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PHARMACOKINETICS AND PHARMACODYNAMICS |
From the Department of Research and Development, BIAL, S Mamede do Coronado, Portugal.
Address for reprints: P. Soares-da-Silva, Department of Research & Development, BIAL, À Av. da Siderurgia Nacional, 4745-457 S. Mamede do Coronado, Portugal.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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(day 8)/AUC0- (day 1)) was 3.0 after repeated, twice-daily dosing and 1.4 to 1.7 after once-daily dosing. Steady-state plasma licarbazepine concentrations were attained at 4 to 5 days of once- or twice-daily dosing, consistent with an effective half-life on the order of 20 to 24 h. The mean renal clearance of licarbazepine from plasma was approximately 20 to 30 mL/min, which is low compared with the glomerular filtration rate. The total amount of licarbazepine recovered in urine was approximately 20% within 12 h postdose and 40% within 24 h postdose. All adverse events were mild in severity, except for 1 case of somnolence of moderate severity, which occurred in a subject receiving 1200 mg BIA 2-093. The incidence of adverse events was similar between all treatment groups, including placebo. There were no serious adverse events. In conclusion, BIA 2-093 was well tolerated and appeared to be rapidly and extensively metabolized to licarbazepine following single and repeated administration to healthy young subjects.
Key Words: BIA 2-093 • pharmacokinetics • anticonvulsants • epilepsy
BIA 2-093 (S-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide) is a novel anticonvulsant drug that shares with carbamazepine and oxcarbazepine the dibenzazepine nucleus bearing the 5-carboxamide substituent but is structurally different at the 10,11-position.8 This molecular variation results in differences in metabolism—namely by preventing the formation of toxic epoxide metabolites, such as carbamazepine-10,11 epoxide, and the unnecessary production of enantiomers or diastereoisomers of metabolites and conjugates9—without losing anticonvulsant potency. BIA 2-093 was shown to be an effective anticonvulsant in rats and mice and to exert protecting effects against maximal electroshock seizure (MES) and a variety of convulsant agents. In the rat model, BIA 2-093 was found to be particularly active against MES-induced seizures with anticonvulsant potency similar to that for carbamazepine but more potent than oxcarbazepine.8 In contrast to carbamazepine and oxcarbazepine, BIA 2-093 was found to be less effective in producing neurological impairment in both rats and mice.8
Mechanistically, BIA 2-093 appears not to interfere with receptors for benzodiazepines, 
-aminobutyric acid (GABA), and glutamate but behaves as a potent blocker of voltage-gated sodium channels, namely by interfering with site 2 of the channel.8,10,11 BIA 2-093 under in vitro experimental conditions was found to decrease veratrine-evoked neurotransmitter release.12 This suggests that BIA 2-093, like other antiepileptic drugs in this class, may exert anticonvulsant properties by interfering selectively with rapidly firing neurons over those displaying normal activity. BIA 2-093 was also shown to inhibit Na+ currents in a voltage-dependent way by an interaction with the inactivated state of the channel.13 Its affinity for this state of the channel was similar to that of carbamazepine, whereas the affinity of BIA 2-093 for the resting state of the channel was about 3-fold lower than that of carbamazepine.13 This profile may also suggest an enhanced inhibitory selectivity of BIA 2-093 for rapidly firing neurons over those displaying normal activity.13
In a previous entry-into-man study in healthy young male subjects,14 BIA 2-093 appeared to be rapidly and extensively metabolized to licarbazepine ((±)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide, major metabolite) and oxcarbazepine (minor metabolite) following single oral doses of 20 to 1200 mg BIA 2-093. The extent of systemic exposure, assessed by AUC, to licarbazepine tended to increase in a greater than dose-proportional manner over the studied dose range. However, the renal clearance of licarbazepine appeared to be constant over the dose range studied, indicating that the dose-dependent increased urinary recovery was due either to increased formation of licarbazepine with increasing dose level or to decreased nonrenal elimination of the metabolite. Following chiral analysis, it was concluded that the metabolism of BIA 2-093 in rats, dogs, monkeys, and humans gives origin to the S(+) enantiomer of licarbazepine (S-licarbazepine) and not the R(-) form (R-licarbazepine; see Fig. 1).9 In the present work, we describe the results of a study aiming to evaluate the safety, tolerability, and pharmacokinetics of multiple-dose regimens of BIA 2-093 in young healthy male volunteers.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Group 1: BIA 2-093 of 200 mg/placebo at 12-h intervals (bid) for days 1 to 7 inclusive, with a single dose of BIA 2-093 of 200 mg/placebo on day 8Groups 2, 3, and 4: BIA 2-093 of 400 mg/placebo, 800 mg/placebo, and 1200 mg/placebo, once daily (qd), for days 1 to 8 inclusive, respectively
Tablets of 200 mg BIA 2-093 and placebo tablets identical in appearance were used. Tablets containing BIA 2-093 were manufactured by BIAL in accordance with good manufacturing practice. The study was conducted according to the principles of the current revision of the Declaration of Helsinki and the good clinical practice (International Conference on Harmonization) guidelines. An independent ethics committee (Guy's Hospital Research Ethics Committee, London) reviewed and approved the study protocol and the subject information. Written informed consent was obtained for each subject prior to enrollment in the study.
