Steady-state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine in healthy volunteers

Authors


Address correspondence to Patrício 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@bial.com

Summary

Purpose:  To evaluate the pharmacokinetics and tolerability of once-daily eslicarbazepine acetate (ESL) and twice-daily oxcarbazepine (OXC) and their metabolites in cerebrospinal fluid (CSF) and plasma following repeated oral administration.

Methods:  Single-center, open-label, randomized, parallel-group study in healthy volunteers. Volunteers in ESL group (n = 7) received 600 mg on days 1–3 and 1,200 mg on days 4–9, once daily. Volunteers in the OXC group (n = 7) received 300 mg on days 1–3 and 600 mg on days 4–9, twice daily. Plasma and CSF sampling was performed following the last dose.

Key Findings:  Eslicarbazepine was the major drug entity in plasma and CSF, accounting for, respectively, 93.84% and 91.96% of total exposure in the ESL group and 78.06% and 76.42% in the OXC group. The extent of exposure to drug entities R-licarbazepine and oxcarbazepine was approximately four-fold higher with OXC as compared with ESL. There was relatively little fluctuation from peak-to-trough (ratio) in the CSF for both eslicarbazepine (ESL = 1.5; OXC = 1.2) and R-licarbazepine (ESL = 1.2; OXC = 1.2). In contrast, oxcarbazepine showed larger differences between peak and trough (ESL = 3.1; OXC = 6.4). A total of 84 and 24 treatment-emergent adverse events (TEAEs) were reported with OXC and ESL, respectively.

Significance:  In comparison to OXC, administration of ESL resulted in more eslicarbazepine, less R-licarbazepine, and less oxcarbazepine in plasma and CSF, which may correlate with the tolerability profile reported with ESL. The smaller peak-to-trough fluctuation of eslicarbazepine in CSF (a measure of sustained delivery to the brain) than in plasma supports once-daily dosing of ESL.

Eslicarbazepine acetate (ESL) was initially described as endowed with distinctive anticonvulsant properties (Ambrosio et al., 2002; Benes et al., 1999) and was later approved by the European Medicines Agency (EMA) as once-daily adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization. The ESL epilepsy clinical program included an initial proof-of-concept phase II study (Elger et al., 2007) and three subsequent phase III studies in patients who were refractory to conventional antiepileptic drug (AED) therapy (Ben-Menachem et al., 2010; Elger et al., 2009; Gil-Nagel et al., 2009). Long-term safety and maintenance of therapeutic effect was demonstrated in 1-year open-label extensions of these studies (Gabbai et al., 2008; Lopes-Lima et al., 2008; Halasz et al., 2010). Incidence of rash, hyponatremia, and changes in body weight were low (Almeida et al., 2009).

Although structurally distinct from carbamazepine (CBZ) and oxcarbazepine (OXC), ESL is chemically related to these carboxamide derivatives (Benes et al., 1999). This molecular distinction results in differences in 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).

Following oral administration, ESL undergoes extensive first-pass hydrolysis to its major active metabolite eslicarbazepine (S-licarbazepine) (Falcao et al., 2007; Almeida et al., 2008a,b; Maia et al., 2008; Perucca et al., 2009), which represents approximately 95% of circulating active moieties. Plasma levels of ESL usually remain below the limit of quantification (50 ng/ml). Minor active metabolites are R-licarbazepine and oxcarbazepine. Steady-state of eslicarbazepine plasma concentrations are reached within 4–5 days of 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).

Oxcarbazepine 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 (S-MHD) and R-licarbazepine (R-MHD) in the proportion of 4:1 (Volosov et al., 1999). A small fraction (4%) of OXC is oxidized to the inactive dihydroxy derivative (DHD) (Faught & Limdi, 2009). 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).

Eslicarbazepine acetate and OXC active metabolites are formed in peripheral tissues (intestinal mucosa and liver) during and after intestinal absorption and have to cross the blood–brain barrier to exert their action in the central nervous system (CNS). It is unknown, however, how the ESL and OXC metabolites differ in their ability to cross the blood–brain barrier, whether their concentrations in the cerebrospinal fluid (CSF) correlate with their plasma concentrations, and whether eventual differences in CSF pharmacokinetics correlate with their therapeutic regimens.

The objectives of this study were to evaluate the steady-state pharmacokinetics in CSF and plasma, as well as the tolerability, of once-daily ESL and twice-daily OXC following oral administration of equivalent daily doses to healthy volunteers.

