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PEDIATRICS |
From the Department of Research and Development, BIAL (Portela & Co, SA), S Mamede do Coronado, Portugal (Dr Almeida, Dr Nunes, Dr Soares-da-Silva); 4Health Limited, Cantanhede, Portugal (Dr Falcão); and Pediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania (Dr Minciu, Dr Butoianu, Dr Magureanu).
Address for reprints: Professor Patricio Soares-da-Silva, Department of Research and Development, BIAL, À Av. da Siderurgia Nacional, 4745-457 S. Mamede do Coronado, Portugal; e-mail: psoares.silva{at}bial.com.
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ABSTRACT |
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 TOP ABSTRACT MATERIAL AND METHODSRESULTSDISCUSSION AND CONCLUSIONREFERENCES |
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Key Words: Eslicarbazepine acetate • children • adolescents • epilepsy • pharmacokinetics
Eslicarbazepine acetate (ESL, formerly known as BIA 2-093) is a novel AED that shares with carbamazepine and oxcarbazepine the dibenzazepine nucleus bearing the 5-carboxamide substitute but is structurally different at the 10,11-position.2 This molecular variation results in differences in metabolism.3 Unlike carbamazepine, ESL is not metabolized to carbamazepine-10,11-epoxide and is not susceptible to metabolic autoinduction.4 Unlike oxcarbazepine, which is a prodrug to both eslicarbazepine (also called S-licarbazepine or S-MHD) and R-licarbazepine (also called R-MHD),5 ESL is a prodrug of eslicarbazepine, the major active metabolite responsible for pharmacological activity. R-licarbazepine and oxcarbazepine are minor active metabolites, corresponding to approximately 5% and 1% of systemic exposure, respectively.6 In vitro electrophysiological studies indicate that both ESL and its major metabolite, eslicarbazepine, stabilize the inactivated state of voltage-gated sodium channels (VGSCs), preventing their return to the activated state and sustaining repetitive neuronal firing.7 The affinity of ESL for the VGSC in the resting state is similar to that of carbamazepine, but the affinity for the resting state of the channel is about 3-fold lower, suggesting higher inhibitory selectivity of ESL for rapidly firing neurons over those displaying normal activity.8 In a study in cultured hippocampal neurons, ESL was less neurotoxic than carbamazepine and oxcarbazepine.9
In clinical trials in adults, ESL 800 mg and 1200 mg once daily significantly reduced the frequency of partial-onset seizures and showed a favorable safety profile when administered as adjunctive therapy.10,11 Therefore, the clinical development of ESL for the treatment of epileptic children was pursued. A relatively low-dose tablet formulation (200 mg) and an oral suspension formulation (50 mg/mL) of ESL were developed especially for use in children. These formulations were found to be bioequivalent to the adult tablet formulations.12
Because the pharmacokinetics of a drug in children may vary with age, information on the pharmacokinetics of ESL in children with epilepsy is essential for appropriate design of further therapeutic studies in this population. Therefore, the present study was conducted to investigate the pharmacokinetics of ESL in children and adolescents suffering from partial-onset epilepsy refractory to standard therapy. The secondary objective consisted of exploring its efficacy and tolerability in such a population.
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MATERIAL AND METHODS |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSION AND CONCLUSIONREFERENCES |
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Study participants were male or female patients between 2 and 17 years with at least 4 partial-onset seizures during the last 4 weeks of the baseline phase (simple or complex seizures with or without secondary generalization) receiving treatment with 1 to 3 AEDs (any except oxcarbazepine or carbamazepine) in a stable dosage regimen during at least 1 month prior to screening.
