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Keywords:

  • Eslicarbazepine acetate;
  • Oxcarbazepine;
  • Pharmacokinetics;
  • Once-daily;
  • Twice-daily;
  • Tolerability;
  • Healthy volunteers

Summary

  1. Top of page
  2. Summary
  3. Population and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosures
  8. References
  9. Supporting Information

Purpose

Investigate the pharmacokinetics of once-daily (QD; 900 mg) and twice-daily (BID; 450 mg) regimens of eslicarbazepine acetate (ESL) and BID (450 mg) regimen of oxcarbazepine (OXC) at steady state in healthy volunteers.

Methods

Single-center, open-label, randomized, three-way (n = 12) crossover studies in healthy volunteers.

Key Findings

Mean eslicarbazepine Cmax,ss (in μm) following ESL QD (87.3) was 33.3% higher (p < 0.05) compared to ESL BID (65.5) and 82.1% higher (p < 0.05) compared to OXC BID (48.0). The mean area under the curve (AUC)ss,0–τ (in μmol h/L) following the last dose of an 8-day repeated dosing was 1156.3, 1117.6, and 968.4 for ESL QD, ESL BID, and OXC BID, respectively. The ratio eslicarbazepine plasma exposure (μmol h/L) to ESL daily-dose (μmol) was 0.381 (1156.3:3037.3), 0.368 (1117.6:3037.3), and 0.271 (968.4:3567.6) for ESL-QD, ESL-BID, and OXC-BID, respectively, which translates into a 40.6% increase in the ability of ESL-QD compared to OXC-BID to deliver into the plasma their major active entity eslicarbazepine. The extent of plasma exposure to ESL minor metabolites: (R)-licarbazepine and oxcarbazepine after ESL-QD was 71.5% and 61.1% lower, respectively, than after OXC-BID. Twenty, 24 and 38 treatment emergent adverse events were reported with ESL-QD, ESL-BID, and OXC-BID, respectively.

Significance

ESL-QD resulted in 33.3% higher peak plasma concentration (Cmax,ss) of eslicarbazepine and similar extent of plasma exposure (AUCss,0–τ) when compared to ESL-BID, which may contribute to the efficacy profile reported with once-daily ESL. In comparison to OXC-BID, administration of ESL-QD resulted in 40.6% increase in the delivery of eslicarbazepine into the plasma as well as a significantly lower systemic exposure to (R)-licarbazepine and oxcarbazepine.

Eslicarbazepine acetate (ESL) was initially described as endowed with distinctive anticonvulsant properties (Benes et al., 1999; Ambrosio et al., 2002) and later approved by the European Medicines Agency (EMA) as once-daily adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization. ESL is structurally distinct from carbamazepine (CBZ) and oxcarbazepine (OXC), although the three compounds are dibenz[b,f]azepine derivatives (Benes et al., 1999). This molecular distinction results in differences in pharmacokinetics, pharmacodynamics, and metabolism (Hainzl et al., 2001). Unlike CBZ, ESL is not metabolized to carbamazepine-10,11-epoxide and is not susceptible to metabolic autoinduction (Almeida et al., 2009; Bialer & Soares-da-Silva, 2012).

The distinctive anticonvulsant properties of ESL and eslicarbazepine (Benes et al., 1999; Ambrosio et al., 2002) are characterized by a wider (1.5- to 2.5-fold) protective-index in the mouse maximal electroshock and the 6 Hz psychomotor tests when compared to CBZ (Pires et al., 2011; Torrao et al., 2011). Although on its own ESL preferentially blocks voltage-gated sodium channels (VGSCs) in rapidly firing neurons (Bonifacio et al., 2001), the in vivo effects of ESL may be limited to its extensive conversion to eslicarbazepine. Mechanistically, however, it is important to underscore that the affinity of eslicarbazepine for VGSCs in the resting state is about 15- to 5-fold lower than that of CBZ, OXC, and (R)-licarbazepine, a feature that may translate into an enhanced inhibitory selectivity of eslicarbazepine for rapidly firing “epileptic” neurons over those with normal activity (Hebeisen et al., 2011). This is further substantiated by the fact that eslicarbazepine does not share with CBZ and OXC the ability to alter fast inactivation of VGSC, but rather appears to modify the kinetics and voltage dependence of slow inactivation states (Aires et al., 2012; Soares-da-Silva & Hebeisen, 2012).

Following oral administration to humans, ESL undergoes extensive first-pass metabolic hydrolysis to its major active metabolite eslicarbazepine (also known as (S)-licarbazepine or (S)-MHD), which represents approximately 95% of ESL circulating active moieties (Falcao et al., 2007; Almeida et al., 2008a,b; Maia et al., 2008; Perucca et al., 2011); a schematic representation of the metabolism of ESL is displayed in Fig. 1. Plasma levels of ESL usually remain below the limit of quantification. Minor active metabolites are (R)-licarbazepine and oxcarbazepine. Eslicarbazepine steady-state plasma concentrations are reached within 4–5 days of ESL once-daily dosing (Almeida & Soares-da-Silva, 2004; Almeida et al., 2005). Inactive metabolites in plasma are the glucuronic acid conjugates of ESL, eslicarbazepine, (R)-licarbazepine, and oxcarbazepine, all found in minor amounts (Almeida et al., 2008b; Maia et al., 2008). More than 90% of an oral ESL dose is recovered in urine as ESL metabolites (Almeida et al., 2008b; Maia et al., 2008).

