-) and S-(+) enan iome s o he monohyd oxyla ed me aboli e o oxca bazepine in human plasma by enan ioselec i e high-pe o - mance liquid ch oma og aphy. J Ch oma og . 1992;581:147-151. 13. Voloso A, Xiaodong S, Pe ucca E, Yagen B, Sin o A, Biale M. Enan ioselec i e pha macokine ics o 10-hyd oxyca bazepine a e o al adminis a ion o oxca bazepine o heal hy Chinese subjec s. Clin Pha macol The . 1999;66:547-553. 14. Lloyd P, Flesch G, Die e le W. Clinical pha macology and pha macokine ics o oxca bazepine. Epilepsia. 1994;35(suppl 3):S10-S13. 1066 •J Clin Pha macol 2005;45:1062-1066 ALMEIDA ET AL © 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