Subjects
Thirty-two healthy male volunteers ages 18 to 45 years and with a body mass index (BMI) ranging from 19 to 28 kg/m2 participated in the study. Volunteers were considered to be healthy on the basis of medical history, physical examination, electrocardiogram (ECG), electroencephalogram (EEG), and clinical laboratory safety tests (hematology, plasma biochemistry, urinalysis, and hepatitis B, hepatitis C, and HIV serology) performed at screening. Tests for drugs of abuse and alcohol in urine were performed at screening and admission. No concomitant medication was allowed during the study. Volunteers were admitted to the unit approximately 24 h prior to receiving the study medication and remained in the unit under clinical supervision for at least 72 h after receiving the final dose. During admission, a standard diet was served. Caffeine, alcohol, and grapefruit-containing food and beverages were prohibited.
Assessment Procedures
At admission to the unit, medical history and physical examination were updated. During admission, supine and standing blood pressure and pulse rate were measured at frequent intervals. Continuous lead-II ECG monitoring was performed 0 to 6 h postdose on day 1 and day 8. Computerized 12-lead ECG recordings and a brief neurological examination for possible drug effects were obtained at frequent intervals during admission. Clinical laboratory tests (hematology, coagulation, plasma biochemistry, and urinalysis) were performed at admission; on days 1, 4, and 8; and 72 h after the final dose (discharge). Five to 7 days after discharge, a follow-up visit occurred; then, the medical history was updated and clinical laboratory safety tests performed.
All clinical adverse events were monitored throughout the entire study period. Their severity (intensity) was categorized according to a 3-point scale (mild, moderate, and severe), and the causality (potential relationship to drug) was assessed by the investigator before breaking the blind.
Blood samples (10 mL) for the assay of plasma BIA 2-093 and its metabolites licarbazepine and oxcarbazepine were taken by means of direct venipuncture or an intravenous catheter into lithium heparin Vacutainers at predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 7, 8, and 12 h after the first dose on day 1 and after the final dose on day 8. On day 8, further blood samples were taken at 24, 36, 48, and 72 h postdose. Predose blood samples were also taken on days 2 to 7, inclusively. After collection, the blood samples were centrifuged, and the resulting plasma was stored at -20°C until required for analysis. Plasma concentrations of BIA 2-093, licarbazepine, and oxcarbazepine were assayed using a method previously validated.
Urine samples were collected on day 1 predose and over the intervals from 0 to 4, 4 to 8, 8 to 12, and 12 to 24 h postdose. Urine samples were also collected on day 8 predose and over the intervals from 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 48, and 48 to 72 h after the final dose. The general procedure for handling and analyzing urine samples was the same as the procedure for handling and analyzing plasma samples.
Assay of BIA 2-093, Licarbazepine, and Oxcarbazepine Concentrations in Plasma
Plasma concentrations of BIA 2-093, licarbazepine, and oxcarbazepine were determined using isocratic liquid chromatography (LC) with single quadrupole mass-spectrometric detection (MS).