Population and Methods

Study design and ethics compliance

This was a phase I, single center, open-label, randomized, parallel-group, multiple-dose study in healthy volunteers. The study was conducted according to the principles of the Declaration of Helsinki and the Good Clinical Practice (ICH) guidelines. An Independent Ethics Committee (Commissie voor Medische Ethiek, ZNA Middelheim, Lindendreef 1, 2020 Antwerpen) reviewed and approved the study protocol and the subject information. Written informed consent was obtained for each subject before enrollment in the study.

Participants

Healthy male and female volunteers were recruited and tested by a single center in Belgium (SGS Life Sciences Services, Antwerp, Belgium). Volunteers satisfied the following main inclusion criteria: age within 18 and 55 years; body mass index (BMI) within 18.5–29.0 kg/m2; “healthy” as determined by medical history, vital signs, physical examination, 12-lead electrocardiography (ECG), and clinical laboratory evaluation (including hematology, coagulation, plasma biochemistry, urinalysis, and hepatitis B, hepatitis C, and human immunodeficiency virus serology).

The main exclusion criteria included any clinically relevant disorder, including evidence of significant active neuropsychiatric disease or history of neurologic disorder; medical or surgical conditions in which lumbar puncture is contraindicated or likely difficult access to the lumbar sack, such as prior lumbar surgery, lumbar stenosis, significant osteoarthritis or clinically significant congenital deformities of the spine; history of frequent headache, intracranial or intraspinal pathology. With the exception of paracetamol for the treatment of mild adverse events (AEs) (e.g., headache), no drugs were to be taken within 14 days before the first administration of study medication. Women of childbearing potential were not allowed to take hormonal contraceptives and they had to agree to use a double-barrier method. Lactating or pregnant women were excluded from participation.

Interventions

Participants underwent health status screening within 21 days before admission to the study. On day 1, volunteers were admitted to the clinical center. Following confirmation of eligibility, volunteers were randomized to one of two treatment groups (ESL group or OXC group) according to a randomization list prepared by using computerized techniques. Allocation to the treatment groups was gender balanced. Volunteers assigned to ESL group received 600 mg (1 tablet strength 600 mg, Zebinix/Exalief [eslicarbazepine acetate] tablets, BIAL – Portela & Ca, S.A., S. Mamede do Coronado, Portugal, batch 060157-L), once daily, from day 1 to day 3, and 1,200 mg (2 × 600 mg tablets) ESL, once daily, from day 4 to day 9. Volunteers assigned to OXC group received 300 mg (one tablet strength 300 mg, Trileptal [oxcarbazepine] tablets, Novartis Pharma (Novartis Pharma N.V., Vilvoorde, Belgium), batch T0355), twice daily, from day 1 to day 3, and 600 mg OXC, twice daily, from day 4 to day 9. ESL was administered in the morning, whereas OXC was administered approximately every 12 h, in the morning and the evening. The dosage regimens for the current study were determined based on the results of the ESL phase III studies (Elger et al., 2009; Gil-Nagel et al., 2009; Ben-Menachem et al., 2010) and the recommended posology of OXC (Schmidt & Sachdeo, 2000) as adjunctive therapy for partial-onset seizures.

Administration of study medication occurred under supervision of the investigation staff. For this purpose, volunteers were asked to visit the clinic every day from day 1 to day 8 for investigational product administration. The doses of investigational product were administered with 240-ml water, in fasted conditions. In the evening of day 8, volunteers were confined to the clinic for a period of approximately 60 h. In each group, the last dose of investigational product was administered on the morning of day 9 and blood and CSF sampling taken for pharmacokinetic assessments.

On day 11, after physical examination, blood and urine clinical laboratory tests, vital signs, and ECG recordings, the volunteers were discharged from the clinic. The end-of-study visit was performed approximately 5 days after discharge. The procedure included a general physical examination, vital signs measurement, 12-lead ECG recordings, and blood and urine clinical laboratory tests. A urine pregnancy test was performed in women of childbearing potential.

Standardized meals were served during volunteers’ confinement in the clinic. No alcohol or xanthine- or grapefruit-containing beverages or foods were to be taken from 48 h before the first dose of investigational product until 24 h after the last dose.

Safety assessments

Safety assessments consisted of adverse events monitoring, physical examinations, vital signs measurements, 12-lead ECG recordings, and standard blood and urine clinical laboratory tests. All AEs were monitored throughout the entire study period. AEs were assessed with respect to intensity (severity) and relationship to the investigational product by the clinical investigator. On day 9, blood pressure, heart rate, and 12-lead ECG parameters were recorded after 5 min in the supine position at predose and at 2, 4 (vital signs only), and 48 h postdose.

