The Experts below are selected from a list of 1404 Experts worldwide ranked by ideXlab platform

Patrício Soares-da-silva - One of the best experts on this subject based on the ideXlab platform.

  • Exposure-safety and efficacy response relationships and population pharmacokinetics of Eslicarbazepine acetate.
    Acta neurologica Scandinavica, 2018
    Co-Authors: Barry E. Gidal, Patrício Soares-da-silva, Amilcar Falcao, Elinor Ben-menachem, David Blum, Mercedes P. Jacobson, Mar Carreño, F. Rocha, Joana Moreira, Todd Grinnell
    Abstract:

    Objectives Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED) for focal-onset seizures (FOS). Pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to assess dose selection, identify significant AED drug interactions, and quantitate relationships between exposure and safety and efficacy outcomes from Phase 3 trials of adjunctive ESL. Methods Eslicarbazepine (the primary active metabolite of ESL) population PK was evaluated using data from 1351 subjects enrolled in 14 studies (11 Phase 1 and three Phase 3 studies) after multiple oral doses ranging from 400 to 1200 mg. Population PK and PD models related individual Eslicarbazepine exposures to safety outcomes and efficacy responses. Results Eslicarbazepine PK was described by a one-compartment model with linear absorption and elimination. The probability of a treatment-emergent adverse event (TEAE; dizziness, headache, or somnolence) was higher with an initial dose of ESL 800 mg than with an initial dose of ESL 400 mg QD. Body weight, sex, region, and baseline use of carbamazepine (CBZ) or lamotrigine were also found to influence the probability of TEAEs. Eslicarbazepine exposure influenced serum sodium concentration, standardized seizure frequency, and probability of response; better efficacy outcomes were predicted in patients not from Western Europe (WE; vs WE patients) and those not taking CBZ (vs taking CBZ) at baseline. Conclusions Pharmacokinetic and PK/PD modeling were implemented during the development of ESL for adjunctive treatment of FOS in adults. This quantitative approach supported decision-making during the development of ESL, and contributed to dosing recommendations and labeling information related to drug interactions.

  • Efficacy and safety of Eslicarbazepine acetate versus controlled-release carbamazepine monotherapy in newly diagnosed epilepsy: A phase III double-blind, randomized, parallel-group, multicenter study.
    Epilepsia, 2018
    Co-Authors: Eugen Trinka, Elinor Ben-menachem, Pedro A. Kowacs, Christian E. Elger, Birgit Keller, Kurt Löffler, José Francisco Rocha, Patrício Soares-da-silva
    Abstract:

    Objective We assessed the efficacy and safety of once-daily Eslicarbazepine acetate in comparison with twice-daily (BID) controlled-release carbamazepine (carbamazepine-CR) monotherapy in newly diagnosed focal epilepsy patients. Methods This randomized, double-blind, noninferiority trial (NCT01162460) utilized a stepwise design with 3 dose levels. Patients who remained seizure-free for the 26-week evaluation period (level A: Eslicarbazepine acetate 800 mg/carbamazepine-CR 200 mg BID) entered a 6-month maintenance period. If a seizure occurred during the evaluation period, patients were titrated to the next target level (level B: Eslicarbazepine acetate 1200 mg/carbamazepine-CR 400 mg BID, level C: Eslicarbazepine acetate 1600 mg/carbamazepine-CR 600 mg BID) and the evaluation period began again. The primary endpoint was the proportion of seizure-free patients for 6 months after stabilization in the per protocol set. The predefined noninferiority criteria were -12% absolute and -20% relative difference between treatment groups. Results Eight hundred fifteen patients were randomly assigned; 785 (388 in the Eslicarbazepine acetate group and 397 in the carbamazepine-CR group) were included in the per protocol set, and 813 (401 in the Eslicarbazepine acetate group and 412 in the carbamazepine-CR group) were included in the full analysis set for the primary analysis. Overall, 71.1% of Eslicarbazepine acetate-treated patients and 75.6% of carbamazepine-CR-treated patients were seizure-free for ≥6 months at the last evaluated dose (average risk difference = -4.28%, 95% confidence interval [CI] = -10.30 to 1.74; relative risk difference = -5.87%, 95% CI = -13.50 to 2.44) in the per protocol set. Rates of treatment-emergent adverse events were similar between groups for patients in the safety set. Noninferiority was also demonstrated in the full analysis set, as 70.8% of patients with Eslicarbazepine acetate and 74.0% with carbamazepine-CR were seizure-free at the last evaluated dose (average risk difference = -3.07, 95% CI = -9.04 to 2.89). Significance Treatment with Eslicarbazepine acetate was noninferior to BID carbamazepine-CR. With its once-daily formulation, Eslicarbazepine acetate provides a useful option for first-line monotherapy for adults with newly diagnosed epilepsy and focal onset seizures.