image

Figure 1. Metabolic pathways of eslicarbazepine acetate (ESL) and oxcarbazepine (OXC) to eslicarbazepine and (R)-licarbazepine. Epilepsia ©ILAE

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The ESL epilepsy clinical program included an initial proof-of-concept phase II study (Elger et al., 2007) and three subsequent double-blind, randomized, placebo-controlled phase III studies in patients refractory to conventional antiepileptic drug (AED) therapy (Elger et al., 2009; Gil-Nagel et al., 2009; Ben-Menachem et al., 2010). In total, 1,049 patients were enrolled by 125 centers distributed by 23 countries, and their pooled results were described elsewhere (Gil-Nagel et al., 2013). Long-term safety and maintenance of therapeutic effect was demonstrated in 1-year open-label extensions of these studies (Halasz et al., 2010; Hufnagel et al., 2013). In the phase II placebo-controlled, adjunctive-therapy study in adult patients with partial-onset seizures, ESL 800 mg and 1,200 mg/day once-daily (QD), was found to be efficacious and well tolerated (Elger et al., 2007). However, the same dose given twice daily (BID) was not significantly more efficacious than placebo (Elger et al., 2007). This suggested that ESL efficacy is affected by the dosing rate and might be correlated more closely with eslicarbazepine peak plasma concentration (Cmax,ss) than with its total plasma exposure (area under the curve, AUCss) (Elger et al., 2007).

OXC is a widely used AED currently approved as monotherapy or adjunct treatment for partial epilepsy, usually administered in twice-daily doses. Following oral administration, OXC is rapidly and extensively reduced by cytosolic aldo-ketoreductase enzymes in the liver to monohydroxycarbazepine (MHD) (Faught & Limdi, 2009), an enantiomeric mixture of eslicarbazepine (also known as (S)-licarbazepine or (S)-MHD) and (R)-licarbazepine (also known as (R)-MHD) in the proportion of 4:1 (Volosov et al., 1999). A schematic representation of the metabolism of OXC is displayed in Fig. 1. A small fraction (4%) of OXC is oxidized to the inactive dihydroxy derivative (DHD). Most of an OXC oral dose is recovered in urine as MHD glucuronide (51%) and unchanged MHD (28%). Steady-state of MHD plasma concentrations are reached within 2–3 days of twice-daily dosing (Faught & Limdi, 2009).

The aim of the present study was to investigate the pharmacokinetics and tolerability after repeated-dose administration of once-daily (QD; 900 mg) and twice-daily (BID; 450 mg) regimens of ESL and BID (450 mg) regimen of OXC at steady state in healthy volunteers. It was envisaged that such an evaluation could also provide a better understanding of why ESL has shown efficacy when given QD.

Population and Methods

  1. Top of page
  2. Summary
  3. Population and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosures
  8. References
  9. Supporting Information

Study design and ethics compliance

The repeated-dose study (trial registration NCT01679002, at ClinicalTrials.gov) was a single-center, open-label, randomized, three-way crossover study in 12 healthy subjects (six male and six female) aged 29.0 ± 4.7 years. The study consisted of three 8-day treatment periods separated by washout periods of 10–15 days. On each of the treatment periods, the subjects received either ESL 900 mg QD, ESL 450 mg BID, or OXC (450 mg BID). In humans, the exposure to eslicarbazepine is linear over the 400–2,400 mg QD ESL dose range (Almeida & Soares-da-Silva, 2007). Dosages tested in adult patients with epilepsy were 400, 800, and 1,200 mg QD ESL (Perucca et al., 2011). Because the available strengths of OXC are 150, 300, and 600 mg, a 450 mg BID (150 + 300) OXC dose was used for comparison with ESL 450 mg BID. The 900 mg QD ESL dose is adequate to compare with ESL 450 mg BID, because these are close to the dosages used in the QD versus BID phase II trial with ESL in patients with epilepsy (Elger et al., 2007). The study was conducted according to the principles of the Declaration of Helsinki and the Good Clinical Practice (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) guidelines. An Independent Ethics Committee (Human Pharmacology Unit's Independent Ethics Committee [IEC], Porto) reviewed and approved the study protocol and the subject information. Written informed consent was obtained for each subject prior to enrollment in the study. Further details on participants and interventions are available as Supporting Information. The randomization and treatment allocations are depicted in Tables S1 and S2, respectively.

Safety assessments

Safety assessments consisted of adverse events (AEs) monitoring, physical examinations, vital signs measurements, 12-lead electrocardiography (ECG) recordings, and standard blood and urine clinical laboratory tests. All AEs were monitored throughout the entire study periods. AEs were assessed regarding intensity (severity) and relationship to the investigational product by the clinical investigator.

Pharmacokinetic assessments and bioanalytical methods

Blood samples for the determination of drug concentrations were taken in each treatment period (days 1–7) at predose and on day 8 at predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, and 96 h post-dose. Blood samples were collected into tubes containing lithium-heparin anticoagulant and centrifuged at approximately 1,500 g for 10 min at 4°C. The resulting plasma was then separated into two aliquots of 750 μL and stored at −20°C until required for analysis.