For group 1 (2-6 years), ESL oral suspension 50 mg/mL was used; the dose was rounded to the nearest 25-mg unit. For group 2 (7-11 years) and group 3 (12-17 years), ESL tablets with strengths of 200 mg, 400 mg, 600 mg, and 800 mg were used. The dose was rounded to the nearest 100-mg unit. Only patients able to swallow tablets were recruited for groups 2 and 3. Tablets were scored, to allow the use of half tablets when needed. Patients' caregivers were given the quantity of oral suspension or tablets of ESL adequate for the following treatment period plus at least 1 extra week. Patients and caregivers were instructed that study medication had to be taken in the morning, between 07:00 and 09:00 AM, with water. The last dose of each 4-week treatment period was taken while hospitalized, approximately 24 hours after the previous dose. ESL oral suspension and tablets were manufactured by BIAL (S. Mamede do Coronado, Portugal) in accordance with current good manufacturing practice recommendations.
A traditional pharmacokinetic, multisample evaluation was employed for the purpose of this study. The sample size of 10 patients per age group was empirically defined. Previous pharmacokinetic studies have shown that steady-state concentrations of eslicarbazepine (the major active metabolite) are reached within 4 to 5 days of repeated dosing.6,13 Therefore, a 4-week period at each dose was considered sufficient to fully disclose pharmacokinetic properties of the particular dosing level.
The study was conducted according to the principles of the Declaration of Helsinki and good clinical practice. The study site ethics committee reviewed and approved the protocol before the study started, and parent(s)/caregiver(s) of all participants and the patients when feasible, gave their written informed consent prior to participation.
Primary Endpoint: Pharmacokinetics
Pharmacokinetic Assessments
Blood samples for the plasma assay of ESL and metabolites were taken during the 3 hospitalization periods (H1, H2, and H3) at the following times: predose and .5, 1.5, 3, 4.5, 6, and 12 hours postdose. Blood samples (2.5 mL) were drawn via an intravenous catheter into lithium heparin microtainers and centrifuged at approximately 1500 g for 10 minutes. Blood samples were kept in ice until plasma separated. The resulting plasma was stored at –20°C prior to shipment to the laboratory responsible for the plasma drug assay (Scope International AG, Hamburg, Germany). ESL and metabolite concentrations in plasma were determined by a previously validated method described elsewhere.14 The method consists of solid-phase extraction followed by high-performance liquid chromatography (HPLC) analysis on a mass spectrometer (chiral liquid chromatography/tandem mass spectrometry [LC/MS/MS]). During assay method validation, it was demonstrated that patient plasma matrix and concomitant AEDs do not interfere with the analysis. The lower limit of quantification (LLOQ) for each analyte was 50 ng/mL.
Pharmacokinetic Analysis
The following parameters for ESL and its major metabolite, eslicarbazepine, were derived from the individual plasma concentration-time profiles: maximum plasma concentration (Cmax) post last dose; time of occurrence of Cmax (tmax); area under the plasma concentration-time curve over the dosing interval (AUC0-24), calculated by the linear trapezoidal rule; apparent terminal half-life (t1/2), calculated from ln2/
z, where z is the apparent terminal rate constant; and plasma clearance at steady state, normalized by body weight (CLss/F). Pearson's correlations between eslicarbazepine AUC0-24 and the actual ESL dose administered, between AUC0-24 and age, and between CLss/F and age were performed. For minor metabolites R-licarbazepine and oxcarbazepine, Cmax, tmax, AUC0-24, and t1/2 were estimated, and the ratios of their AUC0-24 versus eslicarbazepine AUC0-24 were calculated. The pharmacokinetic parameters were derived from noncompartmental analysis using WinNonlin (Version 4.0, Pharsight Corporation, Mountain View, Calif).
Actual doses and sampling times were used for the pharmacokinetic analysis. Only plasma concentrations above the LLOQ were included in the calculations. Values of z were calculated from a minimum of 3 data points. All calculations were made using raw data. Values for tmax were displayed as nominal times. The statistical package SAS (Version 8.2, SAS Institute Inc, Cary, NC) was used in statistical calculations.
Secondary Endpoints: Efficacy and Safety
Analysis of all secondary variables was exploratory in nature.
The efficacy assessment was based on seizures recorded in the patient's diary during the baseline phase and during the following 4-week treatment periods. Seizure frequency for each patient was standardized to a frequency per 28-day period. The efficacy variables were the percentage change in seizure frequency during each 4-week treatment period compared with the baseline phase, as well as the percentage of patients who became seizure free.