  • Safety Profile of Eslicarbazepine Acetate as Add-On Therapy in Adults with Refractory Focal-Onset Seizures: From Clinical Studies to 6 Years of Post-Marketing Experience.
    Drug safety, 2017
    Co-Authors: Helena Gama, Mariana Vieira, Raquel Costa, Joana Graça, Luís Magalhães, Patrício Soares-da-silva
    Abstract:

    Eslicarbazepine acetate was first approved in the European Union in 2009 as adjunctive therapy in adults with partial-onset seizures with or without secondary generalization. The objective of this study was to review the safety profile of Eslicarbazepine acetate analyzing the data from several clinical studies to 6 years of post-marketing surveillance. We used a post-hoc pooled safety analysis of four phase III, double-blind, randomized, placebo-controlled studies (BIA-2093-301, -302, -303, -304) of Eslicarbazepine acetate as add-on therapy in adults. Safety data of Eslicarbazepine acetate in special populations of patients aged ≥65 years with partial-onset seizures (BIA-2093-401) and subjects with moderate hepatic impairment (BIA-2093-111) and renal impairment (BIA-2093-112) are also considered. The incidences of treatment-emergent adverse events, treatment-emergent adverse events leading to discontinuation, and serious adverse events were analyzed. The global safety database of Eslicarbazepine acetate was analyzed for all cases from post-marketing surveillance from 1 October, 2009 to 21 October, 2015. From a pooled analysis of four phase III studies, it was concluded that the incidence of treatment-emergent adverse events, treatment-emergent adverse events leading to discontinuation, and adverse drug reactions were dose dependent. Dizziness, somnolence, headache, and nausea were the most common treatment-emergent adverse events (≥10% of patients) and the majority were of mild-to-moderate intensity. No dose-dependent trend was observed for serious adverse events and individual serious adverse events were reported in less than 1% of patients. Hyponatremia was classified as a possibly related treatment-emergent adverse event in phase III studies (1.2%); however, after 6 years of post-marketing surveillance it represents the most frequently (10.2%) reported adverse drug reaction, with more than half of these cases occurring with Eslicarbazepine acetate at daily doses of 1200 mg. Other adverse drug reactions reported in post-marketing surveillance are seizure (5.8%), dizziness (4.1%), rash (2.6%), and fatigue (2.1%). The safety profile of Eslicarbazepine acetate in renal and hepatic impairment subjects (phase I studies) and in elderly patients (phase III study) did not raise any specific concern. After 6 years of post-marketing surveillance, Eslicarbazepine acetate maintains a similar safety profile to that observed in pivotal clinical studies.

  • Eslicarbazepine and the enhancement of slow inactivation of voltage-gated sodium channels: A comparison with carbamazepine, oxcarbazepine and lacosamide
    Neuropharmacology, 2014
    Co-Authors: Simon Hebeisen, Ana I. Loureiro, Maria João Bonifácio, Nuno Pires, Nuno Palma, Andrew D. Whyment, David Spanswick, Patrício Soares-da-silva
    Abstract:

    This study aimed at evaluating the effects of Eslicarbazepine, carbamazepine (CBZ), oxcarbazepine (OXC) and lacosamide (LCM) on the fast and slow inactivated states of voltage-gated sodium channels (VGSC). The anti-epileptiform activity was evaluated in mouse isolated hippocampal slices. The anticonvulsant effects were evaluated in MES and the 6-Hz psychomotor tests. The whole-cell patch-clamp technique was used to investigate the effects of Eslicarbazepine, CBZ, OXC and LCM on sodium channels endogenously expressed in N1E-115 mouse neuroblastoma cells. CBZ and Eslicarbazepine exhibit similar concentration dependent suppression of epileptiform activity in hippocampal slices. In N1E-115 mouse neuroblastoma cells, at a concentration of 250 mM, the voltage dependence of the fast inactivation was not influenced by Eslicarbazepine, whereas LCM, CBZ and OXC shifted the V0.5 value (mV) by � 4.8, � 12.0 and � 16.6, respectively. Eslicarbazepine- and LCM-treated fast-inactivated channels recovered similarly to control conditions, whereas CBZ- and OXC-treated channels required longer pulses to recover. CBZ, Eslicarbazepine and LCM shifted the voltage dependence of the slow inactivation (V0.5 ,m V) by � 4.6, � 31.2 and � 53.3, respectively. For Eslicarbazepine, LCM, CBZ and OXC, the affinity to the slow inactivated state was 5.9, 10.4, 1.7 and 1.8 times higher than to the channels in the resting state, respectively. In conclusion, Eslicarbazepine did not share with CBZ and OXC the ability to alter fast inactivation of VGSC. Both Eslicarbazepine and LCM reduce VGSC availability through enhancement of slow inactivation, but LCM demonstrated higher interaction with VGSC in the resting state and with fast inactivation gating.

  • Co-administration of Carbamazepine with Eslicarbazepine Acetate Decreases Eslicarbazepine Exposure: A Population Pharmacokinetic Analysis (P3.243)
    Neurology, 2014
    Co-Authors: Blanca Vazquez, Patrício Soares-da-silva, Jahnavi Kharidia, Christian E. Elger, Joana Moreira, Robert T. Wechsler, William E. Rosenfeld, Pedro André Kowacs, Gary Maier, David Blum
    Abstract:

