Joana Maia

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.

Purpose:  To study the efficacy and safety of eslicarbazepine acetate (ESL) as adjunctive therapy for refractory partial seizures in adults with ≥4 partial‐onset seizures (simple or complex, with or without secondary generalization) per 4 weeks despite treatment with 1–2 antiepileptic drugs (AEDs).

Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy

OBJECTIVE To investigate the efficacy and safety of once-daily eslicarbazepine acetate (ESL) when used as add-on treatment in adults with > or = 4 partial-onset seizures per 4-week despite treatment with 1 to 3 antiepileptic drugs (AEDs). METHODS This double-blind, parallel-group, multicenter study consisted of an 8-week observational baseline period, after which patients were randomized to placebo (n=100) or once-daily ESL 400 mg (n=96), 800 mg (n=101), or 1200 mg (n=98). Patients then entered a 14-week double-blind treatment phase. All patients started on their full maintenance dose except for those in the ESL 1200 mg group who received once-daily ESL 800 mg for 2 weeks before reaching their full maintenance dose. RESULTS Seizure frequency per 4-week (primary endpoint) over the 14-week double-blind treatment period was significantly lower than placebo in the ESL 800 mg and 1200 mg (p<0.001) groups. Responder rate (> or = 50% reduction in seizure frequency) was 13.0% (placebo), 16.7% (400 mg), 40.0% (800 mg, p<0.001), and 37.1% (1200 mg, p<0.001). Median relative reduction in seizure frequency was 0.8% (placebo), 18.7% (400 mg), 32.6% (800 mg, p<0.001), and 32.8% (1200 mg). Discontinuation rates due to adverse events (AEs) were 3.0% (placebo), 12.5% (400 mg), 18.8% (800 mg), and 26.5% (1200 mg). The most common (>5%) AEs in any group were dizziness, somnolence, headache, nausea, diplopia, abnormal coordination, vomiting, blurred vision, and fatigue. The majority of AEs were of mild or moderate severity. CONCLUSIONS Treatment with once-daily eslicarbazepine acetate 800 mg and 1200 mg was more effective than placebo and generally well tolerated in patients with partial-onset seizures refractory to treatment with 1 to 3 concomitant AEDs.

Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial‐onset seizures

Objectives  –  To evaluate the efficacy and safety of eslicarbazepine acetate (ESL) as adjunctive therapy in adults with partial‐onset seizures.

Eslicarbazepine acetate: a double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures.

Summary:  Objective: To explore the efficacy and safety of eslicarbazepine acetate (BIA 2‐093), a new antiepileptic drug, as adjunctive therapy in adult patients with partial epilepsy.

Pharmacokinetics of eslicarbazepine acetate in patients with moderate hepatic impairment.

ObjectiveTo evaluate the effect of moderate liver impairment on the pharmacokinetics of eslicarbazepine acetate (BIA 2-093, ESL), a novel voltage-gated sodium channel blocker currently in clinical development.MethodsThe pharmacokinetics of ESL following an administration regimen of 800 mg once-daily for 8 days was characterized in patients with moderate liver impairment (n = 8) and in subjects with normal liver function (n = 8, control group).ResultsEslicarbazepine acetate was rapidly and extensively metabolized by first-pass metabolism to its main active metabolite, eslicarbazepine (S-licarbazepine). There were more subjects with measurable plasma concentrations of the parent drug (ESL) in the hepatic impairment group than in the control group, suggesting that first-pass metabolism was slightly decreased by liver impairment. However, ESL plasma concentrations remained very low, representing only about 0.01% of total systemic exposure. No differences in the pharmacokinetics of eslicarbazepine or its metabolites were found between the hepatic impairment and control groups. Urinary excretion of eslicarbazepine and its glucuronide form was similar in the liver impaired and control subjects. The sum of drug moieties recovered in the urine corresponded to 91% of the administered dose in the control group and to 84% of the administered dose in the liver impairment group.ConclusionThe pharmacokinetics of ESL was not affected by moderate hepatic impairment. Therefore, patients with mild to moderate liver impairment treated with ESL do not require dosage adjustment.

Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate

OBJECTIVE Antiepileptic drugs are often used in patients with some degree of renal impairment. The objective of this study was to evaluate the effect of renal function on the pharmacokinetics of eslicarbazepine acetate (ESL, formerly known as BIA 2-093), a new antiepileptic drug under clinical development. METHODS ESL pharmacokinetics following 800 mg single dose was characterized in subjects with normal renal function (n=8, control group), and in patients with mild renal impairment (n=8), moderate renal impairment (n=8), severe renal impairment (n=8), and end-stage renal disease requiring hemodialysis (n=8). RESULTS ESL suffered extensive first-pass hydrolysis to eslicarbazepine (S-licarbazepine), the main active metabolite. While eslicarbazepine Cmax did not significantly differ between the different groups, the extent of systemic exposure, assessed by AUC, increased when renal function decreased. Eslicarbazepine CL/F and CLR were, respectively, 3.40 l/h and 1.04 l/h (17.3 ml/min) in the control group, and 2.10 l/h (35.0 ml/min) and 0.61 l/h (10.2 ml/min) in the mild, 1.60 l/h (26.7 ml/min) and 0.22 l/h (3.7 ml/min) in the moderate, and 1.33 l/h (21.2 ml/min) and 0.09 l/h (1.5 ml/min) in the severe renal impairment groups. Although the total amount of eslicarbazepine recovered in urine until 72 h post-dose was similar in the control and mild renal impairment groups, a decrease was found in the moderate and severe renal impairment groups. Major metabolites recovered in urine were eslicarbazepine and its glucuronide form. Clearance of minor metabolites (R-licarbazepine, oxcarbazepine and their glucuronides) was also dependent on renal function. In patients with end-stage renal disease, dialysis was effective in removing the ESL metabolites from the circulation. CONCLUSIONS ESL metabolites are excreted primarily by renal route and their clearance is dependent on renal function. ESL dosage adjustment may be necessary in patients with a creatinine clearance <60 ml/min.

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.

Purpose:  To evaluate the long‐term efficacy and safety of once daily eslicarbazepine acetate (ESL) as adjunctive therapy for partial‐onset seizures in adults with epilepsy.

Effect of Food on the Pharmacokinetic Profile of Eslicarbazepine Acetate (BIA 2-093)

AbstractObjective: To investigate the effect of food on the pharmacokinetics of eslicarbazepine acetate (BIA 2-093), a new voltage-gated sodium channel antagonist. Material and methods: Single-centre, open-label, randomised, two-way crossover study in 12 healthy subjects. The study consisted of two consecutive treatment periods separated by a washout of 14 days or more. In each of the study periods subjects were administered a single dose of eslicarbazepine acetate 800mg following either a standard high-fat content meal or 10 hours of fasting. Results: Eslicarbazepine acetate was rapidly and extensively metabolised to BIA 2-005. Maximum BIA 2-005 plasma concentrations (Cmax) in fed (test) and fasting (reference) conditions were, respectively, 12.8 ± 1.8 μg/mL and 11.3 ± 1.9 μg/mL, and the areas under the plasma concentration time curve from 0 to infinity (AUC∞) were, respectively, 242.5 ± 32.1 μg · h/mL and 243.6 ± 31.1 μg · h/mL (arithmetic mean ± SD). The point estimate (PE) and 90% confidence interval (90% CI) of the test/reference Cmax geometric mean ratio were 1.14 and 1.04, 1.25, respectively; for the AUC∞ ratio, the PE and 90% CI were 1.00 and 0.95, 1.04, respectively. Bioavailability of eslicarbazepine acetate administered in fed and fasting conditions was similar and bioequivalence is accepted for both AUC∞ and Cmax because the 90% CI lies within the acceptance range of 0.80–1.25. No statistically significant differences were found in time of occurrence of Cmax. Conclusion: The presence of food had no significant effect on the pharmacokinetics of eslicarbazepine acetate and therefore this new voltage-gated sodium channel antagonist may be administered without regard to meals.

Effect of Eslicarbazepine Acetate on the Steady-State Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Subjects During a Three-Stage, Open-Label, Multiple-Dose, Single-Period Study