Pharmacokinetic assessments and bioanalytic methods

Blood and CSF samples for the determination of drug concentrations were taken on day 9 from predose up to the end of a dosing interval. Blood samples for plasma assays were collected by venipuncture at the following time points: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 h post-dose (16 and 24 h postdose only in ESL group). Blood samples were collected into tubes containing lithium-heparin anticoagulant and centrifuged at approximately 1,500 g for 10 min at 4–8°C. The resulting plasma was then separated into three aliquots of 500 μl and stored at −70°C until required for analysis.

CSF samples (approximately 1.5 ml) were taken by lumbar puncture at the following time points: predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 h postdose (16 and 24 h postdose only in ESL group). Local anesthetic (lidocaine 2% with epinephrine) was infiltrated subcutaneously for the lumbar puncture. An indwelling intrathecal catheter was inserted by a trained and experienced physician. A volume of CSF equivalent to the calculated dead volume of the catheter was discarded before each sample collection. While the catheter was in situ, volunteers remained in the supine position. The CSF samples were separated into three tubes with 500 μl per tube. On day 9 evening (OXC group) or day 10 morning (ESL group), the catheter was removed. Volunteers had to remain in bed until at least 6 h after removal of the catheter and to remain under clinical observation until at least the morning of day 11; then, they could leave the clinic if there were no symptoms of CSF leakage from the lumbar puncture site.

After the administration of ESL and OXC, plasma and CSF concentrations of ESL, eslicarbazepine, R-licarbazepine, and oxcarbazepine were determined by Algorithme Pharma Inc (Laval, QC, Canada) using validated liquid chromatography with tandem mass spectrometry detection (LC-MS/MS) methods derived from a method described elsewhere (Falcao et al., 2007). In brief, aliquots of human CSF and artificial CSF (50.0 μl) were added to 750 μl of internal standard working solution (60.0 ng/ml 10,11-dihydrocarbamazepine), except the blank sample to which was added 750 μl of water 3% of acetonitrile (v/v) solution. For plasma samples, 100 μl of human plasma was added to 500 μl of internal standard working solution (500.0 ng/ml 10,11-dihydrocarbamazepine), except the blank sample to which was added 500 μl of water 3% of acetonitrile (v/v) solution. Next, CSF and plasma samples placed into (16*125 mm) glass culture tubes were vortex-mixed and loaded into Varian Bond-Elut C18 cartridges (100 mg/1 ml), which were conditioned previously with 0.5 ml of methanol and 0.5 ml of water 3% of acetonitrile (v/v) solution. After sample elution, the loaded cartridges were centrifuged at 54 g for 2 min at 22°C nominal, acceleration low, deceleration high. Cartridges were rinsed with 500 μl of water 3% acetonitrile (v/v) solution and centrifuged at 485 g for 1 min at 22°C nominal, acceleration low, deceleration high. Following transfer into clean glass culture tubes (13 × 100 mm), 250 μl of acetonitrile was added to the cartridges and centrifuged at 54 g for 1 min at 22°C nominal, acceleration low, deceleration high. A second cartridge wash was performed with acetonitrile followed by centrifugation at 1942 g for 2 min at 22°C nominal, acceleration low, deceleration high. Cartridges were then discarded and the eluted sample evaporated in a TurboVap with the temperature control set at 50°C for approximately 10 min. Residue was reconstituted with 150 μl (CSF samples) or 1,000 μl (plasma samples) of n-hexane-to-isopropyl alcohol (90/10; v/v) solution, vortex-mixed, and transferred to a polypropylene vial to be injected. The analysis was performed using an LC-MS/MS system consisting of an 1100 HPLC (Hewlett Packard, Santa Clara, CA, U.S.A.) and an API 3000 MS/MS detector (PE Biosystems, Framingham, MA, U.S.A.). A Chiralcel OD-H column (50 × 4.6 mm, 5 μm, Chiral Technologies Europe SAS, Illkirch, France) was employed. High performance liquid chromatography (HPLC) mobile phase A was n-hexane, mobile phase B was ethanol-to-isopropyl alcohol (66.7/33.3% v/v) with an isocratic mixture of 80% mobile phase A: 20% mobile phase B and the HPLC flow rate was 0.8 ml/min. A sample volume of 20 μl was injected. The autosampler cooler was maintained at 4°C, and the column temperature was kept at 30°C for a run time of 8 min. Electrospray ionization in positive mode was used for the mass spectrometer methods. Ethanol: 200 mm ammonium acetate solution 95:5% v/v 0.1 ml/min was added postcolumn. The multiple reaction monitoring were m/z 297.3→194.4, collision energy of 31 eV for ESL; m/z 255.2→194.4, collision energy of 31 eV for eslicarbazepine and R-licarbazepine; m/z 253.2→208.3, collision energy of 31 eV for oxcarbazepine; m/z 239.4→194.4, collision energy of 31 eV for 10,11-dihydrocarbamazepine. The retention times for each compound were the following: 3.02 min for ESL; 3.02 min for eslicarbazepine; 2.37 min for R-licarbazepine; 4.10 min for oxcarbazepine; 2.30 min for 10,11-dihydrocarbamazepine. For all analytes, the lower limit of quantification of the assay was 10 ng/ml in CSF and 50 ng/ml in plasma. The data for the quality control samples from all four analytes showed that the overall imprecision of the method, measured by the coefficient of variation, ranged from 3.2% to 12.5% in CSF and from 2.5% to 12.1% in plasma. The mean accuracy (% nominal) ranged from 95.6% to 110.2% in CSF and from 98.7% to 107.2% in plasma.