    OBJECTIVE: Investigate the effects of co-administered carbamazepine (CBZ) on the pharmacokinetics of Eslicarbazepine, the major active metabolite of Eslicarbazepine acetate (ESL). BACKGROUND: ESL is a novel once-daily (QD) anticonvulsant, extensively converted after oral administration to Eslicarbazepine, which blocks voltage-gated sodium- and calcium-channels. DESIGN/METHODS: A population pharmacokinetic model was developed using 24h sampling data from 11 Phase I and 3 Phase III studies in which ESL was dosed QD at 400-1200mg. Exponential error models described inter-individual variability (IIV) in absorption rate constant (k a ), apparent oral clearance (CL/F) and apparent volume of distribution (V/F). Two additive plus proportional error models corrected for differences in residual variability between Phase I and III data. Effects of concomitant CBZ were assessed by presence/absence, and then by dose. RESULTS: Eslicarbazepine pharmacokinetics were described by a one-compartment model with first-order absorption and elimination. Estimates had good precision, IIV was large (k a ) or moderate (CL/F, V/F), and residual variability was moderate (Phase III) or low (Phase I). Estimated base Eslicarbazepine CL/F, V/F, and first-order absorption half-life (t 1/2 ) were 2.43L/h, 61.3L, and 0.296h, respectively. Compared with no concomitant antiepileptic drugs, CBZ increased Eslicarbazepine CL/F (by 33.4-52.5% for CBZ doses between 200mg BID and 400mg TID) and decreased Eslicarbazepine area-under-the-concentration-time-curve at steady-state (AUC ss ; by 25.1-34.4% for CBZ doses between 200mg BID and 400mg TID [median decrease=30.8% with CBZ 400mg BID]). CONCLUSIONS: Co-administration of CBZ with ESL decreases Eslicarbazepine exposure. Adjustment of ESL dose may be necessary when CBZ is co-administered, based on the need for additional seizure control. Study Supported by: Sunovion Pharmaceuticals Inc. Disclosure: Dr. Vazquez has received personal compensation for activities with UCB Pharma, Upsher-Smith Laboratories Inc., Acorda Therapeutics, Supernus, and Sunovion Pharmaceuticals. Dr. Vazquez has received research support from Eisai Inc., Idis, UAP Pharma, Upsher-Smith Laboratories Inc., UCB Pharma, and Sunovion Pharmaceuticals. Dr. Wechsler has received personal compensation for activities with USB Pharma, GlaxoSmithKline Inc., Lundbeck, Cyberonics, Eisai Inc., Gerson Lehrman Group, Jazz Pharmaceuticals, Upsher-Smith Laboratories Inc. Dr. Wechsler has received research support from UCB Pharma, Lundbeck, Eisai Inc., Vertex, Icagen, King Pharmaceuticals, Sunovion Pharmaceuticals, Upsher-Smith Laboratories Inc., Pfizer Inc., and GlaxoSmithKline Inc. Dr. Rosenfeld has received personal compensation for activities with USB Pharma, Lundbeck Research USA Inc., and Supernus Pharmaceuticals. Dr. Rosenfeld has received research support from Pfizer Inc., UCB Pharma, Eisai Inc., Valeant, Medtronic Inc., Lundbeck Research USA Inc., Sunovion Pharmaceuticals, Artemis, SK Life, and Upsher-Smith Laboratories Inc. Dr. Elger has received personal compensation for activities with Bial, Desitin, Novartis, Eisai Inc., and UCB Pharma. Dr. Kowacs has received personal compensation for activities with Abbott Laboratories, Inc., GlaxoSmithKline Inc., and Cyberonics. Dr. Soares da Silva has received personal compensation for activities with Bial. Dr. Moreira has received personal compensation for activities with BIAL. Dr. Kharidia has received personal compensation for activities with Infinity Pharmaceuticals as an employee. Dr. Maier has received personal compensation for activities with Sunovion Pharmaceuticals as an employee. Dr. Blum has received personal compensation for activities with Sunovion Pharmaceuticals as an employee. Dr. Blum has received research support from Sunovion Pharmaceuticals. Dr. Grinnell has received personal compensation for activities with Sunovion Pharmaceuticals.

Amilcar Falcao - One of the best experts on this subject based on the ideXlab platform.

  • Exposure-safety and efficacy response relationships and population pharmacokinetics of Eslicarbazepine acetate.
    Acta neurologica Scandinavica, 2018
    Co-Authors: Barry E. Gidal, Patrício Soares-da-silva, Amilcar Falcao, Elinor Ben-menachem, David Blum, Mercedes P. Jacobson, Mar Carreño, F. Rocha, Joana Moreira, Todd Grinnell
    Abstract:

    Objectives Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED) for focal-onset seizures (FOS). Pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to assess dose selection, identify significant AED drug interactions, and quantitate relationships between exposure and safety and efficacy outcomes from Phase 3 trials of adjunctive ESL. Methods Eslicarbazepine (the primary active metabolite of ESL) population PK was evaluated using data from 1351 subjects enrolled in 14 studies (11 Phase 1 and three Phase 3 studies) after multiple oral doses ranging from 400 to 1200 mg. Population PK and PD models related individual Eslicarbazepine exposures to safety outcomes and efficacy responses. Results Eslicarbazepine PK was described by a one-compartment model with linear absorption and elimination. The probability of a treatment-emergent adverse event (TEAE; dizziness, headache, or somnolence) was higher with an initial dose of ESL 800 mg than with an initial dose of ESL 400 mg QD. Body weight, sex, region, and baseline use of carbamazepine (CBZ) or lamotrigine were also found to influence the probability of TEAEs. Eslicarbazepine exposure influenced serum sodium concentration, standardized seizure frequency, and probability of response; better efficacy outcomes were predicted in patients not from Western Europe (WE; vs WE patients) and those not taking CBZ (vs taking CBZ) at baseline. Conclusions Pharmacokinetic and PK/PD modeling were implemented during the development of ESL for adjunctive treatment of FOS in adults. This quantitative approach supported decision-making during the development of ESL, and contributed to dosing recommendations and labeling information related to drug interactions.