Quantifications of ESL, eslicarbazepine, (R)-licarbazepine, and oxcarbazepine were determined using a validated high pressure liquid chromatography with mass spectrometry detection (HPLC-MS) method derived from a method described elsewhere (Falcao et al., 2007). Analyses were performed over the range of 100–1,000 ng/ml for ESL, eslicarbazepine, (R)-licarbazepine, and oxcarbazepine. During method validation, a lower limit of quantification (LLOQ) for ESL, eslicarbazepine, (R)-licarbazepine, and oxcarbazepine of 100 ng/ml was established. Mean accuracy of the quality control samples in human plasma for ESL ranged from 93.2% to 99.5%, whereas mean precision ranged from 7.6% to 8.0%. For eslicarbazepine, mean accuracy ranged from 94.9% to 102.0%, whereas mean precision ranged from 8.0% to 10.0%. For (R)-licarbazepine, mean accuracy ranged from 92.8% to 100.0%, whereas mean precision ranged from 7.4% to 10.0%. For oxcarbazepine, mean accuracy ranged from 93.2% to 97.7%, whereas mean precision ranged from 7.6% to 9.2%.

When displaying the results, OXC abbreviation refers to oxcarbazepine as investigational product; oxcarbazepine is not abbreviated when it means the analyte assayed.

Analyses

No formal sample size calculation was performed. At least 11 volunteers completing each study group were considered compatible with a reasonable clinical interpretation and descriptive statistics.

All subjects who received at least one dose of study medication, including those who did not complete the study, were included in the safety data analysis (safety population). Adverse events were tabulated and summarized according to the Medical Dictionary for Regulatory Activities.

The following pharmacokinetic parameters were calculated by noncompartmental analysis from the individual plasma concentration-time profiles: peak plasma concentration (Cmax); time to Cmax (tmax); trough plasma concentration (Cmin), that is, concentration at the end of the dosing interval (drug assay on the premorning dose plasma sample on days 2–8); area under the plasma concentration-time curve (AUC) from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUC0–t) and AUC over the dosing interval (AUCss,0–τ, i.e., AUCss,0–24 in the ESL QD group and 2*AUCss,0–12 in the ESL BID and OXC BID groups), both calculated by the trapezoidal rule, and AUC from time zero to infinity (AUC0–∞), calculated from AUC0–t + (Clastz), where Clast is the last quantifiable concentration and λz the apparent terminal rate constant. The terminal half-life (t½) was calculated from the quotient ln2/λz. At steady state the fluctuation (%) was calculated from the ratio 100*(Cmax − Cmin)/Cavg, where Cavg is the average concentration.

The pharmacokinetic parameters were calculated with WinNonlin (Pharsight Corporation, Mountain View, CA). Nominal sampling times were used for the pharmacokinetic analysis. Plasma concentrations below the limit of quantification of the assay were taken as zero. All calculations used raw data. Summary statistics were reported, as appropriate, using the geometric mean, arithmetic mean, standard deviation (SD), coefficient of variation (CV%), standard error of the mean (SEM), median, and range (minimum and maximum).

Statistical calculations were performed with SAS Software (SAS Institute Inc, Cary, NC, U.S.A.) in all computations when considered appropriate. Cmin, Cmax, and AUCss,0–τ of eslicarbazepine, (R)-licarbazepine, and oxcarbazepine were compared for plasma within each group using one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison test. To allow between-group AUCss,0–24 comparisons, AUCss,0–24 in the BID groups was obtained by doubling AUCss,0–τ (i.e., AUCss,0–12). Tmax of eslicarbazepine, (R)-licarbazepine, and oxcarbazepine were compared for plasma within each group using Friedman test followed by Dunn's multiple comparison test.

Results

  1. Top of page
  2. Summary
  3. Population and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosures
  8. References
  9. Supporting Information

Study population

In total, 12 Caucasian volunteers were admitted to the study. Their demographic characteristics are summarized in Table S3.

Pharmacokinetic results

Mean plasma drug (eslicarbazepine, (R)-licarbazepine, or oxcarbazepine) concentration-time profiles following ESL 900 mg QD, ESL 450 mg BID, and OXC 450 mg BID are displayed in Fig. 2. The corresponding pharmacokinetic parameters are presented in Table 1. Concentration-time profiles and pharmacokinetic parameters could not be calculated for parent compound ESL because its plasma levels were below the limit of quantification (LOQ = 0.17 μm) at all sampling times.

Table 1. Pharmacokinetic parameters of eslicarbazepine, (R)-licarbazepine, and oxcarbazepine following the last dose of an 8-day treatment with ESL 900 mg QD, ESL 450 mg BID, and OXC 450 mg BID to 11 healthy subjects
TreatmentCminm)Cmaxm)tmax (h)AUCss,0–τ (μmol h/L)t½ (h)Fluctuation (%)Dose (μmol)Ratio exposure/dose (μmol h/L)/(μmol)
  1. Results are expressed as arithmetic means with coefficient variation (%) in parentheses: tmax values are medians with range values in parentheses.

