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

  • analysis of cutaneous allergic reactions in clinical trials of Eslicarbazepine Acetate
    Acta Neurologica Scandinavica, 2020
    Co-Authors: Joanne Rogin, Patricio Soaresdasilva, David Blum, Helena Gama, Elinor Benmenachem, Laura Strom, Trevor Resnick, Silvia Kochen, Todd Grinnell
    Abstract:

    Objectives To evaluate cutaneous allergic reactions in clinical trials of adjunctive Eslicarbazepine Acetate (ESL) for focal seizures. Materials and methods Data were analyzed from three phase III randomized, double-blind, placebo-controlled studies of adjunctive ESL in adults (placebo, n = 426; ESL, n = 1021) and two randomized, double-blind, placebo-controlled studies (and open-label extensions [OLEs]) of adjunctive ESL in children aged 4-17 years (placebo, n = 160; ESL, n = 202; OLE, n = 337). Results Adult studies: Rash (ESL 1.9%, placebo 0.9%) and pruritus (ESL 1.2%, placebo 0.9%) were the most frequent rash-related treatment-emergent adverse events (TEAEs). Most rash-related TEAEs were mild or moderate in severity. Incidence of rash increased with increasing ESL dose, but was not higher for patients who initiated treatment with higher ESL doses. Pediatric studies: Allergic dermatitis (ESL 3.0%, placebo 0) and rash (controlled studies: ESL 1.0%, placebo 1.3%; OLE periods: ESL ≤1.2%) were the most frequent rash-related TEAEs. There was one case of DRESS in the ESL group. Most rash-related TEAEs were mild or moderate in severity and judged as not related to treatment with ESL. Conclusions Serious skin rashes were rare during adult and pediatric clinical trials of ESL. Although the incidence of rash with ESL was low, it is important for patients/caregivers to be made aware of the potential signs and symptoms associated with serious skin rashes.

  • effects of adjunctive Eslicarbazepine Acetate on neurocognitive functioning in children with refractory focal onset seizures
    Epilepsy & Behavior, 2018
    Co-Authors: Sergiusz Joźwiak, Patricio Soaresdasilva, Helena Gama, F. Rocha, Joana Moreira, Pierangelo Veggiotti
    Abstract:

    Abstract Purpose This was a phase-II, randomized, double-blind (DB), placebo-controlled study aimed to evaluate neurocognitive effects of Eslicarbazepine Acetate (ESL) as adjunctive therapy in pediatric patients with refractory focal-onset seizures (FOS). Methods Children (6–16 years old) with FOS were randomized (2:1) to ESL or placebo. Treatment started at 10 mg/kg/day, was up-titrated up to 30 mg/kg/day (target dose), and maintained for 8 weeks, followed by one-year open-label follow-up. The primary endpoint was change from baseline to the end of maintenance period in the composite Power of Attention assessed with the Cognitive Drug Research (CDR) system. Behavioral and emotional functioning and quality of life (QOL), secondary endpoints, were assessed with Child Health Questionnaire-Parent Form 50 (CHQ-PF50), Child Behavior Checklist (CBCL), and Raven's Standard Progressive Matrices (SPM). Efficacy was evaluated through changes in standardized seizure frequency (SF), responder rate, and proportion of seizure-free patients. Safety was evaluated by the incidence of treatment-emergent adverse events (TEAEs). Results One hundred and twenty-three patients were randomized. A noninferiority analysis failed to reject the null hypothesis that the change from baseline in the Power of Attention score in the ESL group was at least 121 ms inferior to the placebo group for all age groups. The CDR scores showed no differences between placebo and ESL in Power of Attention (1868.0 vs 1759.5), Continuity of Attention (1.136 vs − 1.786), Quality of Working Memory (− 0.023 vs − 0.024), and Speed of Memory (− 263.4 vs − 249.6). Nonsignificant differences between placebo and ESL were seen for CHQ-PF50, CBCL scores, and Raven's SPM. Episodic Memory Index showed significant negative effect on ESL. Efficacy results favored the ESL group (SF least square [LS] means 1.98 vs 4.29). The TEAEs had a similar incidence between treatment groups (41.0% vs 47.5%). Conclusions Overall ESL did not produce statistically significant effects on neurocognitive and behavioral functioning in patients with epilepsy aged 6 to 16 years. Additionally, ESL was effective in reducing seizure frequency and was well-tolerated.