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

Analyses

For this exploratory study, no formal sample size calculation was performed. At least six volunteers completing each study group were considered compatible with a reasonable clinical interpretation and descriptive statistics.

Adverse events were tabulated and summarized according to the Medical Dictionary for Regulatory Activities (MedDRA, version 11.1). QTc was calculated using the Bazett formula (QTcB = QT interval divided by the square root of the RR interval) and the Fridericia formula (QTcF = QT interval divided by the cube root of the RR interval). Blood pressure, heart rate, ECG parameters, and clinical laboratory data were summarized using descriptive statistics.

The following pharmacokinetic parameters for each analyte were derived by noncompartmental analysis from the individual plasma and CSF concentration-time profiles: maximum observed concentration (Cmax); time of occurrence of Cmax (tmax); minimum observed concentration (Cmin); 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 (AUCτ, i.e., AUC0–24 in the ESL group and AUC0–12 in the OXC group), 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; apparent terminal half-life (t1/2) calculated from ln2/λz; fluctuation (%), calculated from 100*(Cmax − Cmin)/Cavg, where Cavg is the average concentration and fluctuation (peak-to-trough) calculated as Cmax/Cmin.

The pharmacokinetic parameters were calculated with WinNonlin (Version 5.2; Pharsight Corporation, Mountain View, CA, U.S.A.). 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 (Version 9.1.3; SAS Institute Inc, Cary, NC, USA). Cmax and AUCτ of eslicarbazepine, R-licarbazepine and oxcarbazepine were compared for CSF versus plasma within each group, and for plasma versus plasma and CSF versus CSF between groups using an analysis of variance (ANOVA). The point estimates (PEs) and 90% confidence intervals (90% CIs) for the geometric mean ratios (GMRs) of the log-transformed Cmax and AUCτ were calculated. Statistical significance was accepted when the 90% CI interval did not include 100%. To allow between-group AUC0–24 comparisons, AUC0–24 in the OXC group was obtained by doubling AUCτ (i.e., AUC0–12).

Results

Study population

In total, 14 volunteers (7 in each group) were admitted to the study. Their demographic characteristics are summarized in Table 1. No between-group relevant differences were found in demographic characteristics.

Table 1.   Main demographic characteristics by treatment group
ParameterESL group (n = 7)OXC group
(n = 7)
Age, years  
 Mean ± SD44.6 ± 8.342.3 ± 6.9
 Median (range)48 (26–49)41 (33–54)
Height, cm  
 Mean ± SD174.0 ± 8.8169.1 ± 6.3
 Median (range)172 (163–185)168 (161–178)
Weight, kg  
 Mean ± SD76.8 ± 11.470.6 ± 10.0
 Median (range)75.6 (65.4–97.4)70.0 (57.4–83.4)
BMI, kg/m2  
 Mean ± SD25.3 ± 2.124.7 ± 3.2
 Median (range)25.0 (23.1–28.8)23.2 (21.0–29.1)
Sex, n (%)  
 Female3 (42.9)4 (57.1)
 Male4 (57.1)3 (42.9)
Race, n (%)  
 White/Caucasian6 (85.7)7 (100.0)
 Asian1 (14.3)0

Initially, 12 volunteers were admitted and randomized to one of the treatment groups (six volunteers in each group; three men and three women). A male subject in the ESL group did not consent to the CSF sampling and was replaced. Due to catheterization difficulties caused by spinal scoliosis, CSF sampling was not possible in a female subject of the OXC group and she was replaced. Therefore, 12 volunteers (six volunteers in each group; three men and three women) constituted the CSF pharmacokinetics population. All enrolled volunteers (seven volunteers in each group) were included in the safety and plasma pharmacokinetic analyses.

