Luis Almeida

Eslicarbazepine acetate (BIA 2-093)

SummaryEslicarbazepine acetate (ESL) [(S)-(−)-10-acetoxy-10, 11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide], formerly known as BIA 2-093, is a novel central nervous system (CNS)-active compound with anticonvulsant activity. It behaves as a voltage-gated sodium channel (VGSC) blocker and is currently under clinical development for the treatment of epilepsy and bipolar disorder. ESL shares with carbamazepine and oxcarbazepine the dibenzazepine nucleus bearing the 5-carboxamide substitute, but is structurally different at the 10,11-position. This molecular variation results in differences in metabolism, preventing the formation of toxic epoxide metabolites such as carbamazepine-10,11 epoxide. In pharmacokinetic studies in humans, ESL was rapidly and extensively metabolized to eslicarbazepine (S-licarbazepine), which is responsible for pharmacological activity. ESL has been tested in patients with refractory partial-onset seizures and was found to be efficacious and well tolerated. Monotherapy studies in adult epileptic patients and add-on studies in epileptic children are in the planning process. The efficacy and safety data appear to be very promising considering the refractory nature of the epileptic population enrolled in studies to date. Results of ongoing phase III studies in adult epileptic patients are expected to be available in 2007 and are required to define the position of ESL in the therapy of patients with epilepsy.

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.

Safety, Tolerability, and Pharmacokinetic Profile of BIA 2‐093, a Novel Putative Antiepileptic, in a Rising Multiple‐Dose Study in Young Healthy Humans

This was a double‐blind, randomized, placebo‐controlled study to investigate rising oral doses of BIA 2‐093 (S‐(−)‐10‐acetoxy‐10,11‐dihydro‐5H‐dibenz/b,f/azepine‐5‐carboxamide), a putative new antiepileptic drug. Within each of 4 dosage groups of 8 healthy male adult subjects, 2 subjects were randomized to receive placebo, and the remaining 6 subjects were randomized to receive BIA 2‐093 (200 mg bid, 400 mg qd, 800 mg qd, and 1200 mg qd) for 8 days. Concentrations of BIA 2‐093 in plasma or urine were generally not measurable. Median maximum plasma concentrations of the major metabolite (licarbazepine, (±)‐10,11‐dihydro‐10‐hydroxy‐5H‐dibenz/b,f/azepine‐5‐carboxamide) were attained (tmax) at 2 to 3 h postdose; thereafter, plasma concentrations declined with a mean apparent terminal half‐life of 9 to 13 h following repeated dosing. The extent of systemic exposure to licarbazepine increased in an approximately dose‐proportional manner following single and repeated administration. Licarbazepine accumulated in plasma following repeated administration of BIA 2‐093; the mean extent of accumulation (RO, calculated from AUC0‐τ (day 8)/AUC0‐τ (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.

Pharmacokinetics, Efficacy, and Tolerability of Eslicarbazepine Acetate in Children and Adolescents With Epilepsy

This study investigates the pharmacokinetics of eslicarbazepine acetate (ESL), a new voltage‐gated sodium channel blocker, in epileptic children aged 2 to 7 years (n = 11) and 7 to 11 years (n = 8) and adolescents aged 12 to 17 years (n = 10). The study explores ESL efficacy and tolerability. Patients were treated with ESL once‐daily doses of 5 mg/kg/day on weeks 1 to 4, 15 mg/kg/day on weeks 5 to 8, and 30 mg/kg/day (or 1800 mg/day, whichever was less) on weeks 9 to 12. At the end of each 4‐week period, a 24‐hour pharmacokinetic profiling was performed. Similar to adults, ESL was rapidly metabolized to eslicarbazepine. In all age groups, eslicarbazepine peak concentrations were reached 0.5 hour to 3 hours after ESL dosing, and Cmax and AUC0–24 were dose proportional. Eslicarbazepine Cmax was similar between age groups following administration of identical ESL dose/kg, but AUC0–24 depended on age due to a faster plasma clearance of eslicarbazepine in younger children compared with adolescents. R‐licarbazepine and oxcarbazepine were minor metabolites. A dose‐dependent decrease in seizure frequency was observed in children aged 2 to 7 years and adolescents aged 12 to 17 years but not in children aged 7 to 11 years. One patient in each group became seizure free. ESL was generally well tolerated.

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.

Safety, Tolerability and Pharmacokinetic Profile of BIA 2-093, a Novel Putative Antiepileptic Agent, during First Administration to Humans

AbstractObjective: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of BIA 2-093 [S-(−)-10-acetoxy-10,11-dihydro-5H-dibenzo/b,f/azepine- 5-carboxamide] in healthy male volunteers. Design: This was a double-blind, randomised, placebo-controlled, single ascending dose study performed with BIA 2-093, a new putative antiepileptic drug. Participants and methods: Groups of eight healthy male subjects (two randomised to receive placebo and the remaining six to receive BIA 2-093) received single oral doses of BIA 2-093 of 20, 50, 100, 200, 400, 600, 900 and 1200mg. A total of 64 healthy male volunteers aged 18–35 years participated in the study. Results: The incidence of adverse events, which were mild in severity, was similar between all treatment groups, including the placebo group. There were no serious adverse events during this study. No clinically significant abnormalities in laboratory safety tests, vital signs, weight, physical examination or ECG were reported. BIA 2-093 appeared to be rapidly and extensively metabolised to BIA 2-005 [RS(±)-10,11-dihydro-10-hydroxy-5H-dibenzo/b,f/azepine-5-carboxamide], the major metabolite, and oxcarbazepine (the minor metabolite), following single oral doses of BIA 2-093 of 20–1200mg. Plasma BIA 2-093 concentrations were generally below the limit of quantification of the assay. Maximum plasma concentrations (Cmax) of BIA 2-005 and oxcarbazepine were reached, respectively, at 0.75–4h and 6h postdose, after which they declined with an approximate mean apparent terminal half-life of 8–17h and 7–12h, respectively. The increase in systemic exposure to BIA 2-005 was approximately proportional to the administered dose for Cmax and greater than dose proportional for the area under the concentration-time curve. Renal clearance of BIA 2-005 (20 mL/ min) appeared to be constant over the dose range studied, indicating that the dose-dependent urinary recovery was due either to increased formation of BIA 2-005 with increasing dose level or to decreased non-renal elimination of the metabolite. Conclusion: BIA 2-093 undergoes extensive metabolism to BIA 2-005 and was well tolerated at oral doses of 20–1200mg. The results provide a basis for further clinical trials with BIA 2-093.