  • po046 safety and tolerability of Eslicarbazepine Acetate as monotherapy in patients with newly diagnosed partial onset seizures
    Journal of Neurology Neurosurgery and Psychiatry, 2017
    Co-Authors: Eugen Trinka, Pedro A. Kowacs, Christian E. Elger, Joana Moreira, J F Rocha, Elinor Benmenachem, R P Pinto, F Ikedo, A Pereira, Patricio Soaresdasilva
    Abstract:

    Purpose To describe the safety of once-daily (QD) Eslicarbazepine Acetate (ESL) as assessed in a phase-III, randomised, double-blind, active-controlled, non-inferiority monotherapy study in adults with newly diagnosed partial-onset seizures (POS), in comparison with twice-daily (BID) controlled-release carbamazepine (CBZ-CR). Method Patients (≥18 years) were randomised (1:1) to receive either ESL or CBZ-CR in a 3-step dose-level design. Each dose-level was then maintained through a 26 week Evaluation-Period (EP). Subjects who remained seizure-free at any dose-level continued through subsequent periods/phases. Safety assessments were carried out throughout the study. Results The safety analysis set comprised of 813 patients (ESL, 401; CBZ-CR, 412). A similar percentage of subjects experienced at least 1 TEAE in the ESL group (75.3%) and CBZ-CR group (77.7%) and the majority of events were of mild intensity. The most frequently reported possibly-related TEAEs were (ESL; CBZ): headache (6.5%; 5.6%), dizziness (7.2%; 6.8%), nausea (4.5%; 6.8%), fatigue (4.7%; 4.4%), somnolence (5.2%; 7.0%) and increased gamma-glutamyltransferase (2.7%; 12.4%). Fewer subjects discontinued treatment due to a TEAE in the ESL group (13.5%) compared to the CBZ-CR group (18.0%). Conclusion Once-daily ESL monotherapy demonstrated favourable safety in the study population. No new or unexpected safety findings emerged, compared with the adjunctive studies. Sponsored by BIAL-Portela and Ca S.A.

  • 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.

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.

  • Effect of Eslicarbazepine Acetate in the corneal kindling progression and the amygdala kindling model of temporal lobe epilepsy.
    Epilepsy research, 2013
    Co-Authors: Heidrun Potschka, Ana I. Loureiro, Jonna Soerensen, Anton Pekcec, Patrício Soares-da-silva
    Abstract:

    Summary Objective The present study was aimed at determining the effect of Eslicarbazepine Acetate (ESL), Eslicarbazepine and (R)-licarbazepine administration in the mouse corneal kindling and amygdala kindling models. Methods NMRI mice were kindled by bilateral corneal stimulation twice daily. In amygdala kindling, mice were stimulated once daily via an implanted depth electrode until 10 generalized seizures were elicited. Maximal electroshocks (MES) were administered via corneal electrodes. Results The average number of stimulations to reach a fully kindled generalized seizure was markedly increased by ESL. Administration of Eslicarbazepine also inhibited the acquisition of kindling, whereas administration of R-licarbazepine did not affect the number of stimulations necessary to induce a specific seizure stage, and did not exert any relevant effect on mean seizure severity during kindling progression. ESL dose-dependently increased the focal seizure threshold and reduced seizure severity in amygdala kindling. Whereas Eslicarbazepine treatment increased the afterdischarge threshold in a significant manner, (R)-licarbazepine treatment failed to exert a significant effect on thresholds in fully kindled mice. Administration of ESL and of Eslicarbazepine significantly protected mice against MES-induced seizures, whereas that of (R)-licarbazepine failed to provide protection. Conclusions These data provide evidence of the anticonvulsant effect of ESL and its active metabolite Eslicarbazepine on partial-onset seizures in corneal and amygdala kindling models. Based on an effect of the parent compound and the active metabolite Eslicarbazepine, ESL treatment may not merely suppress seizure activity but may also provide a disease-modifying or antiepileptogenic effect. Future studies will be necessary to further evaluate a putative preventive effect, in particular when considering that re-stimulation following wash-out did not indicate a persistent effect. The findings reported here raise doubts on the contribution of (R)-licarbazepine as an active anticonvulsant.