  2. a

    Significantly different from corresponding values for ESL 900 mg QD using one-way ANOVA followed by Tukey's multiple comparison test (p < 0.05).

  3. b

    Significantly different from corresponding values for ESL 450 mg QD using one-way ANOVA followed by Tukey's multiple comparison test (p < 0.05).

  4. c

    Significantly different from corresponding values for ESL 900 mg QD using Friedman test followed by Dunn's multiple comparison test (p < 0.05).

  5. d

    Significantly different from corresponding values for ESL 450 mg QD using Friedman test followed by Dunn's multiple comparison test (p < 0.05).

Eslicarbazepine        
ESL 900 mg QD22.7 (24.1)87.3 (32.7)3 (1.5–4)1156.3 (19.9)9.12 (13.1)131.0 (25.6)3037.30.381
ESL 450 mg BID32.3 (15.6)a65.5 (23.9)a2 (1–3)1117.6 (18.3)9.17 (16.2)69.7 (29.3)3037.30.368
OXC 450 mg BID31.8 (12.9)a48.0 (16.8)a3 (1.5–6)968.4 (13.5)9.24 (35.2)39.4 (22.9)3567.60.271
(R)-Licarbazepine        
ESL 900 mg QD1.8 (22.5)2.7 (27.4)12 (1.5–18)53.7 (23.5)15.0 (24.4)41.1 (37.4)3037.30.018
ESL 450 mg BID2.1 (28.3)2.8 (26.0)6 (1.5–12)59.7 (27.4)14.5 (27.7)28.6 (27.1)3037.30.020
OXC 450 mg BID5.8 (24.2) a,b9.8 (14.6) a,b3 (1.5–8)188.5 (12.3) a,b11.0 (18.7)50.4 (35.2)3567.60.053
Oxcarbazepine        
ESL 900 mg QD0.2 (31.4)0.8 (25.5)6 (1.5–12)12.3 (23.0)13.2 (33.7)128.0 (33.0)3037.30.004
ESL 450 mg BID0.3 (31.2)a0.7 (26.0)3 (1–12)13.3 (28.2)11.9 (24.1)69.4 (38.9)3037.30.004
OXC 450 mg BID0.4 (22.2)a4.3 (50.7) a,b1 (0.5–3) c,d31.6 (28.1)a,b10.1 (33.7)278.0 (27.7)3567.60.009
image

Figure 2. Mean plasma concentration-time profile of (A) eslicarbazepine, (B) (R)-licarbazepine, and (C) oxcarbazepine following the last dose of an 8-day repeated dosing with ESL 900 mg QD, ESL 450 mg BID, or OXC 450 mg BID to 11 healthy subjects. The inset represents the concentration-time profile of eslicarbazepine, (R)-licarbazepine and oxcarbazepine up to 24 h following ESL 900 mg QD, ESL 450 mg BID, or OXC 450 mg BID; for ESL 450 mg BID and OXC 450 mg BID from 12 to 24 h (open circles and dotted line) is a duplication of the concentration-time profile from 0 to 12 h as used for the calculation of AUCss,0–τ over a 24 h period. ESL, eslicarbazepine acetate; OXC, oxcarbazepine; BID, twice-daily; QD, once-daily.

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Eslicarbazepine was the predominant drug entity in plasma after oral administration of ESL 900 mg QD, ESL 450 mg BID, and OXC 450 mg BID (Table 1). Using AUCss,0–τ as a measure of total steady-state plasma exposure within the corresponding dosing interval (τ), eslicarbazepine corresponded to 94.6%, 93.9%, and 81.5% of total drug moieties in plasma following ESL QD, ESL BID, and OXC BID, respectively. Eslicarbazepine Cmax,ss (in μm) following ESL QD (87.3) was 33.3% higher (p < 0.05) compared to ESL BID (65.5) and 82.1% higher (p < 0.01) compared to OXC BID (48.0) (Fig. 2A). The AUCss,0–τ (in μmol h/L) following the last dose of an 8-day repetitive dosing was 1156.3, 1117.6, and 968.4 for ESL QD, ESL BID, and OXC BID, respectively (Table 1). Trough eslicarbazepine plasma concentration at steady-state (Cmin,ss) before the last dose was 29.7% lower in the ESL QD in relation to ESL BID and 28.6% lower in relation to OXC BID (22.7, 32.3, and 31.8 μm, respectively). The ratio eslicarbazepine plasma exposure (μmol h/L) to daily dose (μmol) was 0.381 (1156.3:3037.3), 0.368 (1117.6:3037.3), and 0.271 (968.4:3567.6) for ESL QD, ESL BID, and OXC BID, respectively, which translates in a 40.6% increase in the ability of ESL QD versus OXC BID to deliver into the plasma their major active metabolite eslicarbazepine.