Eslicarbazepine Acetate (BIA 2-093)

AbstractPurpose: To investigate the bioavailability and bioequivalence of three different formulations of eslicarbazepine acetate (BIA 2-093): 50 mg/mL oral suspension (test 1), 200mg tablets (test 2) and 800mg tablets (reference). Design, subjects and methods: Single-centre, open-label, randomised, three-way crossover study in 18 healthy subjects. The study consisted of three consecutive periods separated by a washout period of 7 days or more. Each subject received a single dose of eslicarbazepine acetate 800mg on three different occasions: 16mL of oral 50 mg/mL suspension, four 200mg tablets or one 800mg tablet. Results: Eslicarbazepine acetate was rapidly and extensively metabolised to BIA 2-005. Maximum BIA 2-005 plasma concentrations (Cmax) and area under the plasma concentration-time curve from time 0 to infinity (AUC∞) were, respectively (arithmetic mean ± SD), 18.0 ± 4.6 μg/mL and 325.7 ± 64.9 μg · h/mL for test 1, 16.0 ± 4.0 μg/mL and 304.2 ± 66.0 μg · h/mL for test 2, and 17.0 ± 4.1 μg/mL and 301.1 ± 60.0 μg · h/mL for the reference formulation. Point estimate (PE) and 90% confidence intervals (CIs) for AUC∞ test 1/reference geometric mean ratio were 1.09 and 1.01, 1.15; for Cmax ratio, PE and 90% CI were 1.07 and 0.97, 1.15. When test 2 and the reference formulations were compared, the PE and 90% CI were 0.99 and 0.94, 1.07 for the AUC∞ ratio, and 0.94 and 0.86, 1.02 for the Cmax ratio. Bioequivalence of test versus reference formulations is thus accepted for both AUC∞ and Cmax because the 90% CIs lie within the acceptance range of 0.80–1.25. Conclusion: The pharmacokinetic profiles of eslicarbazepine acetate oral 50 mg/mL suspension, 200mg tablet and 800mg tablet formulations were essentially similar, and the formulations can be considered bioequivalent.

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.

Pharmacokinetics and pharmacodynamics of BIA 3-202, a novel COMT inhibitor, during first administration to humans.

AbstractObjective: To determine the tolerability, pharmacodynamics and pharmacokinetics of single oral doses of BIA 3-202, a novel catechol-O-methyltransferase (COMT) inhibitor, in healthy male volunteers. Methods: Single increasing oral doses of BIA 3-202 (10, 30, 50, 100, 200, 400 and 800mg) were administered under fasting conditions to seven sequential groups of nine subjects, under a double-blind, randomised, placebo-controlled design. In an additional group of eight subjects (group 8), a single dose of BIA 3-202 400mg was administered on two occasions, once under fasting conditions and once with a high-fat meal, under an open-label, two-way crossover design. Results: BIA 3-202 was well tolerated at all doses tested. Most adverse events were mild in severity and their incidence was similar between BIA 3-202 and placebo. Maximum plasma concentrations (Cmax) of BIA 3-202 were attained at 0.522.5h (tmax) and thereafter declined with an apparent terminal half-life (t1/2) of 1.52–5h. Over the dose range of 102800mg, there was an approximately dose-proportional increase in the area under the plasma concentration-time curve (AUC) values of BIA 3-202: for a dose level increase in the ratio 3.0:1.7:2.0:2.0:2.0:2.0, AUC increased in the ratio 3.1:1.7:1.9:2.2:2.1:1.7. Plasma concentrations of the O-methylated derivative, BIA 3-270, increased markedly less than predicted from a proportional relationship: for a dose level increase in the ratio 1:80, AUC0-t increased in the ratio 1:5. In most subjects, the tmax of BIA 3-270 was attained at the last sampling time and, therefore, t1/2 could not be estimated. Urine assays showed that less than 1% of the total dose admi nistered was excreted in urine as BIA 3-202. Urine concentrations of BIA 3-270 were below the limit of quantification. In group 8, the rate and extent of systemic availability (tmax, AUC and Cmax) of BIA 3-202 and BIA 3-270 after a high-fat meal were similar to those under fasting conditions. Inhibition of COMT activity in erythrocytes reached maximum levels at 2–2.5h post dose, with sustained inhibition up to approximately 4–6 hours, returning to baseline by about 16 hours. Conclusion: BIA 3-202 was well tolerated at single 10–800mg oral doses and presented dose-proportional kinetics. It effectively inhibited COMT activity and the presence of food did not affect its pharmacokinetics or COMT inhibitory activity. The results provide a basis for further clinical studies with BIA 3-202.