  • pharmacokinetics and tolerability of Eslicarbazepine acetate and oxcarbazepine at steady state in healthy volunteers
    Epilepsia, 2013
    Co-Authors: Christian E. Elger, Amilcar Falcao, Patricio Soaresdasilva, Meir Bialer, Luís Pereira De Almeida, Teresa G. Nunes, Manuel Vazdasilva
    Abstract:

    Summary Purpose Investigate the pharmacokinetics of once-daily (QD; 900 mg) and twice-daily (BID; 450 mg) regimens of Eslicarbazepine acetate (ESL) and BID (450 mg) regimen of oxcarbazepine (OXC) at steady state in healthy volunteers. Methods Single-center, open-label, randomized, three-way (n = 12) crossover studies in healthy volunteers. Key Findings Mean Eslicarbazepine Cmax,ss (in μm) following ESL QD (87.3) was 33.3% higher (p < 0.05) compared to ESL BID (65.5) and 82.1% higher (p < 0.05) compared to OXC BID (48.0). The mean area under the curve (AUC)ss,0–τ (in μmol h/L) following the last dose of an 8-day repeated dosing was 1156.3, 1117.6, and 968.4 for ESL QD, ESL BID, and OXC BID, respectively. The ratio Eslicarbazepine plasma exposure (μmol h/L) to ESL daily-dose (μmol) was 0.381 (1156.3:3037.3), 0.368 (1117.6:3037.3), and 0.271 (968.4:3567.6) for ESL-QD, ESL-BID, and OXC-BID, respectively, which translates into a 40.6% increase in the ability of ESL-QD compared to OXC-BID to deliver into the plasma their major active entity Eslicarbazepine. The extent of plasma exposure to ESL minor metabolites: (R)-licarbazepine and oxcarbazepine after ESL-QD was 71.5% and 61.1% lower, respectively, than after OXC-BID. Twenty, 24 and 38 treatment emergent adverse events were reported with ESL-QD, ESL-BID, and OXC-BID, respectively. Significance ESL-QD resulted in 33.3% higher peak plasma concentration (Cmax,ss) of Eslicarbazepine and similar extent of plasma exposure (AUCss,0–τ) when compared to ESL-BID, which may contribute to the efficacy profile reported with once-daily ESL. In comparison to OXC-BID, administration of ESL-QD resulted in 40.6% increase in the delivery of Eslicarbazepine into the plasma as well as a significantly lower systemic exposure to (R)-licarbazepine and oxcarbazepine.

  • Pharmacokinetics and tolerability of Eslicarbazepine acetate and oxcarbazepine at steady state in healthy volunteers
    Epilepsia, 2013
    Co-Authors: Christian E. Elger, Amilcar Falcao, Meir Bialer, Luís Pereira De Almeida, Teresa G. Nunes, Manuel Vaz-da-silva, Patrício Soares-da-silva
    Abstract:

    Summary Purpose Investigate the pharmacokinetics of once-daily (QD; 900 mg) and twice-daily (BID; 450 mg) regimens of Eslicarbazepine acetate (ESL) and BID (450 mg) regimen of oxcarbazepine (OXC) at steady state in healthy volunteers. Methods Single-center, open-label, randomized, three-way (n = 12) crossover studies in healthy volunteers. Key Findings Mean Eslicarbazepine Cmax,ss (in μm) following ESL QD (87.3) was 33.3% higher (p 

  • Bioequivalence of Eslicarbazepine Acetate from Two Different Sources of its Active Product Ingredient in Healthy Subjects
    Drugs in R&D, 2013
    Co-Authors: Amilcar Falcao, Teresa G. Nunes, Ricardo Lima, Rui Sousa, Patrício Soares-da-silva
    Abstract:

    Purpose To compare the bioavailability (BA) and pharmacokinetic (PK) properties and to demonstrate the bioequivalence (BE) between two active product ingredient (API) sources of Eslicarbazepine acetate (ESL) in healthy volunteers.

  • steady state plasma and cerebrospinal fluid pharmacokinetics and tolerability of Eslicarbazepine acetate and oxcarbazepine in healthy volunteers
    Epilepsia, 2013
    Co-Authors: Teresa G. Nunes, Amilcar Falcao, Patricio Soaresdasilva, José Francisco Rocha, Luís Pereira De Almeida
    Abstract:

    SUMMARY Purpose: To evaluate the pharmacokinetics and tolerability of once-daily Eslicarbazepine acetate (ESL) and twicedaily oxcarbazepine (OXC) and their metabolites in cerebrospinal fluid (CSF) and plasma following repeated oral administration. Methods: Single-center, open-label, randomized, parallelgroup 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 ESLresultedinmoreEslicarbazepine,lessR-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 supportsonce-daily dosing of ESL.

Patricio Soaresdasilva - One of the best experts on this subject based on the ideXlab platform.

  • Eslicarbazepine acetate for the treatment of focal epilepsy an update on its proposed mechanisms of action
    Pharmacology Research & Perspectives, 2015
    Co-Authors: Ana I. Loureiro, Maria João Bonifácio, Patricio Soaresdasilva, Nuno Palma, Nuno Filipe Pires, Lyndon C. Wright
    Abstract:

    Eslicarbazepine acetate (ESL) is a once daily antiepileptic drug (AED) approved by the European Medicines Agency (EMA), the Food and Drug Administration (FDA) and Health Canada as an adjunctive therapy in adults with partial-onset seizures (POS). In humans and in relevant animal laboratory species, ESL undergoes extensive first pass hydrolysis to its major active metabolite Eslicarbazepine that represents ~95% of circulating active moieties. ESL and Eslicarbazepine showed anticonvulsant activity in animal models. ESL may not only suppress seizure activity but may also inhibit the generation of a hyperexcitable network. Data reviewed here suggest that ESL and Eslicarbazepine demonstrated the following in animal models: (1) the selectivity of interaction with the inactive state of the voltage-gated sodium channel (VGSC), (2) reduction in VGSC availability through enhancement of slow inactivation, instead of alteration of fast inactivation of VGSC, (3) the failure to cause a paradoxical upregulation of persistent Na+ current (INaP), and (4) the reduction in firing frequencies of excitatory neurons in dissociated hippocampal cells from patients with epilepsy who were pharmacoresistant to carbamazepine (CBZ). In addition, Eslicarbazepine effectively inhibited high- and low-affinity hCaV3.2 inward currents with greater affinity than CBZ. These preclinical findings may suggest the potential for antiepileptogenic effects; furthermore, the lack of effect upon KV7.2 outward currents may translate into a reduced potential for Eslicarbazepine to facilitate repetitive firing.

