Copyright 2010 Informa UK Limited Not for Sale or Commercial Distribution

Transcription

1 Current Medical Research & Opinion Vol. 26, No. 6, 2, Article 5168a/47468 doi:.1185/ All rights reserved: reproduction in whole or part not permitted Original article Pharmacokinetic interaction study between eslicarbazepine acetate and topiramate in healthy subjects Teresa Nunes Department of Research and Development, BIAL (Portela & Ca SA), S. Mamede do Coronado, Portugal Eric Sicard Algorithme-Pharma Inc., Montréal, Québec, Canada Luis Almeida Department of Research and Development, BIAL (Portela & Ca SA), S. Mamede do Coronado, Portugal Health Sciences Section, University of Aveiro, Portugal, Portugal Amílcar Falcão 4Health Consulting, Cantanhede, Portugal José-Francisco Rocha Department of Research and Development, BIAL (Portela & Ca SA), S. Mamede do Coronado, Portugal Jean-Sebastien Brunet Pharsight Corporation, Montréal, Québec, Canada Marc Lefebvre Algorithme-Pharma Inc., Montréal, Québec, Canada Patricio Soares-da-Silva Department of Research and Development, BIAL (Portela & Ca SA), S. Mamede do Coronado, Portugal Institute of Pharmacology and Therapeutics, Faculty of Medicine of the University of Porto, Porto, Portugal Address for correspondence: Professor P. Soares-da-Silva, Department of Research and Development, BIAL, À Av. da Siderurgia Nacional, S. Mamede do Coronado, Portugal. Tel.: þ ; Fax: þ ; Key words: Drug interaction Eslicarbazepine Eslicarbazepine acetate Healthy subjects Pharmacokinetics Topiramate Accepted: 2 March 2; published online: 8 April 2 Citation: Curr Med Res Opin 2; 26: Abstract Objective: Combination therapy is frequently required in the management of epilepsy. The primary objective of this study was to investigate the pharmacokinetic interaction between eslicarbazepine acetate (ESL) 12 mg once daily and topiramate (TPM) 2 mg once daily in healthy subjects. Methods: Multiple-dose, open-label, one-sequence study in two parallel groups of 16 healthy male volunteers. After an 8-day treatment with ESL (Group A) or TPM (Group B), ESL and TPM were co-administered for 19 days. A bioequivalence approach based on a within-subject comparison was used to investigate a potential drug drug interaction. End/start of treatment geometric mean ratios (GMR, %) and 9% confidence intervals (9% CI) were calculated for maximum plasma concentration (C max ) and area under the plasma concentration time curve over the dosing interval at steady-state (AUC ss ) of eslicarbazepine (ESL major active metabolite), R-licarbazepine (ESL minor active metabolite) and TPM at Day 8 and Day 27. Results: In Group A, eslicarbazepine GMR (9% CI) was 86.79% (81.6%; 92.94%) for C max and 92.7% (89.21%; 96.32%) for AUC ss. In Group B, TPM GMR (9% CI) was 81.5% (77.48%; 85.89%) for C max and 81.81% (79.69%; 84.%) for AUC ss. The 9% CI of eslicarbazepine C max and AUC ss fell within the pre-specified bioequivalence range (8.%; 125.%), allowing it to be concluded that the extent of systemic exposure to eslicarbazepine was unaffected by the concomitant administration of TPM. The 9% CI for topiramate AUC ss was borderline in relation to the pre-specified bioequivalence range and topiramate C max fell outside the pre-specified bioequivalence range. Therefore, the extent of systemic exposure to TPM following Copyright 2 Informa UK Limited Not for Sale or Commercial Distribution co-administration with ESL was not formally bioequivalent to the extent of systemic exposure to TPM when TPM was administered alone. However, there was no difference between TPM elimination half-life following TPM co-administered with ESL and TPM administered alone (24. and 24.3 h, respectively). The bioavailability of R-licarbazepine was essentially bioequivalent. Two subjects discontinued due to adverse events. No clinical interaction appeared to be present in terms of adverse events when both drugs were given concomitantly. Unauthorized use prohibited. Authorised users can download, display, view and print a single copy for personal use Conclusion: Concomitant administration of eslicarbazepine acetate 12 mg once daily and topiramate 2 mg once daily showed no significant change in exposure to eslicarbazepine but an 18% decrease in exposure to topiramate, most likely caused by a reduced bioavailability of topiramate. No dose adjustment is required. Introduction Epilepsy is a common chronic neurological disorder that often requires long-term use of antiepileptic drugs (AEDs). Although a high percentage of! 2 Informa UK Ltd Interaction between eslicarbazepine acetate and topiramate Nunes et al. 1355