Using AUCss,0–τ as a measure of steady-state total plasma exposure within the corresponding dosing interval (τ), (R)-licarbazepine corresponded to 4.4%, 5.0%, and 15.9% of total drug moieties in plasma following ESL QD, ESL BID, and OXC BID, respectively. (R)-Licarbazepine Cmax,ss (in μm) following ESL QD (2.7) was similar to that after ESL BID (2.8) and 3.6-fold lower (p < 0.05) than that with OXC BID (9.8) (Fig. 2B). The AUCss,0–τ (in μmol h/L) following the last dose of an 8-day repetitive dosing was 53.7, 59.6, and 188.4 for ESL QD, ESL BID, and OXC BID, respectively (Table 1). Trough (R)-licarbazepine plasma concentration at steady-state before the last dose were 3.2- and 2.7-fold lower (p < 0.05) in the ESL QD and ESL BID compared to OXC BID (1.8, 2.1 and 5.8 μm, respectively). The ratio of (R)-licarbazepine plasma exposure (μmol h/L) to daily dose (μmol) was 0.018 (53.7:3037.3), 0.020 (59.6:3037.3), and 0.053 (188.4:3567.6) for ESL QD, ESL BID, and OXC BID, respectively, which translates in a 66.0% decrease in the ability of ESL QD versus OXC BID to deliver (R)-licarbazepine into the plasma.

Using AUCss,0–τ as a measure of steady-state total plasma exposure within the corresponding dosing interval (τ), oxcarbazepine corresponded to 1.0%, 1.1%, and 2.7% of total drug moieties in plasma following ESL QD, ESL BID, and OXC BID, respectively. Oxcarbazepine Cmax,ss (in μm) following ESL QD (0.8) was similar to that after ESL BID (0.7) and 5.4-fold lower (p < 0.05) than that with OXC BID (4.3) (Fig. 2C). The AUCss,0–τ (in μmol h/L) following the last dose of an 8-day repetitive dosing was 12.3, 13.3, and 31.6 for ESL QD, ESL BID, and OXC BID, respectively (Table 1). Trough oxcarbazepine plasma concentrations at steady-state before the last dose in the ESL QD and ESL BID were lower compared to OXC BID (0.2, 0.3 and 0.4 μm, respectively). The ratio of oxcarbazepine plasma exposure (μmol h/L) to daily dose (μmol) was 0.004 (12.3:3037.3), 0.004 (13.2:3037.3), and 0.009 (31.6:3567.6) for ESL QD, ESL BID, and OXC BID, respectively, which translates in a 55.5% decrease in the ability of ESL QD (and ESL BID) versus OXC BID to deliver oxcarbazepine into the plasma.

Safety results

During the course of the repeated-dose study, 12 subjects reported a total of 82 treatment-emergent adverse events (TEAEs): 20 TEAEs reported by nine subjects during ESL 900 mg QD; 24 TEAEs reported by 10 subjects during ESL 450 mg BID; 38 TEAEs reported by 11 subjects during OXC 450 mg BID (Table S4). There were no deaths or serious adverse events. Most adverse events (87.8%) were of mild severity; 9.8% were moderate in severity and none (0%) was considered severe; severity assessment was not performed in 2.4% adverse events, which corresponded to laboratory abnormalities (increases in transaminases) in an ESL-treated subject. Two subjects were discontinued due to adverse events: one subject with macular rash that appeared with ESL 450 mg BID, and one subject with aminotransferases increase following ESL 450 mg BID, which recurred with subsequent exposure to OXC 450 mg BID. All adverse events resolved without sequela.

Discussion

  1. Top of page
  2. Summary
  3. Population and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosures
  8. References
  9. Supporting Information

The aim of the work reported herein was to provide an explanation for the different level of antiepileptic efficacy of ESL following once-daily compared to twice-daily dosing (of the same daily dose) observed in a phase II placebo-controlled, adjunctive-therapy study in adult patients with partial-onset seizures (Elger et al., 2007). Consequently, the pharmacokinetics of eslicarbazepine, (R)-licarbazepine, and oxcarbazepine was investigated in healthy subjects at steady-state after ESL QD and BID dosing and OXC (Trileptal, Novartis Pharma GmbH, Nuremberg, Germany) BID. ESL and OXC were administered at equivalent doses.

Eslicarbazepine was the major drug entity (metabolite) in plasma following oral administration of ESL and OXC. Using AUCss,0–τ as a measure of total plasma exposure within the corresponding dosing interval (τ) at steady state, eslicarbazepine corresponded to 94.6%, 93.9%, and 81.5% of total drug moieties in plasma following ESL QD, ESL BID, and OXC BID, respectively. These results are consistent with those from previous reports that eslicarbazepine- to (R)-licarbazepine AUC ratio is approximately 20:1 following ESL administration (Almeida et al., 2005) and 4:1 following OXC administration (Volosov et al., 1999). In a recent multiple-dose study aiming to evaluate the pharmacokinetics (and tolerability) of ESL (once-daily) and OXC (twice-daily) in the cerebrospinal fluid (CSF) and plasma, eslicarbazepine was the major drug entity in plasma and CSF, accounting for 93.8% and 92.0%, respectively, of total exposure in the ESL group and 78.1% and 76.4% in the OXC group (Nunes et al., 2013). The total plasma exposure to (R)-licarbazepine and oxcarbazepine was approximately fourfold higher following OXC as compared with ESL (Nunes et al., 2013).