  • targeting pharmacoresistant epilepsy and epileptogenesis with a dual purpose antiepileptic drug
    Brain, 2015
    Co-Authors: Anna Doeser, Maria João Bonifácio, Patricio Soaresdasilva, Mischa Uebachs, Gesa Dickhof, Margit Reitze, Christina Schaub, Nuno Pires, Heinz Beck
    Abstract:

    In human epilepsy, pharmacoresistance to antiepileptic drug therapy is a major problem affecting a substantial fraction of patients. Many of the currently available antiepileptic drugs target voltage-gated sodium channels, leading to a rate-dependent suppression of neuronal discharge. A loss of use-dependent block has emerged as a potential cellular mechanism of pharmacoresistance for anticonvulsants acting on voltage-gated sodium channels. There is a need both for compounds that overcome this resistance mechanism and for novel drugs that inhibit the process of epileptogenesis. We show that Eslicarbazepine acetate, a once-daily antiepileptic drug, may constitute a candidate compound that addresses both issues. Eslicarbazepine acetate is converted extensively to Eslicarbazepine after oral administration. We have first tested using patch-clamp recording in human and rat hippocampal slices if Eslicarbazepine, the major active metabolite of Eslicarbazepine acetate, shows maintained activity in chronically epileptic tissue. We show that Eslicarbazepine exhibits maintained use-dependent blocking effects both in human and experimental epilepsy with significant add-on effects to carbamazepine in human epilepsy. Second, we show that Eslicarbazepine acetate also inhibits Cav3.2 T-type Ca(2+) channels, which have been shown to be key mediators of epileptogenesis. We then examined if transitory administration of Eslicarbazepine acetate (once daily for 6 weeks, 150 mg/kg or 300 mg/kg) after induction of epilepsy in mice has an effect on the development of chronic seizures and neuropathological correlates of chronic epilepsy. We found that Eslicarbazepine acetate exhibits strong antiepileptogenic effects in experimental epilepsy. EEG monitoring showed that transitory Eslicarbazepine acetate treatment resulted in a significant decrease in seizure activity at the chronic state, 8 weeks after the end of treatment. Moreover, Eslicarbazepine acetate treatment resulted in a significant decrease in mossy fibre sprouting into the inner molecular layer of pilocarpine-injected mice, as detected by Timm staining. In addition, epileptic animals treated with 150 mg/kg, but not those that received 300 mg/kg Eslicarbazepine acetate showed an attenuated neuronal loss. These results indicate that Eslicarbazepine potentially overcomes a cellular resistance mechanism to conventional antiepileptic drugs and at the same time constitutes a potent antiepileptogenic agent.

  • the effects of Eslicarbazepine on persistent na current and the role of the na channel β subunits
    Epilepsy Research, 2014
    Co-Authors: Anna Doeser, Patricio Soaresdasilva, Heinz Beck, Mischa Uebachs
    Abstract:

    Summary Eslicarbazepine is the major active metabolite of Eslicarbazepine acetate, a once-daily antiepileptic drug approved in Europe as adjunctive therapy for refractory partial-onset seizures in adults. This study was aimed to determine the effects of Eslicarbazepine on persistent Na + currents ( I NaP ) and the role of β subunits in modulating these effects. To study the role of β subunits of the Na + channel we used a mouse line genetically lacking either the β 1 or β 2 subunit, encoded by the SCN1B or SCN2B gene, respectively. Whole cell patch-clamp recordings were performed on CA1 neurons in hippocampal slices under control conditions and application of 300μM Eslicarbazepine. We examined I NaP in acutely isolated CA1 neurons and repetitive firing in hippocampal slices of mice lacking β subunits and corresponding wild-type littermates. We found that Eslicarbazepine caused a significant reduction of maximal I NaP conductance and an efficient reduction of the firing rate in wild-type mice. We have shown previously a paradoxical increase of conductance of I NaP caused by carbamazepine in mice lacking β 1 subunits in the subthreshold range, leading to a failure in affecting neuronal firing (Uebachs et al., 2010). In contrast, Eslicarbazepine did not cause this paradoxical effect on I NaP in SCN1B null mice. Consequently, the effects of Eslicarbazepine on repetitive firing were maintained in these animals. These results indicate that Eslicarbazepine exerts effects on I NaP similar to those known for carbamazepine. However, in animals lacking the β 1 Na + channel subunit these effects are maintained. Therefore, Eslicarbazepine potentially overcomes a previously described putative mechanism of resistance to established Na + channel acting antiepileptic drugs.