2 patients are stable under monotherapy, there is still a need for combinations of AEDs in approximately 3% of patients who cannot effectively control their seizures without the use of more than one AED 1. Eslicarbazepine acetate (ESL) is a novel voltage-gated sodium channel blocker that completed Phase III studies in adult patients with uncontrolled partial epilepsy despite treatment with one to three AEDs and was shown to be effective and generally well tolerated 2 5. ESL presents a dibenzazepine nucleus as seen in carbamazepine and oxcarbazepine, but is structurally different at the,11- position 6 8 ; this modification results in differences in metabolism that appear to decrease the potential for drug interactions 9. Following oral administration, ESL is rapidly absorbed and extensively hydrolysed during first pass to eslicarbazepine, the drug moiety responsible for the pharmacological activity in humans 9. Plasma concentrations of parent drug usually remain below the lower limit of quantification (LLOQ). Steady-state eslicarbazepine plasma concentrations are attained after 4 or 5 days of once-daily dosing, which is consistent with an effective half-life of 2 24 h. Renal excretion represents the main elimination route of ESL metabolites 11,12. More than 9% of an ESL oral dose is recovered in urine; eslicarbazepine represents approximately 92% of total drug material excreted in urine, whether in its unchanged form (2/3) or conjugated with glucuronic acid (1/3). Minor metabolites are R-licarbazepine and oxcarbazepine, and their glucuronyl conjugates 11. Topiramate (TPM) is a frequently used AED. TPM is rapidly and well absorbed with a bioavailability above 8% 13. Food slightly reduces the rate of absorption (% decrease in C max and 2 h increase in t max ), but not the extent of absorption 14. TPM is excreted primarily in urine in the form of parent compound (8%). Six metabolites have been identified and are formed via hydroxylation, hydrolysis, and glucuronidation 15. None of these metabolites constitutes more than 5% of an administered dose. Although less than 2% of the total drug excreted is presented in the form of metabolites 13, the TPM metabolism may be induced in patients receiving concomitant antiepileptic therapy with known inducers of drug metabolising enzymes, such as carbamazepine or phenytoin 16. In clinical studies, TPM was shown to cause a dosedependent increase in the clearance of ethinylestradiol which is likely to be due to an induction of CYP3A4 17. TPM titration should begin at 25 mg and the dose be gradually escalated over a few weeks. The average daily dose is less than 2 mg/day 13. The recommended target dose for TPM in adults ranges from mg to a maximum of 5 mg/day 11. Since TPM and ESL are likely to be co-administered as therapies of partial-onset seizures, the potential for a drug interaction needs to be evaluated. This study aimed primarily to evaluate the potential of a pharmacokinetic interaction between ESL and TPM at steady state and secondarily to assess the safety and tolerability of ESL and TPM when used in combination in healthy subjects. Material and methods Study design The study was an open-label, parallel-group, multiple-dose pharmacokinetic drug interaction study in healthy subjects, performed by the clinical research unit of Algorithme Pharma Inc. (Montreal, Québec, Canada). An institutional review board (ETHIPRO, Comité d Étique de la Recherche Indépendant, Montreal, Quebec, Canada) reviewed and approved the protocol before study start and all participants gave written informed consent prior participation. The study was performed in accordance with the Good Clinical Practice recommendations issued by the International Conference on Harmonisation, the ethical principles of the Declaration of Helsinki and all the applicable laws. Healthy male subjects were eligible for enrolment in the study based on the following inclusion criteria: between 18 and 45 years of age (inclusive); non-smokers; body mass index (BMI) between 19 and 3 kg/m 2 ; judged to be in good health as determined by a medical