Safety assessments consisted of treatment-emergent adverse events (AEs), which were monitored throughout the study, as well as vital sign measurements, laboratory safety tests, and 12-lead electrocardiogram (ECG) monitored at admission to the study and at the end of each 4-week treatment period and follow-up visit.
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RESULTS |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSION AND CONCLUSIONREFERENCES |
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All patients were Caucasian. Main demographic and baseline characteristics of the pharmacokinetic population are presented in Table I. The body weight in all patients was within the 10th and 90th percentiles, accounted by age and sex. Total duration of epilepsy ranged between 9 months and 15 years. The most frequently used concomitant AEDs at baseline were lamotrigine, valproic acid, topiramate, and clonazepam. Etiology of epilepsy was reported for only 10 (34.5%) patients: these were congenital or hereditary disorders in 6 patients of group 1, infectious diseases in 3 patients of group 3, and cerebrovascular disease in 1 patient of group 3.
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Pharmacokinetic Results
Plasma levels of ESL were systematically below the LLOQ (50 ng/mL) at all sampling times. Consistent with what has been reported in adult subjects,6 ESL was found to be rapidly and extensively hydrolyzed to eslicarbazepine in children and adolescents. Figure 2 displays the mean eslicarbazepine concentration-time profile, and Table II presents the mean pharmacokinetic parameters following each dosage regimen in the different age groups. Maximum eslicarbazepine plasma concentrations were usually attained between 0.5 hour and 3 hours following administration of ESL in all age groups. Both the rate (as assessed by Cmax) and the extent (as assessed by AUC0-24) of systemic exposure to eslicarbazepine were dose proportional in all age groups.
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Table IV presents an estimation of relative systemic exposure to eslicarbazepine in the different age groups. Geometric means ratios of eslicarbazepine Cmax, AUC0-24, and CLss/F were calculated. Following a similar dose of ESL, eslicarbazepine Cmax was identical between the different age groups. However, eslicarbazepine AUC0-24 was found to be age dependent (Figure 4). When compared with group 3, mean AUC0-24 was 36% less in group 1 and 41% less in group 2 with 5 mg/kg/day, 33% less in group 1 and 18% less in group 2 with 15 mg/kg/day, and 29% less in group 1 and 21% less in group 2 with 30 mg/kg/day. Thus, when dosing ESL per kilogram of body weight, eslicarbazepine AUC0-24 was lower in young children than in older children. There was an inverse correlation between eslicarbazepine CLss/F and age (Figure 5). When compared with group 3, the mean CLss/F increased by 53% in group 1 and 43% in group 2 with 5 mg/kg/day, 49% in group 1 and 25% in group 2 with 15 mg/kg/day, and 36% in group 1 and 22% in group 2 with 30 mg/kg/day.
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Descriptive pharmacokinetic parameter estimates of R-licarbazepine and oxcarbazepine are presented in Table V. Both were found to be minor metabolites. As assessed by AUC0-24, the extent of systemic exposure relative to that of eslicarbazepine was between 4% and 7% for R-licarbazepine and 1% to 2% for oxcarbazepine.
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Secondary Endpoints
Efficacy
A dose-dependent decrease in relative (%) seizure frequency was observed in group 1 and group 3. In group 1, the median relative (%) change in seizure frequency relative to baseline was –28.2% (95% confidence interval [CI]: –60, 13) with 5 mg/kg/day, –24.8% (95% CI: –93, –6) with 15 mg/kg/day, and –40.6% (95% CI: –86, –4) with 30 mg/kg/day. In group 3, the median relative (%) change in seizure frequency in relation to baseline was –17.1% (95% CI: –56, 30) with 5 mg/kg/day, –31.7% (95% CI: –71, 19) with 15 mg/kg/day, and –43.1% (95% CI: –77, 21) with 30 mg/kg/day. In group 2 (7-11 years), no noticeable dose-dependent change was observed in seizure frequency: the median relative (%) change in seizure frequency was –11.7% (95% CI: –20, 278) with 5 mg/kg/day, 5.0% (95% CI: –56, 345) with 15 mg/kg/day, and 12.2% (95% CI: –100, 168) with 30 mg/kg/day. One patient in each group became seizure free.