A placebo-controlled, phase II add-on study of ESL in patients with partial-onset seizures uncontrolled with one or two AEDs tested ESL doses of 400, 800, and 1,200 mg, administered daily in one or two equally divided doses (Elger et al., 2007). ESL 800 and 1,200 mg given once daily was shown to be effective at reducing seizure frequency compared to placebo, but the same daily dose when given twice-daily failed to be superior to placebo. Both dosage regimens were generally well tolerated. On the basis of these results, a once-daily regimen was used in the phase III studies. This is one of the first studies showing that AED efficacy is related to dosing rate, indicating that ESL antiepileptic activity correlates more closely with eslicarbazepine Cmax,ss than with its AUCss. This is despite lower trough (Cmin,ss) and higher fluctuations following QD dosing. The steady-state total plasma exposure (AUCss) depends only on clearance and is unaffected by the dosing frequency (τ) and consequently is the same following QD and BID dosing of the same daily dose. Figure 2A shows that eslicarbazepine peak plasma exposure (Cmax,ss) is 33.3% higher (p < 0.05) following ESL 900 mg QD than 450 mg BID, which may contribute to the different level antiepileptic efficacy following ESL QD dosing without increasing concentration-related side effects.

The results of the current study provide further evidence that ESL is suitable for once-daily dosing: eslicarbazepine Cmax,ss (in μm) following ESL 900 mg QD (87.3) was 33.3% higher (p < 0.05) compared to ESL 450 mg BID (65.5); the AUCss,0–τ (in μmol h/L) following the last dose of an 8-day repetitive dosing was 1,156.3 for ESL 900 mg QD and 1,117.6 for ESL 450 mg BID; trough eslicarbazepine plasma concentration at steady-state before the last dose was 29.7% lower in the ESL QD in relation to ESL BID (22.7 and 32.3 μm, respectively). Another finding that supports the rationale of once-daily use of ESL is that fluctuation of eslicarbazepine in the CSF is >50% less than that in plasma in ESL-treated healthy volunteers (Nunes et al., 2013).

Because extent of systemic exposure to the drug entities (R)-licarbazepine and oxcarbazepine was substantially lower following ESL administration as compared to OXC administration, there is an outstanding question to be answered as to what extent ESL and OXC may differ in their safety and tolerability profiles because of differences in their pharmacokinetic and metabolic dissimilarities. Although (R)-licarbazepine and oxcarbazepine are found in lower concentrations than eslicarbazepine, they have greater affinities for the sodium channel in the resting state (Hebeisen et al., 2011). Therefore, despite their low concentrations, it is possible that (R)-licarbazepine and oxcarbazepine may contribute to central nervous system (CNS)–related adverse effects following the administration of OXC and ESL (Pires et al., 2011; Torrao et al., 2011). Of interest, there are in vitro data showing that oxcarbazepine presents a distinctive low safety profile compared to carbamazepine (Ambrosio et al., 2000; Araujo et al., 2004). On the other hand, similar affinities of eslicarbazepine and oxcarbazepine for sodium channel in the inactive state (Hebeisen et al., 2011) fits well with evidence indicating that these entities may have similar anticonvulsant properties (Pires et al., 2011; Torrao et al., 2011). On the other hand, there is evidence that (R)-licarbazepine is much less efficacious than eslicarbazepine in controlling seizures (mouse corneal kindling, Pekcec et al., 2011; mouse amygdala kindling [BIAL data on file]; mouse maximal electroshock [BIAL data on file]). There is also evidence that (R)-licarbazepine is endowed with different pharmacodynamic properties at several biologic targets of interest in the field of seizure control, such as less potent than eslicarbazepine as a blocker of Cav3.2 calcium (Brady et al., 2011) and less selective for VGSCs (Hebeisen et al., 2012). In addition, eslicarbazepine differs from (R)-licarbazepine by the lack of inhibitory effects upon KV7.2 outward currents that may translate into a reduced potential for eslicarbazepine to facilitate repetitive firing, which is apparently not the case with (R)-licarbazepine (Soares-da-Silva et al., 2011). Eslicarbazepine was more potent than (R)-licarbazepine in inhibiting N-methyl-d-aspartate (NMDA) receptor currents (Bulling et al., 2011).

It is concluded that at steady-state conditions administration of once-daily ESL resulted in 33.3% higher peak plasma concentration (Cmax,ss) of eslicarbazepine and similar extent of exposure (AUCss,0–τ) when compared to twice-daily ESL, which may correlate with the improved efficacy profile reported with once-daily ESL. The pharmacokinetic reason provided in this study does not exclude other possible (pharmacodynamic) explanations. In comparison to twice-daily OXC, administration of once-daily ESL resulted in 40.6% increase of plasma eslicarbazepine in association with less (R)-licarbazepine and oxcarbazepine plasma levels, which may correlate with the therapeutic profile reported with ESL.