history, physical examination (including vital signs), electrocardiogram (12-lead ECG), neurological function tests and a battery of clinical laboratory tests (haematology, biochemistry, urinalysis and coagulation); negative tests for HIV and hepatitis B and C viruses; and negative screening of ethanol and drugs of abuse in urine. Exclusion criteria included a history of hypersensitivity to TPM, ESL or chemically related products; history of severe hypersensitivity reaction; presence of significant gastrointestinal, liver or kidney disease or surgery, or any other conditions known to interfere with the drug bioavailability or known to potentiate or predispose to undesired effects; any clinically significant illness in the previous 28 days before Day 1 of the study; use of any enzyme-modifying drugs, including strong inhibitors or inducers of cytochrome P45 (CYP) enzymes, in the previous 28 days before Day 1 of the study; participation in another clinical trial or donation of 5 ml or more of blood in the previous 28 days before Day 1 of the study; or blood donation of 45 ml in the previous 56 days before Day 1 of the study. Volunteers were divided into two groups (A and B) of 16 subjects each. Group A assessed the effect of TPM on ESL pharmacokinetics and Group B assessed the effect of ESL on TPM pharmacokinetics. In each group, subjects were administered with the investigational products as follows (Figure 1): Group A: ESL: Days 1 and 2: 6 mg once daily; Days 3 to 27: 12 mg once daily. TPM: Days 9 and : mg once 1356 Interaction between eslicarbazepine acetate and topiramate Nunes et al. 2 Informa UK Ltd

3 Group A Days Group B Eslicarbazepine acetate (2-day titration dose: 6 mg once-daily; full dose: 12 mg once-daily) Topiramate (2-day mg once-daily followed by 2-day mg BID, followed by 2 mg once-daily) 24-h pharmacokinetic profiling (Group A = Eslicarbazepine; Group B = Topiramate) Figure 1. Study design. Group A: effect of topiramate on the eslicarbazepine acetate pharmacokinetics. Group B: effect of eslicarbazepine acetate on the topiramate pharmacokinetics. daily; Days 11 and 12: mg twice daily; Days 13 to 27: 2 mg once daily. Group B: TPM: Days 1 and 2: mg once daily; Days 3 and 4: mg twice daily; Days 5 to 27: 2 mg once daily. ESL: Days 9 and : 6 mg once daily; Days 11 to 27: 12 mg once daily. For each group, a titration period was performed in order to improve tolerability. A TPM 2 mg dose was chosen in order to maximize the possibility of elucidating a drug interaction with ESL; an ESL 12 mg once-daily dose was chosen because it is the upper dose of the therapeutic dose range of ESL as adjunctive therapy in partial epilepsy 2 5. Subjects were admitted to the clinical research unit at least hours prior to first dose of investigational product (Day ) and were discharged about 24 hours following the last dose (Day 28). The volunteers returned to the clinical site for a follow-up visit 16 days after the last dose. The duration of the clinical part of this study was 44 days. From Days 1 to 27, drug morning dose was administered prior to breakfast except on Days 8 and 27 when no breakfast was served and a meal was provided no less than 4 hours after drug administration. TPM evening dose was given before supper. Each dose was administered with 24 ml of water. Water was not permitted from 2 hours before dosing to 2 hours after dosing, on Days 8 and 27. Water was permitted ad libitum at all other times during their stay. ESL consisted of 6 mg tablets, manufactured by BIAL - Portela & Co, SA, S. Mamede do Coronado, Portugal. TPM consisted of Topamax Õ mg and 2 mg tablets from a commercial batch, manufactured and marketed by Janssen-Ortho Inc., Canada. Blood sampling and plasma drug assays In Group A, venous blood samples of 6 ml were drawn by venepuncture into Vacutainers Õ containing heparinlithium for determination of plasma concentrations of ESL ( parent drug), eslicarbazepine (the major active metabolite) and R-licarbazepine (a minor active metabolite). Samples were collected on Day 1 prior to the first ESL dose, and at the following time-points on Days 8 and 27: within 5 minutes prior to dosing, and.