The method involved the addition of 500 µL of approximately 0.05 µg/mL of 10,11-dihydrocarbamazepine (internal standard prepared in acetonitrile/water, 3:97, v:v) to 250 µL of plasma (centrifuged at 1800 rpm, prior to analysis) in a polypropylene tube. After vortex mixing for 10 sec, the mixture was transferred to a C18 (100 mg, 1 mL) 96-well solid-phase extraction plate. Each well was preconditioned with 950 µL methanol, followed by 950 µL acetonitrile and 950 µL acetonitrile/water (3:97, v:v), prior to application of the total sample volume. Each polypropylene tube was then washed with 500 µL acetonitrile/water (3:97, v:v) and the washings transferred to the respective well. The compounds were eluted into a collection plate with 750 µL acetonitrile and the extract evaporated to dryness under oxygen-free nitrogen at 40°C. All solid-phase extraction manipulations were undertaken using the Tecan Genesis RSP 100 liquid-handling system, and a vacuum was applied at each elution step. The final extract was reconstituted in 500 µL of mobile phase and mixed for approximately 1 min. The collection plate was then centrifuged at approximately 3000 rpm (at approximately 4°C, for approximately 10 min) prior to analysis. An aliquot of the final extract (5 µL) was injected onto the LC-MS system.
The LC-MS system used in the analysis consisted of a PerkinElmer series 200 micro pump, a PerkinElmer series 200 autosampler, and a PerkinElmer Sciex API 150EX single quadrupole mass spectrometer fitted with a Turbo Ionspray® source. Separation was achieved using an XterraTM RP18 column (150 mm x 2.1 mm i.d., 5 µm), an XterraTM RP18 guard column (20 mm x 2.1 mm i.d., 5 µm), a Jones Chromatography 7971 column heater at 50°C, and an isocratic mobile phase (0.3 mL/min) consisting of acetonitrile/methanol/water (20:15:65, v:v:v) with 700 µM sodium acetate trihydrate. The MS detector was operated in single ion mode with monitoring masses for BIA 2-093, licarbazepine, oxcarbazepine, and the internal standard of 319.2 amu (200 ms), 277.0 amu (200 ms), 275.2 amu (200 ms), and 261.1 amu (200 ms), respectively.
Calibration curves, over the nominal concentration, ranged from 10 to 1000 ng/mL for BIA 2-093, licarbazepine, and oxcarbazepine, and a set of quality control (QC) samples (triplicates over 3 concentration levels) was analyzed with each batch of study samples. The QC samples were used to monitor the performance of the assay. The data for the QC samples showed that the overall imprecision of the method, measured by the coefficient of variation, ranged from 4.46% to 6.55% for BIA 2-093, from 5.11% to 6.64% for licarbazepine, and from 6.05% to 7.03% for oxcarbazepine. The overall inaccuracy (as distance of the determined value from the true or nominal value) ranged from -1.58% to 0.90% for BIA 2-093, from 4.94% to 6.90% for licarbazepine, and from -0.34% to 0.72% for oxcarbazepine. The limit of quantification of the assay was 10 ng/mL.
BIA 2-093 and licarbazepine were synthesized in the Laboratory of Chemistry at BIAL with purities > 99.5%. Oxcarbazepine was supplied by Farchemia (Italy). The internal standard, dihydrocarbamazepine, was supplied by Sigma-Aldrich (St Louis, Mo).
Assay of BIA 2-093, Licarbazepine, and Oxcarbazepine Concentrations in Urine
Urine concentrations of BIA 2-093, licarbazepine, and oxcarbazepine were also determined using liquid chromatography with single quadrupole mass-spectrometric detection (LC-MS). The method involved the addition of 500 µL of approximately 0.05 µg/mL of 10,11-dihydrocarbamazepine (internal standard prepared in acetonitrile/water, 3:97, v:v) to 250 µLofurine in a polypropylene tube. After vortex mixing for 10 sec, the mixture was transferred to an IST Multimode (100 mg) 96-well solid-phase extraction plate. Each well was preconditioned with 950 µL methanol, followed by 950 µL acetonitrile/0.1% formic acid and then 950 µL acetonitrile/water with 0.1% formic acid (3:97, v:v), prior to application of the total sample volume. Each polypropylene tube was then washed with 500 µL acetonitrile/water with 0.1% formic acid (3:97, v:v), and the washings were transferred to the respective well on the extraction plate. The compounds were eluted into a collection plate with 500 µL acetonitrile/methanol/water (40:30:30, v:v:v) and vacuum applied. Sodium acetate solution (1.5 mM, 500 µL) was added to each sample and samples centrifuged at 3000 rpm for 10 min at approximately 4°C prior to analysis. All solid-phase extraction manipulations were undertaken using the Tecan Genesis RSP 100 liquid-handling system, and a vacuum was applied at each elution step. An aliquot of the final extract (10 or 50 µL) was injected onto the LC-MS system.