  • pharmacokinetics and tolerability of Eslicarbazepine acetate and oxcarbazepine at steady state in healthy volunteers
    Epilepsia, 2013
    Co-Authors: Christian E. Elger, Amilcar Falcao, Patricio Soaresdasilva, Meir Bialer, Luís Pereira De Almeida, Teresa G. Nunes, Manuel Vazdasilva
    Abstract:

    Summary Purpose Investigate the pharmacokinetics of once-daily (QD; 900 mg) and twice-daily (BID; 450 mg) regimens of Eslicarbazepine acetate (ESL) and BID (450 mg) regimen of oxcarbazepine (OXC) at steady state in healthy volunteers. Methods Single-center, open-label, randomized, three-way (n = 12) crossover studies in healthy volunteers. Key Findings Mean Eslicarbazepine Cmax,ss (in μm) following ESL QD (87.3) was 33.3% higher (p < 0.05) compared to ESL BID (65.5) and 82.1% higher (p < 0.05) compared to OXC BID (48.0). The mean area under the curve (AUC)ss,0–τ (in μmol h/L) following the last dose of an 8-day repeated dosing was 1156.3, 1117.6, and 968.4 for ESL QD, ESL BID, and OXC BID, respectively. The ratio Eslicarbazepine plasma exposure (μmol h/L) to ESL daily-dose (μmol) was 0.381 (1156.3:3037.3), 0.368 (1117.6:3037.3), and 0.271 (968.4:3567.6) for ESL-QD, ESL-BID, and OXC-BID, respectively, which translates into a 40.6% increase in the ability of ESL-QD compared to OXC-BID to deliver into the plasma their major active entity Eslicarbazepine. The extent of plasma exposure to ESL minor metabolites: (R)-licarbazepine and oxcarbazepine after ESL-QD was 71.5% and 61.1% lower, respectively, than after OXC-BID. Twenty, 24 and 38 treatment emergent adverse events were reported with ESL-QD, ESL-BID, and OXC-BID, respectively. Significance ESL-QD resulted in 33.3% higher peak plasma concentration (Cmax,ss) of Eslicarbazepine and similar extent of plasma exposure (AUCss,0–τ) when compared to ESL-BID, which may contribute to the efficacy profile reported with once-daily ESL. In comparison to OXC-BID, administration of ESL-QD resulted in 40.6% increase in the delivery of Eslicarbazepine into the plasma as well as a significantly lower systemic exposure to (R)-licarbazepine and oxcarbazepine.

  • steady state plasma and cerebrospinal fluid pharmacokinetics and tolerability of Eslicarbazepine acetate and oxcarbazepine in healthy volunteers
    Epilepsia, 2013
    Co-Authors: Teresa G. Nunes, Amilcar Falcao, Patricio Soaresdasilva, José Francisco Rocha, Luís Pereira De Almeida
    Abstract:

    SUMMARY Purpose: To evaluate the pharmacokinetics and tolerability of once-daily Eslicarbazepine acetate (ESL) and twicedaily oxcarbazepine (OXC) and their metabolites in cerebrospinal fluid (CSF) and plasma following repeated oral administration. Methods: Single-center, open-label, randomized, parallelgroup 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 ESLresultedinmoreEslicarbazepine,lessR-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 supportsonce-daily dosing of ESL.

Luís Pereira De Almeida - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics and tolerability of Eslicarbazepine acetate and oxcarbazepine at steady state in healthy volunteers
    Epilepsia, 2013
    Co-Authors: Christian E. Elger, Amilcar Falcao, Patricio Soaresdasilva, Meir Bialer, Luís Pereira De Almeida, Teresa G. Nunes, Manuel Vazdasilva
    Abstract:

    Summary Purpose Investigate the pharmacokinetics of once-daily (QD; 900 mg) and twice-daily (BID; 450 mg) regimens of Eslicarbazepine acetate (ESL) and BID (450 mg) regimen of oxcarbazepine (OXC) at steady state in healthy volunteers. Methods Single-center, open-label, randomized, three-way (n = 12) crossover studies in healthy volunteers. Key Findings Mean Eslicarbazepine Cmax,ss (in μm) following ESL QD (87.3) was 33.3% higher (p < 0.05) compared to ESL BID (65.5) and 82.1% higher (p < 0.05) compared to OXC BID (48.0). The mean area under the curve (AUC)ss,0–τ (in μmol h/L) following the last dose of an 8-day repeated dosing was 1156.3, 1117.6, and 968.4 for ESL QD, ESL BID, and OXC BID, respectively. The ratio Eslicarbazepine plasma exposure (μmol h/L) to ESL daily-dose (μmol) was 0.381 (1156.3:3037.3), 0.368 (1117.6:3037.3), and 0.271 (968.4:3567.6) for ESL-QD, ESL-BID, and OXC-BID, respectively, which translates into a 40.6% increase in the ability of ESL-QD compared to OXC-BID to deliver into the plasma their major active entity Eslicarbazepine. The extent of plasma exposure to ESL minor metabolites: (R)-licarbazepine and oxcarbazepine after ESL-QD was 71.5% and 61.1% lower, respectively, than after OXC-BID. Twenty, 24 and 38 treatment emergent adverse events were reported with ESL-QD, ESL-BID, and OXC-BID, respectively. Significance ESL-QD resulted in 33.3% higher peak plasma concentration (Cmax,ss) of Eslicarbazepine and similar extent of plasma exposure (AUCss,0–τ) when compared to ESL-BID, which may contribute to the efficacy profile reported with once-daily ESL. In comparison to OXC-BID, administration of ESL-QD resulted in 40.6% increase in the delivery of Eslicarbazepine into the plasma as well as a significantly lower systemic exposure to (R)-licarbazepine and oxcarbazepine.