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 9, 12, 16 and 24 hours after drug administration. After blood collection, samples were centrifuged at 4 C and 15 g for minutes. The plasma obtained was separated into polypropylene culture tubes, frozen and stored at 2 C, until analysis. Samples were assayed using a validated liquid chromatography with tandem mass spectrometry detection (LC-MS/MS) method with a LLOQ of 5 ng/ml. In Group B, venous blood samples of 7 ml were drawn by venepuncture into Vacutainers Õ containing K 3 EDTA for determination of plasma concentrations of TPM (parent drug). Samples were collected on Day 1 prior to the first TPM, and at the following time-points on Days 8 and 27: within 5 minutes prior to dosing, and.25,.5,.75, 1, 1.33, 1.67, 2, 2.5, 3, 4, 6, 9, 12, 16 and 24 hours after drug administration. After blood collection, samples were centrifuged at 4 C and 15 g for minutes. The plasma obtained was separated into polypropylene culture tubes, frozen and stored at 2 C. Samples were assayed using a validated a validated high-performance liquid chromatography (HPLC) method with mass spectrometry detection (MSD), with a LLOQ of ng/ml. Pharmacokinetic and statistical evaluation The following pharmacokinetic parameters were derived by non-compartmental analysis from the individual drug plasma concentration time profiles: minimum observed plasma concentration (C min ), maximum observed plasma concentration (C max ), time to C max (t max ), area under the plasma concentration time curve over the 24-h dosing interval at steady state (AUC ss ), apparent total body clearance (CL/F), apparent volume of distribution (V/F), apparent elimination rate constant (K el ), elimination half-life (t ½ ) calculated as ln2/k el, and fluctuation (%) defined as the range of steady-state concentrations divided! 2 Informa UK Ltd Interaction between eslicarbazepine acetate and topiramate Nunes et al. 1357

4 by the average concentration. The natural logarithmic transformation of the parameters C max and AUC ss were used for all statistical inference. The trapezoidal rule was used to estimate the AUC ss and the terminal phase was estimated by maximizing the coefficient of determination; however, they were not estimated for individual concentration time profiles where the terminal log-linear phase could not be reliably characterized. Pharmacokinetic parameters were statistically analysed using a random analysis of variance (ANOVA) model for a one-sequence parallel design. The fixed factors included in this model were to be the day of assessment (Day 8 or Day 27). The random factor included in the model consisted of the subject effect. Two-sided 9% confidence interval (9% CI) for the geometric mean ratio (GMR) between Day 27 and Day 8 were calculated by exponentiation of the Day 27 to Day 8 difference in least square means for the ln-transformed C max and AUC ss parameters. The entire statistical analysis was stratified within each of the two groups and based on a within-subject comparison: assessment of the effect of TPM on ESL pharmacokinetics at steady-state (Group A) and assessment of the effect of ESL on TPM pharmacokinetics at steady-state (Group B). A lack of a drug interaction between ESL and TPM was based on a bioequivalence assessment within each of the two groups: bioequivalence was assumed when the 9% CI for Day 27/Day 8 GMR of C max and AUC ss were between the acceptance interval %. The statistical and pharmacokinetic analyses were generated using Kinetic, version 8. (application developed at Algorithme Pharma) and the mixed procedure of SAS version 9.1 (SAS Institute, Cary, NC). Safety and tolerability assessments Subjects were hospitalised and remained under continuous supervision throughout the study. Safety and tolerability assessments included physical examination, clinical laboratory parameters (blood chemistry, haematology and urinalysis), ECG, measurements of vital signs, neurological function tests and neurological signs. Blood pressure and pulse rate were measured before and 5 hours after each morning dose. Neurological signs were assessed approximately 5.5 hours after the morning dose on Days 3, 9, 11, 13, 15, 17, 19, 21, 23 and 25. ECG and clinical laboratory safety tests were performed at pre-study, study completion and post-study follow-up visit. All adverse events spontaneously reported by the subjects, observed by the clinical team, or elicited by general questioning were documented and reported regardless of suspected relation to the study medications. The