Calibration curves, over the nominal concentration, ranged from 10 to 1000 ng/mL for BIA 2-093, licarbazepine, and oxcarbazepine, and a set of QC samples (triplicates over 3 concentration levels) was analyzed with each batch of study samples along with dilution QC samples where appropriate. The QC samples were used to monitor the performance of the assay. The data for the QC samples showed that the overall imprecision of the method, measured by the coefficient of variation, ranged from 4.15% to 9.55% for BIA 2-093, from 7.92% to 12.3% for licarbazepine, and from 2.67% to 7.72% for oxcarbazepine. The overall inaccuracy ranged from 1.80% to 5.43% for BIA 2-093, from 0.746% to 4.16% for licarbazepine, and from -1.76% to 1.35% for oxcarbazepine. The limit of quantification of the assay was 10 ng/mL.
Analysis
Pharmacokinetics Analysis
The appropriate pharmacokinetic parameters included the following: maximum observed plasma drug concentrations (Cmax); time of occurrence of Cmax (tmax); area under the plasma concentration-time curve (AUC) from time 0 to the last sampling time at which concentrations were at or above the limit of quantification (AUC0-t) and the AUC over the dosing interval (AUC0-), both calculated by the trapezoidal rule; AUC from time 0 to infinity (AUC0-
), calculated from AUC0-t +(Clast/
z), where Clast is the last quantifiable concentration; the apparent terminal rate constant (z) and corresponding terminal half-life (t1/2), calculated from ln 2/z; the observed degree of accumulation (RO), calculated from AUC0- (day 8)/AUC0- (day 1); and the theoretical degree of accumulation (RT), calculated from 1/(1 - e-z.), where is the dosing interval. These pharmacokinetic parameters for BIA 2-093, licarbazepine, and oxcarbazepine were to be derived by noncompartmental analysis using WinNonlin (Version 3.0, Pharsight Co, Palo Alto, Calif). In addition, the cumulative amount excreted and renal clearance of the drug from plasma were to be estimated from the urine data, if appropriate.
A nonlinear power model was used to assess dose proportionality following once-daily dosing. The relationship is written as a power function: parameter = a • doseb, where a is a constant, b is the proportionality constant, and the parameter is Cmax and AUC0-. Linearization of this relationship gives the following: log parameter = log a + log dose b. The relationship is dose proportional when b = 1. The exponent of the power function, with 95% confidence intervals, was fitted to the individual Cmax and AUC0-.
Tolerability
Individual and summary blood pressures, heart rate, ECG parameters, neurological examination, and clinical laboratory data were presented in tabular form with mean, median, standard deviation, and range (min and max) as appropriate. For the laboratory safety data, outof-range values were flagged in the data listings, and a list of clinically significantly abnormal values was presented. Adverse events were tabulated and summarized according to the World Health Organization Adverse Reaction Terminology (WHOART) dictionary and classified by body system.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Pharmacokinetics
Plasma concentrations of BIA 2-093 were generally below the limit of quantification of the assay at all time points postdose at all dose levels. Therefore, the pharmacokinetic parameters were not determined for BIA 2-093.