BACKGROUND The anticoagulant warfarin, which is administered as a racemic mixture of R- and S-enantiomers, has been reported to interact with other drugs, including some antiepileptics. Eslicarbazepine acetate (ESL) is a once-daily voltage-gated sodium channel blocker that has been developed for the treatment of partial epilepsy and other indications. OBJECTIVE The aim of this work was to investigate whether multiple-dose administration of ESL had any effect on the steady-state pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers stabilized on warfarin at a subtherapeutic level. METHODS Subjects received ESL 1200 mg once daily for 8 days concomitantly with racemic warfarin, the dose of which had been individually optimized to a stable prothrombin international normalized ratio (INR) of 1.3 to 1.8 during a previous run-in phase (up to 21 days). Coadministration of ESL and warfarin was followed by a 7-day recovery period when warfarin was again administered alone. The effects of ESL on the steady-state pharmacokinetics of R- and S-warfarin and on the INR were assessed. For the R- and S-warfarin assay, blood sampling was to occur at stage 1 (run-in period), 3 days before starting ESL dosing; stage 2 (combined treatment period), on days 1 and 8 at predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose, and on days 4, 6, and 7 at predose; and stage 3 (after the combined treatment period) on days 3, 5, and 7 predose, and on day 8 at 24 hours after the final warfarin dose. For determination of INR, blood sampling was to occur at stage 2 on days 1, 2, 4, 6, 7, and 8 at predose; and at stage 3 on days 1, 3, 5, and 7 at predose and on day 8 at 24 hours after the final warfarin dose. For the assay of the racemic mixture of the S- and the R-enantiomers (eslicarbazepine and R-licarbazepine), blood sampling was to occur at stage 2 on day 8 at predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose, and on days 2, 4, 6, and 7 at predose. C(max) and AUC(0-t) were defined as primary pharmacokinetic parameters. Tolerability was evaluated by monitoring adverse events, clinical laboratory safety tests, vital signs, and 12-lead ECG. RESULTS Of the 15 subjects enrolled, 13 (7 men and 6 women) completed the study. The mean (SD) age was 28.1 (7.3) years (range, 20-42 years), mean weight was 67.3 (10.7) kg (range, 54.0-84.4 kg), and 14 subjects (93.3%) were white. Reductions in S-warfarin C(max) (test:reference geometric means ratio [GMR] = 0.81 [90% CI, 0.76 to 0.86] and in S-warfarin AUC(ss) (test:reference GMR = 0.77 [90% CI, 0.72 to 0.82]) were observed, without any clinically relevant changes in the INR. The mean INR was 1.45 (0.10) when warfarin was used alone in stage 1 (control) and 1.51 (0.25) when ESL was added to warfarin in stage 2. In relation to stage 1, a slight mean INR increase of 4.04% [90% CI, 1.03% to 9.12%] was reported in stage 2. In stage 3, following discontinuation of ESL administration, a change of -5.42% in the INR was found [90% CI, -8.85% to -1.98%]. ESL was not associated with any clinically relevant changes in R-warfarin pharmacokinetic parameters. No deaths, serious adverse events, or discontinuations due to adverse events were noted, and no clinically relevant findings were reported for the other safety variables. During the course of the study, 9 subjects (60%) reported a total of 32 adverse events. Catheter-site ecchymosis, venipuncturesite hematoma, dizziness, vasovagal reaction, and adhesive-tape allergy were the most common adverse events reported. During coadministration of ESL and warfarin, 7 subjects reported a total of 17 adverse events, of which 6 (epigastric discomfort, asthenia, dizziness, lipothymia, irritability, and macular rash) were considered possibly related to treatment; only lipothymia reached moderate intensity, and all symptoms subsided without sequelae after ESL was discontinued. CONCLUSIONS In this short-term study in healthy subjects, coadministration of warfarin and ESL 1200 mg once daily was associated with a small, but statistically significant, reduction in systemic exposure to S-warfarin. There was no statistically significant effect on R-warfarin pharmacokinetics or on coagulation as measured by the INR. Protocol identifier: UFH/BIA-2093-108.

Bioavailability and bioequivalence of two enteric-coated formulations of omeprazole in fasting and fed conditions

AbstractObjective: To investigate the relative bioavailability and bioequivalence, in fasting and fed conditions, of repeated doses of two omeprazole enteric-coated formulations in healthy volunteers. Material and methods: Open label, single-centre study consisting of two consecutive randomised, two-way crossover trials (a fasting trial and a fed trial). Each trial consisted of two 7-day treatment periods in which subjects received one daily dose of the test (Ompranyt®) or reference (Mopral®) formulations. At day 7 and day 14 (fasting trial), products were administered in fasting conditions and blood samples were taken for omeprazole plasma assay over 12 hours. At day 21 and day 28 (fed trial), products were administered after a standard high-calorie and high-fat meal and 12-hour blood samples taken. Omeprazole plasma concentrations were quantified by a validated method using a reverse-phase high performance liquid chromatography with UV detection (HPLC-UV). Results: Twenty-four subjects were enrolled and 23 completed the study. Under fasting conditions, the mean ± SD maximum omeprazole plasma concentration (Cmax) was 797 ± 471 μg/L for Ompranyt® and 747 ± 313 μg/L for Mopral® with a point estimate (PE) of 1.01 and a 90% confidence interval (CI) of 0.88, 1.16. The mean ± SD area under the plasma concentration curve from administration to last observed concentration (AUC0–12) was 1932 ± 1611 μg · h/L and 1765 ± 1327 μg · h/L for Ompranyt® and Mopral®, respectively (PE = 1.09; 90% CI 0.95, 1.25). In the presence of food, the Cmax was 331 ± 227 μg/L and 275 ± 162 μg/L (PE = 1.21; 90% CI 0.92, 1.59) and AUC0–12 was 1250 ± 966 μg · h/L and 1087 ± 861 μg · h/L (PE = 1.16; 90% CI 0.92, 1.47) for Ompranyt® and Mopral®, respectively. Bioequivalence of the formulations in the fasting condition was demonstrated both for AUC0–12 and for Cmax because the 90% CI lay within the acceptance range of 0.80–1.25. In contrast with the fasting condition, there were significant reductions in rate (Cmax) and extent (AUC0–12) of systemic exposure when test and reference formulations were administered with food. The food effect was more marked with Mopral® than with Ompranyt®, and the bioequivalence criterion was not fulfilled because the 90% CI fell out of the acceptance range of 0.80, 1.25, for both Cmax and AUC0–12. The two formulations were similarly well tolerated. Conclusion: Bioequivalence of Ompranyt® (test formulation) and Mopral® (reference) formulations was demonstrated after repeated dosing in the fasting condition. Following a high-calorie and high-fat meal, there was a significant reduction in rate and extent of systemic exposure for both products, with Ompranyt® being less affected than Mopral® by the presence of food.