safety analyses included data from all subjects. Results Population A total of 32 healthy subjects were included in the study. The mean SD (range) demographic data were as follows: age 34 8 years (range: 19 45), weight kg (range: ), height cm (range: ), and BMI 25 2 kg/m 2 (range: 2 29). Twentynine subjects were White, one was Asian and two were Black/African American. Five subjects did not complete the study. Three subjects (two in Group A and one in group B) withdrew their consent for personal reasons. Two subjects (one in Group A and one in group B) were withdrawn by the investigator due to adverse events. Thus, 27 subjects (13 in Group A and 14 in Group B) completed the study according to the protocol and were available for pharmacokinetic analysis. Pharmacokinetic results The mean plasma concentration time profiles of eslicarbazepine and TPM are displayed in Figure 2 and the mean pharmacokinetic parameters are presented in Table 1. Individual main pharmacokinetic parameters (C max and AUC ss ) are displayed in Figure 3. As the plasma concentrations of parent drug (ESL) were below the LLOQ, the concentration time profiles of the parent drug could not be displayed, nor the pharmacokinetic parameters calculated. Effect of topiramate on the eslicarbazepine pharmacokinetics The GMR and corresponding 9% CI for eslicarbazepine C max, AUC ss following co-administration of ESL and TPM in relation to ESL administered alone are displayed in Table 2. The bioavailability of eslicarbazepine following ESL co-administered with TPM was essentially bioequivalent to bioavailability of eslicarbazepine following ESL administered alone as the 9% CI for the pharmacokinetic parameters under consideration were within the pre-specified equivalence interval (8.% 125.%). The intra-subject coefficient of variation for eslicarbazepine, which reflects the residual variability observed in the pharmacokinetic parameters after accounting for possible between-formulation differences as well as inter-subject variation, was 9.8% and 5.5% for C max and AUC ss, respectively. The pharmacokinetics of a minor metabolite of ESL, R-licarbazepine, was also evaluated. The 9% CI for both parameters of interest (C max and AUC ss ) also fell within the pre-specified bioequivalence acceptable range (8.%; 125.%) and, therefore, it was concluded 1358 Interaction between eslicarbazepine acetate and topiramate Nunes et al. 2 Informa UK Ltd

5 (a) Eslicarbazepine 3 ESL ESL + Topiramate Plasma concentration (mg/ml) Time post-dose (h) (b) Plasma concentration (mg/ml) 1 Eslicarbazepine ESL ESL + Topiramate Time post-dose (h) (a) Plasma concentration (mg/ml) 5 Topiramate 15 Topiramate Topiramate + ESL Time post-dose (h) (b) Plasma concentration (mg/ml) 1 Topiramate Topiramate Topiramate + ESL Time post-dose (h) Figure 2. Mean SD plasma concentration versus time profiles of eslicarbazepine (Group A, n ¼ 13) and topiramate (Group B, n ¼ 14). The profiles compare the results on Day 8 (test product administered alone) to those on Day 27 (products administered concomitantly) for each group. (a) linear scale; (b) semi-log scale. Table 1. Mean (coefficient of variation, %) pharmacokinetic parameters of eslicarbazepine following concomitant administration of ESL 12 mg once daily þ TPM 2 mg once daily and ESL 12 mg alone (Group A), and of TPM following concomitant administration of TPM 2 mg once daily þ ESL 12 mg once daily and TPM 2 mg once-daily alone (Group B). Parameter Eslicarbazepine Topiramate ESL þ TPM ESL Alone TPM þ ESL TPM Alone C min (lg/ml) 9.2 (15.5%).1 (13.7%) 3.5 (13.8%) 4.4 (8.3%) C max (lg/ml) 22. (11.3%) 25.4 (14.7%) 7.7 (11.%) 9.5 (12.6%) t max (h) 2. (1. 4.) 2. (1. 6.) 1. (.5 2.).9 (.5 2.5) AUC ss (mg h/ml) (.7%) (9.2%) 121. (.5%) (9.%) CL/F (L/h) 3.4 (.2%) 3.1 (9.7%) 1.7 (11.2%) 1.4 (9.3%) V/F (L) 85.9 (16.8%) 89.4 (17.7%) 57.6 (.2%) 47.9 (15.%) t ½ (h) 17.8 (15.8%) 2.18 (21.2%) 24.4 (.%) (.1%) Fluctuation (%) 85.3 (13.6%) 94.1 (14.4%) 83.9 (.6%) 82.2 (23.9%) t max values are median with range in parenthesis. C min : minimum plasma concentration; C max : maximum plasma concentration; t max : time to C max ; AUC ss : area under the plasma concentration time curve over the dosing interval at steady state; CL/F: apparent total body clearance; V/F: apparent volume of distribution; t ½ : elimination half-life; fluctuation: the range of steady-state concentrations (%) divided by the average concentration.! 2 Informa UK Ltd Interaction between eslicarbazepine acetate and topiramate Nunes et al. 1359