Safety/Tolerability
In total, 54 AEs with any causality (drug related or not) were reported by 21 patients (Table VI). The frequency was dose dependent: 11 AEs occurred with 5 mg/kg/day, 15 AEs with 15 mg/kg/day, and 28 AEs with 30 mg/kg/day. Of these, 5 AEs were considered by the investigator as possibly related to treatment with 5 mg/kg/day, 8 AEs with 15 mg/kg/day, and 21 AEs with 30 mg/kg/day. All drug-related AEs occurring with ESL 5 mg/kg/day and 15 mg/kg/day were of mild intensity, except for 1 case of psychomotor agitation of moderate intensity with 5 mg/kg/day. With 30 mg/kg/day, 10 AEs were of mild intensity, 9 AEs were of moderate intensity (3 cases of somnolence, 2 cases of vomiting, 2 cases of diplopia, 1 case of dizziness, and 1 case of equilibrium trouble), and 2 cases were of severe intensity (seizure worsening leading to patient withdrawal by the investigator). All drug-related AEs, except a case of nausea and a case of abdominal pain, resolved with continued therapy. The 2 patients who were withdrawn were a 2-year-old girl with congenital epilepsy (treated with valproic acid 513 mg thrice daily, lamotrigine 125 mg twice daily, and topiramate 100 mg twice daily) and an 11-year-old girl with an unknown cause for epilepsy (treated with valproic acid 750 mg thrice daily, lamotrigine 150 mg thrice daily, and phenobarbital 50 mg once daily). Both experienced an increase in duration (worsening) of seizures during treatment with ESL 30 mg/kg/day; worsening of seizures alleviated after ESL discontinuation.
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There were no deaths and no clinically significant changes in the laboratory parameters, vital signs and physical examination, and ECG parameters (rhythm, ventricular rate, PR interval, QRS duration, and QT interval).
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DISCUSSION AND CONCLUSION |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSION AND CONCLUSIONREFERENCES |
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Similar to what occurs in adults,6 ESL showed extensive first-pass presystemic biotransformation to eslicarbazepine, the main metabolite. Plasma levels of ESL remained below the LLOQ. R-licarbazepine and oxcarbazepine were minor metabolites, corresponding to 4% to 7% and 1% to 2% of systemic exposure to eslicarbazepine, which is similar to the results reported for adults6 (5% and 1%, respectively). The metabolic steps by which R-licarbazepine and oxcarbazepine are formed are still unclear.3 Glucuronidation is the main metabolic pathway for eslicarbazepine, which is excreted in urine, 2/3 in the unchanged form and 1/3 as a conjugate with glucuronic acid; minor metabolites in urine are R-licarbazepine, oxcarbazepine, and their glucuronyl conjugates.14,15 Eslicarbazepine glucuronidation and formation of R-licarbazepine or oxcarbazepine are unaffected by moderate liver impairment.15 Clearance of eslicarbazepine and other metabolites are affected by renal function.14
In adults, the ESL pharmacokinetics are dose proportional across the dose range of 400 to 2400 mg/day16 and are unaffected by age6 or gender.13 In the current study, eslicarbazepine Cmax was similar between age groups following administration of identical ESL dose/kg, but AUC0-24 was age dependent due to a faster plasma clearance of eslicarbazepine in younger children compared with adolescents. The clearance in children is higher than that found in adults, which is in line with what has been reported for other AEDs.17 These results indicate that age-dependent differences should be considered when determining ESL dosage for pediatric patients.