Pharmacokinetic results

Mean plasma and CSF drug concentration-time profiles following twice-daily 600-mg OXC and once-daily 1,200-mg ESL are displayed in Figures 1–3. The corresponding pharmacokinetic parameters are presented in Table 2. Concentration-time profiles and pharmacokinetic parameters could not be calculated for ESL, because its plasma and CSF levels were always below the limit of quantification. Estimation of the apparent terminal t1/2 of eslicarbazepine, R-licarbazepine, and oxcarbazepine was of limited reliability because the period over which the rate constant (λz) was calculated was lower than 2 times the estimated t1/2 value in several volunteers. The duration of sampling was 24 h for the ESL group, allowing approximate determination of half-life, but was limited to 12 h for the OXC group. AUC0–∞ could also not be reliably assessed because the extrapolated area was >20% of the total AUC in several volunteers. Therefore, Table 2 does not display t1/2 for the OXC group and does not display AUC0–∞ for either group.

Figure 1.


Plasma (A) and CSF (B) concentration-time profiles of eslicarbazepine during a dosing interval following the last dose of a repeated-dose regimen of once-daily 1,200-mg ESL and of twice-daily 600-mg OXC to healthy volunteers (plasma profile: n = 7 in each group; CSF profile: n = 6 in each group).

Figure 2.


Plasma (A) and CSF (B) concentration-time profiles of R-licarbazepine during a dosing interval following the last dose of a repeated-dose regimen of once-daily 1,200-mg ESL and of twice-daily 600-mg OXC to healthy volunteers (plasma profile: n = 7 in each group; CSF profile: n = 6 in each group).

Figure 3.


Plasma (A) and CSF (B) concentration-time profiles of oxcarbazepine during a dosing interval following the last dose of a repeated-dose regimen of once-daily 1,200-mg ESL and of twice-daily 600-mg OXC to healthy volunteers (plasma profile: n = 7 in each group; CSF profile: n = 6 in each group).

Table 2.   Pharmacokinetic parameters of eslicarbazepine, R-licarbazepine, and oxcarbazepine following the last dose of a repeated-dose regimen of once-daily 1,200-mg ESL and twice-daily 600-mg OXC to healthy volunteers (plasma profile: n = 7 in each group; CSF profile: n = 6 in each group)
 Plasma (n = 7)CSF (n = 6)
EslicarbazepineR-licarbazepineOxcarbazepineEslicarbazepineR-licarbazepineOxcarbazepine
  1. Data are given as arithmetic mean ± SD (median and range for tmax). T1/2 is not stated for OXC administration as the duration of sampling was limited to 12 h.

ESL group      
 Cmax, ng/ml24,698 ± 6,630911 ± 235253 ± 737,616 ± 1,050553 ± 14596 ± 27
 tmax, h2.4 (1.0–6.0)8.0 (0.5–16.0)3.0 (1.0–6.0)12.0 (6.0–16.0)12.0 (0.5–16.0)4.0 (4.0–12.0)
 Cmin, ng/ml8,417 ± 2,696642 ± 17157 ± 275,027 ± 1,054451 ± 11531 ± 4
 AUC0–t, ng h/ml345,962 ± 70,41219,182 ± 4,6193,445 ± 762155,777 ± 22,49512,072 ± 2,9091,543 ± 287
 AUCτ (0–24), ng h/ml345,962 ± 70,41219,182 ± 4,6193,520 ± 679155,777 ± 22,49512,072 ± 2,9091,543 ± 287
 Fluctuation, %113.0 ± 33.733.2 ± 9.2133.0 ± 35.240.6 ± 12.120.1 ± 5.699.0 ± 21.3
 Fluctuation (peak-to-trough)2.91.44.41.51.23.1
 T1/215.9 ± 2.264.1 ± 41.710.7 ± 2.324.8 ± 8.161.8 ± 32.110.9 ± 0.7
OXC group      
 Cmax, ng/ml16,353 ± 2,6624,077 ± 6132,129 ± 9417,610 ± 9122,166 ± 327459 ± 109
 tmax, h3.0 (2.0–4.0)3.0 (2.0–4.0)1.5 (1.0–1.5)6.0 (1.5–8.0)6.0 (6.0–8.0)2.0 (1.5–2.0)
 Cmin, ng/ml10,945 ± 1,8432,409 ± 426124 ± 186,567 ± 7791,785 ± 26072 ± 17
 AUC0–t, ng h/ml167,160 ± 29,90439,564 ± 7,0947,439 ± 2,56186,608 ± 9,54524,201 ± 3,4952,513 ± 400
 AUCτ (0–12), ng h/ml167,160 ± 29,90439,564 ± 7,0947,439 ± 2,56186,608 ± 9,54524,201 ± 3,4952,513 ± 400
 Fluctuation, %39.0 ± 6.451.1 ± 10.3315.0 ± 43.814.4 ± 2.118.8 ± 4.0182.0 ± 24.8
 Fluctuation (peak-to-trough)1.51.717.21.21.26.4