6 Eslicarbazepine individual pharmacokinetic parameters (Group A) 5 7 Eslicarbazepine C max (mg/ml) Topiramate C max (mg/ml) ESL alone Topiramate alone ESL + Topiramate Topiramate + ESL Eslicarbazepine AUCss (mg.h/ml) Topiramate AUCss (mg.h/ml) ESL alone Topiramate individual pharmacokinetic parameters (Group B) Topiramate alone ESL + Topiramate Topiramate + ESL Figure 3. Individual C max and AUC ss of eslicarbazepine (Group A, n ¼ 13) and topiramate (Group B, n ¼ 14) on Day 8 (test product administered alone) and on Day 27 (products administered concomitantly). Table 2. Geometric means of the pharmacokinetic parameters of interest (C max and AUC ss ) for eslicarbazepine and topiramate on Day 8 (test product administered alone, Reference) and on Day 27 (products administered concomitantly, Test) and their statistical comparison (n ¼ 13 in group A and 14 in group B). Parameter Eslicarbazepine Test/Reference ESL þ TPM (Test) ESL Alone (Reference) GMR and 9% CI C max, lg/ml (81.6; 92.94) AUC ss, lg.h/ml (89.21; 96.32) Topiramate TPM þ ESL (Test) TPM Alone (Reference) C max, lg/ml (77.48; 85.89) AUC ss, lg.h/ml (79.69; 84.) 136 Interaction between eslicarbazepine acetate and topiramate Nunes et al. 2 Informa UK Ltd

7 that the bioavailability of R-licarbazepine was unaffected by TPM. Effect of eslicarbazepine acetate on the topiramate pharmacokinetics The 9% CI for TPM AUC ss was borderline in relation to the pre-specified bioequivalence range and TPM C max fell outside the pre-specified bioequivalence range (8.%; 125.%). Therefore, the bioavailability of TPM following TPM co-administered with ESL was not formally bioequivalent to bioavailability of TPM following TPM administered alone. The intra-subject coefficient of variation was 7.7% and 3.9% for C max and AUC ss, respectively. Tolerability/safety All subjects enrolled in the study experienced at least one adverse event (AE). Two subjects (one in Group A and one in group B) discontinued due to adverse events: hypersensitivity reaction that appeared after days of treatment with ESL and 2 days with TPM; mood impairment that occurred after days of treatment with TPM and 2 days with ESL. No drug-related clinically relevant abnormalities or trends were reported in the safety tests performed during the study. No serious adverse events were recorded in this study. Discussion The primary objective of this study was to evaluate the effect of ESL on the pharmacokinetics of TPM and the effect of TPM on the pharmacokinetics of ESL. The results showed that the extent of exposure to eslicarbazepine, the entity responsible for the pharmacological action of ESL in humans, was unaffected by the concomitant use of TPM since the 9% CI of eslicarbazepine C max and AUC ss were within the pre-specified bioequivalence range (8.%; 125.%). In relation to the effect of ESL on TPM pharmacokinetics, the 9% CI for TPM AUC ss was borderline in relation to the pre-specified bioequivalence range and TPM C max fell outside the pre-specified bioequivalence range. Therefore, the bioavailability of TPM in the presence of ESL was not formally bioequivalent to TPM administered alone. A likely explanation for the slight decrease in TPM systemic exposure is a decrease in bioavailability caused by an interaction at the absorption level, which is supported by the fact that the effect of ESL on TPM C max was more pronounced than that found on AUC ss, and by the fact that there was no difference between TPM elimination half-life when TPM was administered concomitantly with ESL or alone (24. and 24.3 h, respectively). A similar effect of ESL on the digoxin pharmacokinetics (significant decrease in digoxin C max without significantly decreasing digoxin AUC ss ) was found 18. Intra-subject CV of eslicarbazepine and TPM were low (5%) for both main pharmacokinetic parameters (C max and AUC ss ) which suggests that the entire study was adequately powered statistically. No clinical interaction appeared to be present in terms of AEs when TPM and ESL were co-administered. Conclusion In conclusion, this study showed that concomitant administration of ESL and TPM has no relevant effect on the systemic exposure to ESL metabolites and that the