Plasma concentrations of licarbazepine were measurable at all time points on day 1 and day 8 (Fig. 2). On day 1, plasma concentrations of oxcarbazepine were generally measurable at all time points postdose and on day 8 were generally measurable up to 36 h following administration of 200 mg bid and 400 mg qd, as well as up to 48 h postdose following repeated administration of 800 mg qd and 1200 mg qd (Fig. 3). Mean predose plasma concentrations on days 2 to 8 and 24 h after the final dose (day 9) are shown in Figure 4. Mean pharmacokinetic parameters of licarbazepine and oxcarbazepine are listed in Table I. Following single and repeated oral doses of BIA 2-093, maximum plasma concentrations (tmax) of licarbazepine were reached, on average, at 2 to 3 h postdose. Plasma concentrations of licarbazepine declined with an approximate mean apparent terminal half-life of 8 to 21 h following the first dose and 9 to 13 h following repeated administration. Maximum plasma concentrations of oxcarbazepine were reached, on average, 4 to 6 h postdose. Plasma concentrations of oxcarbazepine declined with an approximate mean apparent terminal half-life of 6 to 9 h following the first dose and 13 to 14 h following repeated administration.
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The extent of systemic exposure to licarbazepine and oxcarbazepine was characterized by the mean AUC0- and Cmax values to describe the relationship between dose and systemic exposure, following single and repeated administration, and to characterize changes in systemic exposure during repeated administration.
Relationship Between Systemic Exposure and Dose Level
Following a single administration of 400 to 1200 mg BIA 2-093, there was an approximately dose-proportional increase in AUC and Cmax values for licarbazepine (Table I, Fig. 5) and oxcarbazepine (Table I, Fig. 6). For a BIA 2-093 dose-level increase in the ratio 1.0:2.0:1.5, mean licarbazepine AUC0- and Cmax values increased in the ratio 1.0:1.7:1.6 and 1.0:1.4:1.5 following single administration, respectively, and 1.0:2.1:1.6 and 1.0:2.1:1.4 after repeated administration. For oxcarbazepine, the ratios for AUC0- and Cmax were 1.0:2.2:1.5 and 1.0:2.1:1.6 following the first dose and 1.0:2.3:1.6 and 1.0:2.2:1.7 after the final dose. The extent of the deviation from dose proportionality is given by the exponent of the power function fitted to the individual Cmax and AUC0- data. Following single and repeated oral administration of BIA 2-093, the exponent values for AUC0- and Cmax of the metabolite licarbazepine were 0.9 to 1.1 and 0.6 to 1.0, respectively. For oxcarbazepine, the values of the exponent of the power function for AUC0- and Cmax ranged from 1.1 to 1.2. Overall, the extent of systemic exposure to licarbazepine and oxcarbazepine tended to increase in an approximately dose-proportional manner over the dose range of 400 to 1200 mg BIA 2-093 (ie, the pharmacokinetics of BIA 2-093 appeared to be linear with respect to dose). Between-subject (interindividual) variability in the extent of systemic exposure (AUC) to licarbazepine and oxcarbazepine was relatively low, with coefficients of variation ranging from 10% to 30% and 12% to 38%, respectively.
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Systemic Exposure During Repeated Administration
The systemic exposure to licarbazepine and oxcarbazepine following repeated administration of BIA 2-093 at 200 mg bid, 400 mg qd, 800 mg qd, and 1200 mg qd was assessed by estimating the extent of accumulation in plasma. Following twice-daily administration of 200 mg BIA 2-093, the mean observed accumulation ratio (RO) for licarbazepine and oxcarbazepine was 3.0 and 3.4, respectively (Table I). Following administration of BIA 2-093 once daily at 400, 800, and 1200 mg, the mean observed accumulation ratios (RO) for licarbazepine and oxcarbazepine ranged from 1.4 to 1.7 and from 1.8 to 2.1, respectively (Table I). AUC0-t and Cmax values of licarbazepine and oxcarbazepine following the first and final doses of BIA 2-093 are presented in Figures 5 and 6, respectively.
The observed extent of accumulation is consistent with an effective half-life of approximately 13 to 21 h and 21 to 24 h for licarbazepine and oxcarbazepine, respectively. The effective half-life values, calculated from the observed accumulation of licarbazepine, were similar to those estimated from the concentration-time profiles, suggesting that the pharmacokinetics for licarbazepine were time invariant (ie, linear with respect to time). The half-life values estimated from the observed accumulation of oxcarbazepine tended to be greater than those estimated from the concentration-time profiles, suggesting either that the half-lives estimated from the concentration-time profile were underestimated or that the pharmacokinetics for oxcarbazepine are time dependent. Mean predose concentrations of licarbazepine and oxcarbazepine (Fig. 4) appeared to attain steady-state levels after approximately 4 to 5 days of repeated once- or twice-daily dosing. The time to reach steady state is consistent with an effective half-life on the order of 20 to 24 h for licarbazepine and the metabolite oxcarbazepine.