Recently completed phase III placebo-controlled studies showed that once-daily oral administration of ESL 800 mg and 1200 mg significantly decreased seizure frequency in an adult population of more than 1000 patients refractory to treatment with 1 to 3 AEDs (unpublished data). The pediatric population enrolled in this study was highly refractory to treatment. The mean number of seizures per 4 weeks during the baseline period was 1077 in group 1, 267 in group 2, and 49 in group 3, despite treatment with 2 or 3 AEDs in 88% of patients in group 1, 100% in group 2, and 70% in group 3. Moreover, the number of seizures per 4 weeks was highly variable between patients, ranging from 5 to 4665 seizures in group 1, 7 to 1183 seizures in group 2, and 5 to 164 in group 3. This large variability decreased the accuracy and reliability of the efficacy assessments, particularly because the number of patients in each age group is relatively low. Despite this limitation, the findings of this phase IIa study show a clear dose-dependent decrease in seizure frequency in groups 1 and 3, and 1 patient in each group attained seizure freedom during treatment, suggesting that the potential antiepileptogenic effect of ESL also may be useful in pediatric patients. Clinical trials in children and adolescents in which efficacy is the primary endpoint are ongoing and will establish the therapeutic value of ESL in such a population.
ESL 5-mg/kg/day and 15-mg/kg/day dosage regimens were well tolerated. All drug-related AEs reported at these doses were mild in intensity, except 1 case of psychomotor agitation of moderate intensity (5 mg/kg/day). With the dosage of 30 mg/kg/day, AEs were more frequent, tended to be more severe, and were mainly related to the nervous system. This profile is in line with what was observed in adult patients. One patient in group 1 and 1 patient in group 2 discontinued due to worsening of seizures during the 30-mg/kg/day period. At admission to the study, both patients presented a high number of seizures (2236/4 weeks and 578/4 weeks, respectively) despite treatment with 3 AEDs (valproic acid + lamotrigine + topiramate and valproic acid + lamotrigine + phenobarbital). A possible pharmacokinetic drug-drug interaction could be speculated. The plasma levels of eslicarbazepine in these 2 patients were similar to the mean plasma concentrations observed in patients who received the 30-mg/kg/day dosage in the corresponding age groups, thus excluding possible toxicity due to abnormally increased plasma levels of eslicarbazepine in such patients. An evaluation of the plasma concentrations of the concomitant AEDs could not be performed, but all the existing cumulative data from adults suggest that a drug-drug interaction is unlikely. Glucuronidation is the major metabolic pathway for both eslicarbazepine and lamotrigine, and therefore an interaction could be expected; however, a study in healthy subjects18 and the population pharmacokinetic analysis in phase III studies in adult epileptic patients (unpublished data) showed no relevant effect of ESL on lamotrigine pharmacokinetics. Also, there was no relevant effect of ESL on the clearance of valproic acid, topiramate, phenobarbital, carbamazepine, clobazam, gabapentin, and levetiracetam as observed in population pharmacokinetic analyses. Worsening of epilepsy is a possible AE with AEDs and could also occur with ESL. There were no significant changes in the laboratory parameters, vital signs, and physical examination, and there was no evidence of QT interval prolongation, which is in agreement with a large body of evidence from studies in more than 2000 adults, including a thorough QT/QTc study with moxifloxacin as active control.
In conclusion, ESL showed dose-proportional pharmacokinetics in epileptic children of different age groups. Similar to adult studied, ESL was rapidly metabolized to eslicarbazepine. Eslicarbazepine Cmax was similar between age groups following administration of identical dose/kg, but AUC0-24 depended on age due to a faster plasma clearance of eslicarbazepine in younger versus older children. Therefore, age-dependent differences should be considered when determining ESL dosage for pediatric patients.
Financial disclosure: This study was financially supported by BIAL—Portela & Co, SA.
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REFERENCES |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSION AND CONCLUSIONREFERENCES |
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1. Pellock JM. Managing pediatric epilepsy syndromes with new antiepileptic drugs. Pediatrics. 1999;104: 1106-1116.