Disclosures

  1. Top of page
  2. Summary
  3. Population and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosures
  8. References
  9. Supporting Information

C. Elger, M. Bialer, and A. Falcão received consultancy honoraria from BIAL – Portela & Cª S.A. The following authors were employees of BIAL – Portela & Cª S.A. at the time of the studies: M. Vaz-da-Silva, T. Nunes, L. Almeida, and P. Soares-da-Silva. C. Elger is a member of the Governing Board at Desitin, Hamburg, Germany; acts as Medical Director of Life & Brain, Bonn; has received honoraria from Bial, Desitin, Eisai, Pfizer, UCB, Novartis, and GlaxoSmithWellcome; and has received Grants from the Deutsche Forschungsgemeinschaft (DFG). M. Bialer received, in the last 3 years, speaker or consultancy fees from BioAvenir, CTS Chemicals, Desitin, Janssen-Cilag, Lundbeck, Rekah, Sepracor, Tombotech, UCB Pharma, and Upsher Smith, and has been involved in the design and development of new antiepileptics and CNS drugs as well as new formulations of existing drugs. None of the other authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Population and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosures
  8. References
  9. Supporting Information
  • Aires C, Hebeisen S, Soares-da-Silva P. (2012) Effects of eslicarbazepine, R-licarbazepine and oxcarbazepine on fast and slow inactivation of voltage-gated sodium channels. Epilepsia 53(Suppl. 5):51.
  • Almeida L, Soares-da-Silva P. (2004) Safety, tolerability, and pharmacokinetic profile of BIA 2–093, a novel putative antiepileptic, in a rising multiple-dose study in young healthy humans. J Clin Pharmacol 44:906918.
  • Almeida L, Soares-da-Silva P. (2007) Eslicarbazepine acetate (BIA 2–093). Neurotherapeutics 4:8896.
  • Almeida L, Falcao A, Maia J, Mazur D, Gellert M, Soares-da-Silva P. (2005) Single-dose and steady-state pharmacokinetics of eslicarbazepine acetate (BIA 2–093) in healthy elderly and young subjects. J Clin Pharmacol 45:10621066.
  • Almeida L, Minciu I, Nunes T, Butoianu N, Falcao A, Magureanu SA, Soares-da-Silva P. (2008a) Pharmacokinetics, efficacy, and tolerability of eslicarbazepine acetate in children and adolescents with epilepsy. J Clin Pharmacol 48:966977.
  • Almeida L, Potgieter JH, Maia J, Potgieter MA, Mota F, Soares-da-Silva P. (2008b) Pharmacokinetics of eslicarbazepine acetate in patients with moderate hepatic impairment. Eur J Clin Pharmacol 64:267273.
  • Almeida L, Bialer M, Soares-da-Silva P. (2009) Eslicarbazepine acetate. In Shorvon S, Perucca E, Engel J (Eds) The treatment of epilepsy. Blackwell Publishing, Oxford, pp. 485498.
  • Ambrosio AF, Silva AP, Araujo I, Malva JO, Soares-da-Silva P, Carvalho AP, Carvalho CM. (2000) Neurotoxic/neuroprotective profile of carbamazepine, oxcarbazepine and two new putative antiepileptic drugs, BIA 2–093 and BIA 2–024. Eur J Pharmacol 406:191201.
  • Ambrosio AF, Soares-da-Silva P, Carvalho CM, Carvalho AP. (2002) Mechanisms of action of carbamazepine and its derivatives, oxcarbazepine, BIA 2–093, and BIA 2–024. Neurochem Res 27:121130.
  • Araujo IM, Ambrosio AF, Leal EC, Verdasca MJ, Malva JO, Soares-da-Silva P, Carvalho AP, Carvalho CM. (2004) 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 45:14981505.
  • Benes J, Parada A, Figueiredo AA, Alves PC, Freitas AP, Learmonth DA, Cunha RA, Garrett J, Soares-da-Silva P. (1999) Anticonvulsant and sodium channel-blocking properties of novel 10,11- dihydro-5H-dibenz[b, f]azepine-5-carboxamide derivatives. J Med Chem 42:25822587.
  • Ben-Menachem E, Gabbai AA, Hufnagel A, Maia J, Almeida L, Soares-da-Silva P. (2010) Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Res 89:278285.
  • Bialer M, Soares-da-Silva P. (2012) Pharmacokinetics and drug interactions of eslicarbazepine acetate. Epilepsia 53:935946.
  • Bonifacio MJ, Sheridan RD, Parada A, Cunha RA, Patmore L, Soares-da-Silva P. (2001) Interaction of the novel anticonvulsant, BIA 2–093, with voltage-gated sodium channels: comparison with carbamazepine. Epilepsia 42:600608.
  • Brady K, Hebeisen S, Konrad D, Soares-da-Silva P. (2011) The effects of eslicarbazepine, R-licarbazepine, oxcarbazepine and carbamazepine on ion transmission Cav3.2 channels. Epilepsia 52 (Suppl. 6):260.
  • Bulling A, Hebeisen S, Konrad D, Soares-da-Silva P. (2011) Effects of eslicarbazepine, R-licarbazepine and carbamazepine on NMDA and AMPA receptor-mediated currents. Epilepsia 52(Suppl. 6):258.
  • Elger C, Bialer M, Cramer JA, Maia J, Almeida L, Soares-da-Silva P. (2007) Eslicarbazepine acetate: a double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures. Epilepsia 48:497504.
  • Elger C, Halasz P, Maia J, Almeida L, Soares-da-Silva P. (2009) 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 50:454463.