  • Pharmacokinetics and tolerability of Eslicarbazepine acetate and oxcarbazepine at steady state in healthy volunteers
    Epilepsia, 2013
    Co-Authors: Christian E. Elger, Amilcar Falcao, Meir Bialer, Luís Pereira De Almeida, Teresa G. Nunes, Manuel Vaz-da-silva, Patrício Soares-da-silva
    Abstract:

    Summary Purpose Investigate the pharmacokinetics of once-daily (QD; 900 mg) and twice-daily (BID; 450 mg) regimens of Eslicarbazepine acetate (ESL) and BID (450 mg) regimen of oxcarbazepine (OXC) at steady state in healthy volunteers. Methods Single-center, open-label, randomized, three-way (n = 12) crossover studies in healthy volunteers. Key Findings Mean Eslicarbazepine Cmax,ss (in μm) following ESL QD (87.3) was 33.3% higher (p 

  • steady state plasma and cerebrospinal fluid pharmacokinetics and tolerability of Eslicarbazepine acetate and oxcarbazepine in healthy volunteers
    Epilepsia, 2013
    Co-Authors: Teresa G. Nunes, Amilcar Falcao, Patricio Soaresdasilva, José Francisco Rocha, Luís Pereira De Almeida
    Abstract:

    SUMMARY Purpose: To evaluate the pharmacokinetics and tolerability of once-daily Eslicarbazepine acetate (ESL) and twicedaily oxcarbazepine (OXC) and their metabolites in cerebrospinal fluid (CSF) and plasma following repeated oral administration. Methods: Single-center, open-label, randomized, parallelgroup 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 ESLresultedinmoreEslicarbazepine,lessR-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 supportsonce-daily dosing of ESL.

  • Steady‐state plasma and cerebrospinal fluid pharmacokinetics and tolerability of Eslicarbazepine acetate and oxcarbazepine in healthy volunteers
    Epilepsia, 2012
    Co-Authors: Teresa G. Nunes, José Francisco Rocha, Amilcar Falcao, Luís Pereira De Almeida, Patrício Soares-da-silva
    Abstract:

    SUMMARY Purpose: To evaluate the pharmacokinetics and tolerability of once-daily Eslicarbazepine acetate (ESL) and twicedaily oxcarbazepine (OXC) and their metabolites in cerebrospinal fluid (CSF) and plasma following repeated oral administration. Methods: Single-center, open-label, randomized, parallelgroup 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 ESLresultedinmoreEslicarbazepine,lessR-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 supportsonce-daily dosing of ESL.

  • Effect of Eslicarbazepine acetate and oxcarbazepine on cognition and psychomotor function in healthy volunteers
    Epilepsy & behavior : E&B, 2010
    Co-Authors: Denise Milovan, José Francisco Rocha, Luís Pereira De Almeida, Myroslava K. Romach, Teresa G. Nunes, Marta Sokowloska, Edward M. Sellers, Patrício Soares-da-silva
    Abstract:

    The results of two single-blind studies conducted to evaluate the cognitive and psychomotor effects of Eslicarbazepine acetate and oxcarbazepine following single and repeated administration in healthy volunteers are reported. The cognitive and psychomotor evaluation consisted of several computerized and paper-and-pencil measures. Eslicarbazepine acetate and oxcarbazepine had similar overall cognitive profiles and did not cause clinically relevant cognitive impairment. The incidence of adverse events was lower with Eslicarbazepine acetate than with oxcarbazepine.

Luis Almeida - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacokinetics, drug interactions and exposure-response relationship of Eslicarbazepine acetate in adult patients with partial-onset seizures: population pharmacokinetic and pharmacokinetic/pharmacodynamic analyses.
    CNS drugs, 2012
    Co-Authors: Amilcar Falcao, Luis Almeida, Eliane Fuseau, Teresa G. Nunes, Patrício Soares-da-silva
    Abstract:

    Background: Eslicarbazepine acetate (Zebenix®) is a voltage-gated sodium channel blocker approved in 2009 by the European Medicines Agency as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization.

  • Pharmacokinetics, Drug Interactions and Exposure-Response Relationship of Eslicarbazepine Acetate in Adult Patients with Partial-Onset Seizures
    CNS Drugs, 2012
    Co-Authors: Amilcar Falcao, Luis Almeida, Eliane Fuseau, Teresa Nunes, Patrício Soares-da-silva
    Abstract:

    Background : Eslicarbazepine acetate (Zebenix®) is a voltage-gated sodium channel blocker approved in 2009 by the European Medicines Agency as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization. Objectives : The objectives of the current population pharmacokinetic (PK) and PK/pharmacodynamic analyses were to characterize the population PK of Eslicarbazepine (the main active metabolite of Eslicarbazepine acetate), to evaluate the influence of patient factors and concomitant antiepileptic drugs (AEDs) on the PK variability of Eslicarbazepine, to assess the effect of Eslicarbazepine acetate on the PK of concomitant AEDs and to investigate the relationship between Eslicarbazepine systemic exposure and Eslicarbazepine acetate antiepileptic activity in patients with partial-onset seizures uncontrolled with one to three AEDs. Methods : Sparse plasma concentrations of Eslicarbazepine and concomitant AEDs, along with efficacy data, were obtained from 641 patients enrolled in Eslicarbazepine acetate phase III studies. Data were analysed using nonlinear mixed-effect modelling methods. Most analyses used a model using log-transformed data from trough concentration (minimum steady-state plasma concentration during a dosage interval [C_min,ss]). The model estimated the apparent total body clearance from plasma (CL/F), which is sufficient to predict average plasma concentrations at steady state (C_av,ss). After the final model was validated, individual concentrations at steady state were predicted, and exposure parameters (area under the plasma concentration-time curve over 24 hours, C_min,ss and C_av,ss) for a one-compartmental model with first-order elimination were calculated. Results : Eslicarbazepine CL/F was affected by bodyweight, dose of carbamazepine (D_CAR) and co-administration of barbiturates or phenytoin (AED_PB), as predicted by the equation CL/F = (2.36 + 0.00149 · D_CAR + 1.41 · AED_PB) · (weight/70)^0.75, which means that CL/F is 2.36L/h for a subject with a bodyweight of 70 kg and without concomitant carbamazepine and barbiturates/phenytoin. Concomitant use of lamotrigine, valproic acid, topiramate, gabapentin, clobazam and levetiracetam showed no effect on the exposure to Eslicarbazepine. Inter-individual variability of Eslicarbazepine CL/F was 44% and the residual error (intra-subject variability) was proportional to the log of concentrations, with a coefficient of variation of 6%. Age, ethnicity, sex and creatinine clearance did not affect Eslicarbazepine CL/F. Eslicarbazepine acetate did not affect the CL/F of clobazam, gabapentin, phenytoin, phenobarbital, levetiracetam and valproic acid. Eslicarbazepine acetate slightly increased the CL/F of carbamazepine (up to 14%), lamotrigine (up to 12%) and topiramate (up to 16%). The antiepileptic effect of Eslicarbazepine acetate, as assessed by a decrease in seizure frequency, increased with the increase of Eslicarbazepine acetate dose and Eslicarbazepine concentrations. The concomitant administration of other AEDs did not affect the Eslicarbazepine acetate exposure-response relationship. Conclusions : The magnitude of the effect of Eslicarbazepine acetate on the CL/F of the concomitant AEDs assessed appears to be not clinically relevant and does not justify the need for dose adjustment in most patients. A continuous dose-response relationship was observed between Eslicarbazepine concentrations and seizure frequency reduction, which was not affected by concomitant AEDs.