2. Benes J, Parada A, Figueiredo AA, et al. Anticonvulsant and sodium channel-blocking properties of novel 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives. J Med Chem. 1999;42: 2582-2587.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3. Hainzl D, Parada A, Soares-da-Silva P. Metabolism of two new antiepileptic drugs and their principal metabolites S(+)- and R(–)-10,11-dihydro-10-hydroxy carbamazepine. Epilepsy Res. 2001;44: 197-206.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
4. Bialer M. New antiepileptic drugs that are second generation to existing antiepileptic drugs. Expert Opin Investig Drugs. 2006;15: 637-647.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. Volosov A, Xiaodong S, Perucca E, Yagen B, Sintov A, Bialer M. Enantioselective pharmacokinetics of 10-hydroxycarbazepine after oral administration of oxcarbazepine to healthy Chinese subjects. Clin Pharmacol Ther. 1999;66: 547-553.[Web of Science][Medline] [Order article via Infotrieve]
6. Almeida L, Falcao A, Maia J, Mazur D, Gellert M, Soares-da-Silva P. Single-dose and steady-state pharmacokinetics of eslicarbazepine acetate (BIA 2-093) in healthy elderly and young subjects. J Clin Pharmacol. 2005;45: 1062-1066.
7. Ambrosio AF, Soares-Da-Silva P, Carvalho CM, Carvalho AP. Mechanisms of action of carbamazepine and its derivatives, oxcarbazepine, BIA 2-093, and BIA 2-024. Neurochem Res. 2002;27: 121-130.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8. Bonifacio MJ, Sheridan RD, Parada A, Cunha RA, Patmore L, Soares-da-Silva P. Interaction of the novel anticonvulsant, BIA 2-093, with voltage-gated sodium channels: comparison with carbamazepine. Epilepsia. 2001;42: 600-608.[Medline] [Order article via Infotrieve]
9. Araujo IM, Ambrosio AF, Leal EC, et al. Neurotoxicity induced by antiepileptic drugs in cultured hippocampal neurons: a comparative study between carbamazepine, oxcarbazepine, and two new putative antiepileptic drugs, BIA 2-024 and BIA 2-093. Epilepsia. 2004;45: 1498-1505.[Medline] [Order article via Infotrieve]
10. Almeida L, Soares-da-Silva P. Eslicarbazepine acetate (BIA 2-093). Neurotherapeutics. 2007;4: 88-96.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Elger C, Bialer M, Cramer JA, Maia J, Almeida L, Soares-da-Silva P. Eslicarbazepine acetate: a double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures. Epilepsia. 2007;48: 497-504.[Medline] [Order article via Infotrieve]
12. Fontes-Ribeiro C, Nunes T, Falcão A, et al. Eslicarbazepine acetate (BIA 2-093): relative bioavailability and bioequivalence of 50 mg/mL oral suspension and 200 mg and 800 mg tablet formulations. Drugs R&D. 2005;6: 253-260.[CrossRef]
13. Falcao A, Maia J, Almeida L, Mazur D, Gellert M, Soares-da-Silva P. Effect of gender on the pharmacokinetics of eslicarbazepine acetate (BIA 2-093), a new voltage-gated sodium channel blocker. Biopharm Drug Dispos. 2007;28: 249-256.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
14. Maia J, Almeida L, Falcão A, et al. Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate. Int J Clin Pharmacol Ther. 2008;46: 119-130.[Web of Science][Medline] [Order article via Infotrieve]
15. Almeida L, Potgieter JH, Maia J, Potgieter MA, Mota F, Soares-da-Silva P. Pharmacokinetics of eslicarbazepine acetate in patients with moderate hepatic impairment. Eur J Clin Pharmacol. 2008;64: 267-273.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
16. Vaz-da-Silva M, Nunes T, Soares E, et al. Eslicarbazepine acetate pharmacokinetics after single and repeated doses in healthy subjects. Epilepsia. 2005;46(suppl 8): 191.
17. Perucca E. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age. Clin Pharmacokinet. 2006;45: 351-363.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
18. Nunes T, Maia J, Almeida L, Soares-da-Silva P. Pharmacokinetic interaction between eslicarbazepine acetate and lamotrigine in healthy subjects. Presented at: 61st Annual Meeting of the American Epilepsy Society; December 2007; Philadelphia, PA.
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