Urinary Excretion Profiles
Mean cumulative urinary excretion of licarbazepine and oxcarbazepine following the first and final doses of the repeated oral administration of BIA 2-093 is shown in Figures 7 and 8, respectively. The urinary excretion of both licarbazepine and oxcarbazepine following repeated administration was found to be almost completed 72 h after the last administration of BIA 2-093, as evidenced by the plateau of cumulative excretion observed between 48 and 72 hours. Urinary concentrations of BIA 2-093 are not illustrated due to minimal recovery (less than 1% of the administered dose). The mean urinary recovery profiles for licarbazepine and oxcarbazepine after single administration are presented in Table II. Recovery of licarbazepine in urine was approximately 20% of the administered dose up to 12 h postdose and 40% of the administered dose up to 24 h postdose (Table II). Urinary recovery of oxcarbazepine was much less than that with licarbazepine (data not shown). Renal clearance of licarbazepine from plasma following a single and repeated oral administration of BIA 2-093 at all dose levels was approximately 20 to 30 mL/min. Reliable estimates of renal clearance of BIA 2-093 and oxcarbazepine could not be determined due to minimal recovery of these analytes in urine.
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Tolerability
During the course of the study, 56 adverse events were reported in total. One adverse event occurred at pre-treatment, and 19 subjects reported 55 treatment-emergent adverse events. Of these, 49 adverse events, reported by 16 subjects, were considered to be possibly related to treatment (Table III). There were no serious adverse events, deaths, or discontinuations due to adverse events. All adverse events were mild in severity except for 1 case of somnolence, reported by a subject who received 800 mg BIA 2-093, which was rated as moderate. Except for 2 subjects who took medication (paracetamol, Corenza C) for upper respiratory tract infections, no adverse events required intervention. A mild increase in the transaminase levels, especially alanine aminotransferase (ALT), appeared on day 8 in a subject who received 1200 mg qd and was maximal at discharge. However, the increase was below 2 times the upper limit of the normal reference range (ULN) for ALT and below 3 times the ULN for AST. There were no clinically significant abnormalities in vital signs, body weight, physical examination, or ECG parameters. There was no evidence for prolongation of the QT interval. QTcB (QT interval corrected using Bazett's formula) remained below the normal limit of 0.430 sec. There were no apparent trends in ECG parameters over time, and there were no apparent differences between BIA 2-093 and placebo or between doses of BIA 2-093.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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BIA 2-093 administered orally at doses up to 1200 mg once daily for 8 days appeared to be safe and was well tolerated. The incidence of adverse events was similar between subjects receiving BIA 2-093 at all doses and placebo. Adverse events were generally rated as mild in severity—there was only 1 moderate adverse event, an episode of somnolence, which was considered to be possibly related to treatment but that resolved despite continued dosing.
BIA 2-093 was generally not measurable in plasma and urine at all dose regimens tested. As previously observed in a single rising-dose (20-1200 mg) study in human healthy volunteers,14 BIA 2-093 was rapidly and extensively metabolized to licarbazepine and oxcarbazepine. A comparison of the systemic exposure to licarbazepine and oxcarbazepine clearly indicates that licarbazepine is the major metabolite representing about 99% of systemic exposure to BIA 2-093 metabolites. At all dose regimens tested, AUC0- for licarbazepine at day 8 is almost 100 times higher than that of oxcarbazepine, and a similar difference was found when maximum plasma concentrations of licarbazepine and oxcarbazepine are compared for groups 400 mg qd, 800 mg qd, and 1200 mg qd. Following single and repeated oral administration of BIA 2-093, maximum plasma concentrations of the metabolite licarbazepine were attained, on average, at 2 to 3 h postdose. Thereafter, plasma licarbazepine concentrations declined with a mean apparent terminal half-life of approximately 8 to 21 h. The extent of systemic exposure to licarbazepine increased in an approximately dose-proportional manner following single and repeated administration. However, licarbazepine accumulated in plasma following repeated administration of BIA 2-093. The mean extent of accumulation (RO) was 3.0 after repeated, twice-daily dosing and 1.4 to 1.7 after once-daily dosing. The observed accumulation of licarbazepine is consistent with an effective elimination half-life on the order of 20 to 24 h and the finding that steady-state plasma licarbazepine concentrations were attained at 4 to 5 days of once- or twice-daily dosing.