effect of ESL on TPM is small and possibly not clinically relevant. Therefore, dosage adjustment of ESL or TPM is expected to be unnecessary when the two drugs are co-administered. Transparency Declaration of funding This trial was sponsored by BIAL (Portela & Co, S.A., S. Mamede do Coronado, Portugal). The authors from BIAL substantially contributed to the design and conception of the study and wrote the first and final versions of the manuscript, but played no role in data collection or pharmacokinetic analysis. All authors had full access to the data and substantially contributed to the interpretation of the data and the writing of the manuscript. Declaration of financial/other relationships T.N., L.A., J.R. and P.S. are or were employees of BIAL (the sponsor of the study) at the time of the study. The other authors are or were employees of contract research organizations contracted by the sponsor to conduct the clinical part and reporting of the study (Algorithme Pharma) or to review the pharmacokinetic data (4Health). Peer reviewers may receive honoraria for their review work for CMRO. The peer reviewers have disclosed no relevant financial relationships. Acknowledgements The authors thank the healthy subjects who participated in the study and the clinical and laboratory staff of Algorithme Pharma. References 1. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2;342: Ben-Menachem E, Gabbai A, Hufnagel A, et al. Efficacy and safety of eslicarbazepine acetate (ESL) as add-on treatment in adults with refractory partialonset seizures: BIA study. Epilepsia 28;49(Suppl. 7): Elger C, Bialer M, Cramer JA, et al. Eslicarbazepine acetate: a double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures. Epilepsia 27;48:497-54! 2 Informa UK Ltd Interaction between eslicarbazepine acetate and topiramate Nunes et al. 1361

8 4. Elger C, Halasz P, Maia J, et al. Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase III study. Epilepsia 29;5: Gil-Nagel A, Lopes-Lima J, Almeida L, et al. Efficacy and safety of 8 and 12 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures. Acta Neurol Scand 29;12: Ambrosio AF, Soares-Da-Silva P, Carvalho CM, et al. Mechanisms of action of carbamazepine and its derivatives, oxcarbazepine, BIA 2-93, and BIA Neurochem Res 22;27: Benes J, Parada A, Figueiredo AA, et al. Anticonvulsant and sodium channel-blocking properties of novel,11- dihydro-5h-dibenz[b,f]azepine- 5-carboxamide derivatives. J Med Chem 1999;42: Benés J, Soares-da-Silva P. Substituted dihydrodibenzo/b,f/azepine, method of their preparation, their use in the treatment of some central nervous system disorders, and pharmaceutical compositions containing them. USPTO Patent No. 5,753,646, May 19, Almeida L, Bialer M, Soares-da-Silva P. Eslicarbazepine acetate. In: Shorvon S, Perucca E, Engel J (eds). The Treatment of Epilepsy, 3rd Edn. Oxford: Blackwell Publishing, 29: Almeida L, Falcão A, Maia J, et al. Single-dose and steady-state pharmacokinetics of eslicarbazepine acetate (BIA 2-93) in healthy elderly and young subjects. J Clin Pharmacol 25;45: Almeida L, Potgieter JH, Maia J, et al. Pharmacokinetics of eslicarbazepine acetate in patients with moderate hepatic impairment. Eur J Clin Pharmacol 28;64: Maia J, Almeida L, Falcão A, et al. Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate. Int J Clin Pharmacol Ther 28; 46: Shank RP, Maryanoff BE. Molecular pharmacodynamics, clinical therapeutics, and pharmacokinetics of topiramate. CNS Neurosci Ther 28; 14: Doose DR, Walker SA, Gisclon LG, et al. Single-dose pharmacokinetics and effect of food on the bioavailability of topiramate, a novel antiepileptic drug. J Clin Pharmacol 1996;36: Caldwell GW, Wu WN, Masucci JA, et al. Metabolism and excretion of the antiepileptic/antimigraine drug, topiramate in animals and humans. Eur J Drug Metab Pharmacokinet 25;3: Bourgeois BF. Drug interaction profile of topiramate. Epilepsia 1996; 37(Suppl. 2):S Nallani SC, Glauser TA, Hariparsad N, et al. Dose-dependent induction of cytochrome P45 (CYP) 3A4 and activation of pregnane X receptor by topiramate. Epilepsia 23;44: Vaz da Silva M, Costa R, Soares E, et al. Effect of eslicarbazepine acetate on the pharmacokinetics of digoxin in healthy subjects. Fundam Clin Pharmacol 29;23: Interaction between eslicarbazepine acetate and topiramate Nunes et al. 2 Informa UK Ltd