Eslicarbazepine was the predominant drug moiety both in plasma and CSF after oral administration of twice-daily 600-mg OXC and once-daily 1,200-mg ESL (Table 2). Using AUCτ as a measure of extent of exposure, eslicarbazepine corresponded to 93.84% of total drug moieties in plasma and to 91.96% in CSF following once-daily 1,200-mg ESL. Following twice-daily 600-mg OXC, eslicarbazepine corresponded to 78.06% in plasma and 76.42% in CSF. R-Licarbazepine and oxcarbazepine corresponded to, respectively, 5.20% and 0.96% in plasma and 7.13% and 0.91% in CSF following ESL, and to, respectively, 18.47% and 3.47% in plasma and 21.36% and 2.22% in CSF following OXC. Exposure to eslicarbazepine, R-licarbazepine, and oxcarbazepine was substantially lower in CSF as compared with plasma, in both groups (Table 3). PEs and 90% CIs for the main pharmacokinetic parameters (Cmax and AUCτ) of all analytes following once-daily 1,200-mg ESL and twice-daily 600-mg OXC are displayed in Table 3 (CSF vs. plasma in each group) and Table 4 (OXC vs. ESL in each matrix). Following ESL administration, the apparent terminal t1/2 for eslicarbazepine is approximately 24.8 h in CSF versus 15.9 h in plasma.

Table 3.   CSF/plasma geometric mean ratios (point estimates, PEs) and 90% confidence intervals (90% CIs) for Cmax and AUCτ (0–24) of eslicarbazepine, R-licarbazepine, and oxcarbazepine following the last dose of a repeated-dose regimen of once-daily 1,200-mg ESL and twice-daily 600-mg OXC to healthy volunteers
CSF/plasma ratioEslicarbazepineR-LicarbazepineOxcarbazepine
ESL group   
 Cmax   
  PE, %31.5860.7638.00
  90% CI25.35–39.3547.23–78.1829.21–49.44
 AUCτ (0–24)   
  PE, %45.4362.9143.86
  90% CI38.21–54.0049.87–79.3536.65–52.50
OXC group   
 Cmax   
  PE, %46.8153.1422.51
  90% CI40.43–54.2045.82–61.6316.24–31.19
 AUCτ (0–12)   
  PE, %52.3261.4834.83
  90% CI44.74–61.1952.29–72.2727.23–44.55
Table 4.   OXC/ESL geometric mean ratios (point estimates, PEs) and 90% confidence intervals (90% CIs) for Cmax and AUCτ of eslicarbazepine, R-licarbazepine, and oxcarbazepine following the last dose of a repeated-dose regimen of once-daily 1,200-mg ESL and twice-daily 600-mg OXC to healthy volunteers
OXC/ESL ratioEslicarbazepineR-LicarbazepineOxcarbazepine
  1. aCalculated as 1 × AUCτ for ESL and 2 × AUCτ for OXC.

Plasma   
 Cmax   
  PE, %67.53455.84811.40
  90% CI54.46; 83.75374.80; 554.39595.78; 1105.06
 AUC0–24a   
  PE, %96.86416.51411.32
  90% CI80.60; 116.41342.87; 505.97325.40; 519.94
CSF   
 Cmax   
  PE, %100.09398.64480.54
  90% CI87.79; 114.13320.42; 495.96366.23; 630.54
 AUC0–24a   
  PE, %111.56407.04326.61
  90% CI98.02; 126.97331.75; 499.42272.67; 391.22

In the CSF, peak-to-trough fluctuations for both eslicarbazepine (1.5 and 1.2 following ESL and OXC, respectively) and R-licarbazepine (1.2 following either ESL or OXC) was small, with no relevant differences between ESL or OXC groups. In contrast, oxcarbazepine showed larger peak-to-trough fluctuations, which were more than twice higher in the OXC group (3.1 and 6.4 following ESL and OXC, respectively) (Table 2).