  • Falcao A, Maia J, Almeida L, Mazur D, Gellert M, Soares-Da-Silva P. (2007) Effect of gender on the pharmacokinetics of eslicarbazepine acetate (BIA 2–093), a new voltage-gated sodium channel blocker. Biopharm Drug Dispos 28:249256.
  • Faught E, Limdi N. (2009) Oxcarbazepine. In Shorvon S, Perucca E, Engel J (Eds) The treatment of epilepsy. Blackwell Publishing, Oxford, pp. 575584.
  • Gil-Nagel A, Lopes-Lima J, Almeida L, Maia J, Soares-Da-Silva P. (2009) Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures. Acta Neurol Scand 120:281287.
  • Gil-Nagel A, Elger C, Ben-Menachem E, Halasz P, Lopes-Lima J, Gabbai AA, Nunes T, Falcao A, Almeida L, Soares-da-Silva P. (2013) Efficacy and safety of eslicarbazepine acetate as add-on treatment in patients with focal-onset seizures: integrated analysis of pooled data from double-blind phase III clinical studies. Epilepsia 54:98107.
  • Hainzl D, Parada A, Soares-da-Silva P. (2001) Metabolism of two new antiepileptic drugs and their principal metabolites S(+)- and R(-)-10,11-dihydro-10-hydroxy carbamazepine. Epilepsy Res 44:197206.
  • Halasz P, Cramer JA, Hodoba D, Czlonkowska A, Guekht A, Maia J, Elger C, Almeida L, Soares-da-Silva P. (2010) Long-term efficacy and safety of eslicarbazepine acetate: results of a 1-year open-label extension study in partial-onset seizures in adults with epilepsy. Epilepsia 51:19631969.
  • Hebeisen S, Brady K, Konrad D, Soares-da-Silva P. (2011) Inhibitory effects of eslicarbazepine acetate and its metabolites against neuronal voltage-gated sodium channels. Epilepsia 52(Suppl. 6):257258.
  • Hebeisen S, Brady K, Soares-da-Silva P. (2012) The effects of eslicarbazepine and R-licarbazepine on sodium currents through Nav1.7 and Nav1.8 channels. Epilepsia 53 (Suppl. 5):4748.
  • Hufnagel A, Ben-Menachem E, Gabbai AA, Falcao A, Almeida L, Soares-da-Silva P. (2013) Long-term safety and efficacy of eslicarbazepine acetate as adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy: results of a 1-year open-label extension study. Epilepsy Res 103:262269.
  • Maia J, Almeida L, Falcão A, Soares E, Mota F, Potgieter JH, Potgieter MA, Soares-da-Silva P. (2008) Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate. Int J Clin Pharmacol Ther 46:119130.
  • Nunes T, Rocha JF, Falcao A, Almeida L, Soares-da-Silva P. (2013) Steady-state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine in healthy volunteers. Epilepsia 54:108116.
  • Pekcec A, Potschka H, Soares-da-Silva P. (2011) Effects of eslicarbazepine acetate and its metabolites in the corneal kindling model of epilepsy. Epilepsia 52(Suppl. 6):257.
  • Perucca E, Elger C, Halasz P, Falcao A, Almeida L, Soares-da-Silva P. (2011) Pharmacokinetics of eslicarbazepine acetate at steady-state in adults with partial-onset seizures. Epilepsy Res 96:132139.
  • Pires N, Palma N, Loureiro AI, Bonifacio MJ, Wright LC, Soares-da-Silva P. (2011) Effects of eslicarbazepine acetate, eslicarbazepine, carbamazepine and oxcarbazepine in the maximal electroconvulsive shock test in the mice. Epilepsia 52(Suppl. 6):118.
  • Soares-da-Silva P, Hebeisen S. (2012) Slow and fast inactivation of voltage-gated sodium channels by eslicarbazepine and carbamazepine. Epilepsia 53(Suppl. 5):54.
  • Soares-da-Silva P, Bulling A, Hebeisen S, Konrad D. (2011) The effects of eslicarbazepine, R-licarbazepine and carbamazepine on ion transmission through Kv7.2 channels. Epilepsia 52(Suppl. 6):258259.
  • Torrao L, Machado R, Pires N, Palma N, Bonifacio MJ, Wright LC, Soares-da-Silva P. (2011) Effects of eslicarbazepine acetate, eslicarbazepine, carbamazepine and oxcarbazepine in the 6-HZ psychomotor seizure model in the mice. Epilepsia 52(Suppl. 6):118119.
  • Volosov A, Xiaodong S, Perucca E, Yagen B, Sintov A, Bialer M. (1999) Enantioselective pharmacokinetics of 10-hydroxycarbazepine after oral administration of oxcarbazepine to healthy Chinese subjects. Clin Pharmacol Ther 66:547553.

Supporting Information

  1. Top of page
  2. Summary
  3. Population and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosures
  8. References
  9. Supporting Information
FilenameFormatSizeDescription
epi12242-sup-0001-DataS1.docxWord document116KData S1. Population and Methods (participants and interventions) and Results (study population).
epi12242-sup-0002-TableS1-S4.docxWord document102K

Table S1. Randomization table.

Table S2. Treatment allocations.

Table S3. Main demographic characteristics.

Table S4. Number of subjects (%) reporting treatment-emergent adverse events (TEAEs) following a repeated-dose regimen of eslicarbazepine acetate (ESL) and oxcarbazepine (OXC).

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