Urinary recovery of BIA 2-093 and oxcarbazepine was low (less than 1% of the administered dose). Recovery of licarbazepine in urine was approximately 20% of the administered dose up to 12 h postdose and 40% of the administered dose up to 24 h postdose. Renal clearance of licarbazepine from plasma following single and repeated oral administration of BIA 2-093 at all dose levels was approximately 20 to 30 mL/min, which is low compared with the glomerular filtration rate (127 mL/min). Reliable estimates of renal clearance of BIA 2-093 and oxcarbazepine could not be determined due to minimal recovery of these analytes in urine.
The metabolic profile described here is in agreement with that previously reported in other species (Fig. 1).
BIA 2-093 was demonstrated to be extensively hydrolyzed to licarbazepine (rat, mouse, and rabbit).9 In the rat, this was followed by an oxidation to oxcarbazepine. According to Feldmann et al,15,16 the rat is not able to metabolize oxcarbazepine to a significant amount. However, the results of Hainzl et al9 show that in rat liver, a significant reduction to the hydroxy derivative occurs. This reduction is reversed rapidly, resulting in diminishing amounts of licarbazepine in plasma. Altogether, this indicates that the rat not only possesses the responsible reducing enzymes (probably the cytosolic arylketone reductase as in humans) in amounts and activities comparable to other species but is also able to reverse this reaction very effectively, in contrast to mice and rabbits. The hydrolysis of BIA 2-093 in the presence of rat, dog, primate, and human liver microsomes occurs through non-P450-mediated metabolism (Soares-da-Silva, unpublished observations). Following chiral analysis, it was concluded that the metabolism of BIA 2-093 in rats, dogs, monkeys, and humans gives origin to the S(+) enantiomer of licarbazepine (S-licarbazepine) and not the R(-) form (R-licarbazepine; see Fig. 1).9 Both enantiomers of licarbazepine (S- and R-licarbazepine) and the racemic mixture are endowed with pharmacological activity as anticonvulsants and were found to be equipotent.8 However, the corresponding acetoxy derivatives of S-licarbazepine and R-licarbazepine—respectively, BIA 2-093 and BIA 2-059—were described as having strikingly different pharmacodynamic and pharmacokinetic properties,8,9 with the former being endowed with a better profile as a putative antiepileptic drug. Oxcarbazepine is rapidly and extensively metabolized to a mixture of the S(+)and R(-)-licarbazepine,17 with both appearing in plasma and urine in the proportion of approximately 4/1.18-20 Considering that BIA 2-093 gives origin to the S(+) and not the R(-) form of racemic licarbazepine,9 and oxcarbazepine represents approximately 1% of metabolites of BIA 2-093 (present results), a low enantiomeric dilution is likely to occur after administration of BIA 2-093. Studies are in progress to determine in humans the proportion of S(+) and R(-) enantiomers of racemic licarbazepine after administration of BIA 2-093. The sequence of events described in Figure 1 most likely also occurs in human subjects and would agree with the findings that the pharmacokinetics of licarbazepine is time invariant, whereas that of oxcarbazepine appears to be time dependent.
In conclusion, BIA 2-093 was well tolerated and appeared to be rapidly and extensively metabolized to licarbazepine following single and multiple oral doses of 200 to 1200 mg BIA 2-093. The extent of systemic exposure to licarbazepine increased in an approximately dose-proportional manner, and steady-state plasma licarbazepine concentrations were attained at 4 to 5 days of once- or twice-daily dosing, consistent with an effective half-life on the order of 20 to 24 h. Oxcarbazepine is a minor metabolite, representing about 1% of total exposure.
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FOOTNOTES |
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Submitted for publication September 1, 2003; Revised version accepted May 23, 2004.
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