The OXC/ESL geometric mean ratios for Cmax and AUCτ of eslicarbazepine, R-licarbazepine, and oxcarbazepine, a measure of the relative exposure with both medications, are depicted in Table 4. Eslicarbazepine Cmax in plasma was significantly lower (PE, 90% CI: 68%, 54–84%) following OXC 600-mg twice-daily as compared with ESL 1,200-mg once-daily, although the between-group analysis of Cmax in CSF and AUC0–24 for eslicarbazepine both in plasma and CSF were comparable (Table 4). Substantial between-group differences were found both for Cmax and AUC0–24 of R-licarbazepine and oxcarbazepine in both plasma and CSF. In comparison with ESL, R-licarbazepine Cmax and AUC0–24 following OXC were, respectively, 456% and 417% higher in plasma and 399% and 407% higher in CSF. For oxcarbazepine, Cmax in plasma and CSF was, respectively, 811% and 481%, and AUC0–24 was respectively, 411% and 327%, higher with OXC 600 mg twice daily as compared with ESL 1,200 mg once daily.

Safety results

During the course of the study, a total of 24 treatment-emergent adverse events (TEAEs) were reported by 6 (86%) volunteers in the ESL group, and a total of 84 TEAEs were reported by 7 (100%) volunteers in the OXC group (Table 5). The most frequent TEAE with ESL was dizziness, reported by 3 (43%) volunteers. The most frequent TEAE with OXC was headache (all volunteers, 100%), followed by dizziness (six volunteers, 86%), and fatigue, nausea, and back pain (5 volunteers each, 71%). All TEAEs were mild or moderate in severity, but syncope in 1 (14%) and 2 (29%) volunteers in OXC and ESL groups, respectively, was reported to be severe and considered by investigator not related to study medication. No serious AEs or TEAEs leading to discontinuation were reported in any group.

Table 5.   Number of treatment-emergent adverse events (TEAEs) and their incidence (% of subjects with that particular AE) of following a repeated-dose regimen of eslicarbazepine acetate (ESL) and oxcarbazepine (OXC)
TEAEsESL groupOXC group
Incidence
n (%)
Number of eventsIncidence
n (%)
Number of events
Headache2 (29)27 (100)13
Dizziness3 (43)46 (86)12
Fatigue2 (29)25 (71)9
Somnolence1 (14)43 (43)7
Nausea1 (14)15 (71)7
Vision blurred003 (43)6
Back pain1 (14)15 (71)5
Stomach discomfort003 (43)5
Memory impairment002 (29)2
Nasopharyngitis002 (29)2
Diarrhea001 (14)2
Syncope2 (29)21 (14)1
Post lumbar puncture syndrome2 (29)200
Muscle spasms2 (29)200
Hypoesthesia oral1 (14)21 (14)1
Dizziness postural1 (14)100
Musculoskeletal stiffness1 (14)11 (14)1
Feeling cold001 (14)1
Emotional disorder001 (14)1
Listless001 (14)1
Thirst001 (14)1
Dermatitis001 (14)1
Abdominal pain001 (14)1
Increased appetite001 (14)1
Vomiting001 (14)1
Neck pain001 (14)1
Dysgeusia001 (14)1
Presyncope001 (14)1
Any TEAE6 (86)247 (100)84

No clinically significant abnormalities were observed in clinical laboratory tests and vital signs. No QTcF or QTcB values ≥450 msec were observed, except in 1 subject in the OXC group who presented a QTcB = 450 msec on day 9, 2-h postdose, corresponding to an increase in QTcB of 40 msec compared to reference. No abnormalities in physical examination were observed.

Discussion

This study aimed to evaluate the plasma and CSF pharmacokinetic profiles and tolerability of ESL and OXC following repeated oral administration of 1,200 mg total daily dose for each drug in healthy volunteers.

Eslicarbazepine was the major drug metabolite both in plasma and CSF following oral administration of ESL and OXC. Using AUCτ as a measure of the extent of exposure, eslicarbazepine corresponded to 93.8% of total exposure of drug moieties in plasma following ESL, and 78.1% of total exposure in plasma following OXC. R-Licarbazepine corresponded to 5.2% of plasma exposure following ESL and 18.5% following OXC. These results are consistent with those from previous reports that showed that eslicarbazepine and R-licarbazepine are found in plasma in the approximate proportion of 20:1 following ESL administration (Almeida et al., 2005) and of 4:1 following OXC administration (Volosov et al., 1999). The proportions between eslicarbazepine and R-licarbazepine in the CSF did not differ substantially from those reported in plasma. However, CSF exposure was approximately half of that reported in plasma for any drug entity in any group. As shown in Table 4, significant between-group differences were found in both plasma and CSF regarding R-licarbazepine and oxcarbazepine. The Cmax and extent of exposure to R-licarbazepine and oxcarbazepine were approximately 4 times higher with twice-daily 600-mg OXC as compared with once-daily 1,200-mg ESL.