  • Pharmacokinetics of Eslicarbazepine acetate at steady-state in adults with partial-onset seizures.
    Epilepsy Research, 2011
    Co-Authors: Emilio Perucca, Luis Almeida, Amilcar Falcao, Christian E. Elger, P Halász, Patrício Soares-da-silva
    Abstract:

    Summary Objective: To evaluate the pharmacokinetics of Eslicarbazepine acetate (ESL) at steady-state in adults with partial-onset seizures who have taken ESL for at least 1 year with one or two concomitant antiepileptic drugs (AEDs). Methods: Blood samples for the pharmacokinetic assessment were taken at pre-dose, and 1, 2, 3, 4, 6, 8, 12 and 24 h post-dose at steady-state in 51 patients stabilised on chronic (beyond 1 year) treatment with ESL 400 mg (n = 7), 800 mg (n = 26) or 1200 mg (n = 18) once-daily. Most patients (n = 29, 56.9%) were receiving 2 concomitant AEDs, and most frequent co-medications were carbamazepine (n = 34, 66.7%) and valproic acid (n = 19, 37.3%). Plasma concentrations of ESL and its metabolites Eslicarbazepine, R-licarbazepine and oxcarbazepine (OXC) were determined by a validated chiral method using liquid chromatography coupled to mass spectrometry.

  • Original article Pharmacokinetic interaction study between Eslicarbazepine acetate and topiramate in healthy subjects
    2010
    Co-Authors: Teresa Nunes, Eric Sicard, Luis Almeida
    Abstract:

    Objective: Combination therapy is frequently required in the management of epilepsy. The primary objective of this study was to investigate the pharmacokinetic interaction between Eslicarbazepine acetate (ESL) 1200 mg once daily and topiramate (TPM) 200 mg once daily in healthy subjects. Methods: Multiple-dose, open-label, one-sequence study in two parallel groups of 16 healthy male volunteers. After an 8-day treatment with ESL (Group A) or TPM (Group B), ESL and TPM were co-administered for 19 days. A bioequivalence approach based on a within-subject comparison was used to investigate a potential drug– drug interaction. End/start of treatment geometric mean ratios (GMR, %) and 90% confidence intervals (90% CI) were calculated for maximum plasma concentration (Cmax) and area under the plasma concentration–time curve over the dosing interval at steady-state (AUCss) of Eslicarbazepine (ESL major active metabolite), R-licarbazepine (ESL minor active metabolite) and TPM at Day 8 and Day 27. Results: In Group A, Eslicarbazepine GMR (90% CI) was 86.79% (81.06%; 92.94%) for Cmax and 92.70% (89.21%; 96.32%) for AUCss. In Group B, TPM GMR (90% CI) was 81.50% (77.48%; 85.89%) for Cmax and 81.81% (79.69%; 84.00%) for AUCss. The 90% CI of Eslicarbazepine Cmax and AUCss fell within the pre-specified bioequivalence range (80.00%; 125.00%), allowing it to be concluded that the extent of systemic exposure to Eslicarbazepine was unaffected by the concomitant administration of TPM. The 90% CI for topiramate AUCss was borderline in relation to the pre-specified bioequivalence range and topiramate Cmax fell outside the pre-specified bioequivalence range. Therefore, the extent of systemic exposure to TPM following co-administration with ESL was not formally bioequivalent to the extent of systemic exposure to TPM when TPM was administered alone. However, there was no difference between TPM elimination half-life following TPM co-administered with ESL and TPM administered alone (24.0 and 24.3 h, respectively). The bioavailability of R-licarbazepine was essentially bioequivalent. Two subjects discontinued due to adverse events. No clinical interaction appeared to be present in terms of adverse events when both drugs were given concomitantly.

  • Pharmacokinetics of Eslicarbazepine acetate in patients with moderate hepatic impairment
    European Journal of Clinical Pharmacology, 2008
    Co-Authors: Luis Almeida, J. Hendrick Potgieter, Joana Maia, M. Alida Potgieter, Fernando Mota, P Soares-da-silva
    Abstract:

    Objective To 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. Methods The 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). Results Eslicarbazepine 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. Conclusion The 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.