The TEAEs reported in this study generally accorded with the known profile of the drugs tested (Barcs et al., 2000; Ben-Menachem et al., 2010; Elger et al., 2009; Gil-Nagel et al., 2009), and CNS-related TEAEs such as dizziness and headache were the most commonly reported. The TEAEs reported here were relatively low in the group of healthy volunteers administered ESL, which is in agreement with the previously reported results from other studies in healthy volunteers administered ESL and OXC following single and repeated administration (Milovan et al., 2010). Despite the lack of head-to-head efficacy trials between ESL and OXC in patients with epilepsy, the overall incidence of discontinuations due to TEAEs was 4.5% for placebo, 8.7% for 400-mg ESL, 11.6% for 800-mg ESL, and 19.3% for 1,200-mg ESL once daily in phase III studies (Elger et al., 2009; Gil-Nagel et al., 2009; Ben-Menachem et al., 2010), whereas incidence of discontinuations for OXC in a large study with similar design was 8.7% for placebo and ranged from 11.9–36.2% on similar doses of twice-daily 300 and 600 mg, respectively (Barcs et al., 2000).

Cerebrospinal fluid exposure to the drug entities R-licarbazepine and oxcarbazepine was substantially lower following ESL administration as compared to OXC administration, in contrast with that for eslicarbazepine. Hence, there is an outstanding question to be answered as to what extent ESL and OXC may differ in their safety and tolerability profiles in patients with epilepsy, and if their pharmacokinetic and metabolic dissimilarities may account for the reported characteristics of their tolerability profiles. Although R-licarbazepine and oxcarbazepine are found in lower concentrations in the CSF than eslicarbazepine, they have greater affinities for the sodium channel in the resting state (Hebeisen et al., 2011). Therefore, despite the low concentrations of R-licarbazepine and oxcarbazepine, it is possible that they may contribute to CNS-related AEs (Pires et al., 2011; Torrao et al., 2011). Of interest, there is in vitro data showing that oxcarbazepine presents a distinctive low safety profile among carboxamide derivatives (Ambrosio et al., 2000; Araujo et al., 2004). On the other hand, similar affinities of eslicarbazepine, R-licarbazepine, 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).

A placebo-controlled, phase II study of ESL in patients with partial-onset seizures uncontrolled with one or two AEDs tested ESL doses of 400 mg, 800 mg, and 1200 mg, administered daily in one or two equally divided doses (Elger et al., 2007). ESL given once daily was shown 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 frequencies were generally well tolerated and tolerability was comparable with the once-daily regimen. On the basis of these results, a once-daily regimen was used in the Phase III studies. Results of the current study provide further evidence that ESL is suitable for once-daily dosing: while a fluctuation of 113% was reported for eslicarbazepine in plasma, the fluctuation of eslicarbazepine in CSF was lower (41%) in ESL-treated healthy volunteers (Table 2). The smaller peak-to-trough fluctuation of eslicarbazepine in CSF (1.5) than in plasma (2.9), a measure of sustained delivery to the brain, as well as the long apparent half-life of eslicarbazepine in CSF (24.8 ± 8.1 h) supports once-daily dosing of ESL.

Administration of ESL 1200 mg once-daily compared to OXC 600 mg twice-daily increased the extent of exposure to eslicarbazepine in both the plasma (93.84% vs. 78.06%, respectively) and CSF (91.96% vs. 76.42%, respectively). On the other hand, administration of OXC resulted in higher exposures to oxcarbazepine in plasma and the CSF compared to that observed after administration of ESL. Additionally, the fluctuation in exposure to residual oxcarbazepine in plasma and CSF was higher after administration of OXC compared to ESL, which may correlate with the tolerability profile reported with ESL.

Acknowledgments

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. This study was supported by BIAL – Portela & Ca, S.A.

Disclosure

A. Falcão received consultancy honoraria. L. Almeida, T. Nunes, J.F. Rocha, and P. Soares-da-Silva were employees of BIAL at the time of the studies. 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.

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