  • Pharmacokinetics and drug interactions of Eslicarbazepine Acetate
    Epilepsia, 2012
    Co-Authors: Meir Bialer, Patrício Soares-da-silva
    Abstract:

    Summary Eslicarbazepine Acetate (ESL) is a novel once-daily antiepileptic drug (AED) approved in Europe since 2009 that was found to be efficacious and well tolerated in a phase III clinical program in adult patients with partial onset seizures previously not controlled with treatment with one to three AEDs, including carbamazepine (CBZ). ESL shares with CBZ and oxcarbazepine (OXC) 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. Unlike OXC, which is metabolized to both Eslicarbazepine and (R)-licarbazepine, ESL is extensively converted to Eslicarbazepine. The systemic exposure to Eslicarbazepine after ESL oral administration is approximately 94% of the parent dose, with minimal exposure to (R)-licarbazepine and OXC. After ESL oral administration, the effective half-life (t1/2,eff) of Eslicarbazepine was 20–24 h, which is approximately two times longer than its terminal half-life (t1/2). At clinically relevant doses (400–1,600 mg/day) ESL has linear pharmacokinetics (PK) with no effects of gender or moderate liver impairment. However, because Eslicarbazepine is eliminated primarily (66%) by renal excretion, dose adjustment is recommended for patients with renal impairment. Eslicarbazepine clearance is induced by phenobarbital, phenytoin, and CBZ and it dose-dependently decreases plasma exposure of oral contraceptive and simvastatin.

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.

  • effect of repeated administration of Eslicarbazepine Acetate on the pharmacokinetics of simvastatin in healthy subjects
    Epilepsy Research, 2013
    Co-Authors: Amilcar Falcao, Patricio Soaresdasilva, Teresa G. Nunes, Roberto Pinto
    Abstract:

    Summary Objective To investigate the effect of Eslicarbazepine Acetate (ESL) on the pharmacokinetics of simvastatin (SMV), a known CYP3A4 substrate, in healthy subjects. Methods Single centre, two-way cross-over, randomized, open-label study in 24 healthy volunteers. The volunteers received an oral single-dose of SMV 80mg on two occasions (once administered alone and once after treatment with an oral once-daily dose of 800mg of ESL for 14 days), separated by a wash-out period of 3 weeks or more. The analysis of variance (ANOVA) was used to test for differences between Test (SMV under co-administration with ESL) and Reference (SMV administered alone) treatments for AUC 0−∞ , AUC 0−t and C max of SMV and SMV-acid. Results Mean systemic exposure (AUC) measurements for both SMV and SMV-β-hydroxyacid (SMV-acid) were up to 54% lower during ESL use. The Test / Reference geometric mean ratios (GMR) (90% CI) for the AUC 0−t of SMV and SMV-acid were 46% (38%; 55%) and 49% (44%; 55%), respectively. Mean peak concentrations ( C max ) of both SMV and SMV-acid were reduced by 60% and 41%, respectively, when SMV was administered with ESL. Conclusions A significant effect of repeated ESL administration on the pharmacokinetics of SMV and its metabolite SMV-acid was observed. Therefore, dose adjustment of SMV may be required when used concomitantly with ESL, if a clinically significant change in lipids is noted.

  • 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.

  • effect of Eslicarbazepine Acetate on the pharmacokinetics of a combined ethinylestradiol levonorgestrel oral contraceptive in healthy women
    Epilepsy Research, 2013
    Co-Authors: Amilcar Falcao, Luis Almeida, Patricio Soaresdasilva, Teresa G. Nunes, Helena Gama, Manuel Vazdasilva
    Abstract:

    Summary Objective To investigate the effect of once-daily (QD) Eslicarbazepine Acetate (ESL) 800mg and 1200mg administration on pharmacokinetics of a combined ethinylestradiol/levonorgestrel oral contraceptive (OC) in women of childbearing potential. Methods Two two-way, crossover, two-period, randomized, open-label studies were performed in 20 healthy female subjects, each. In one period (ESL+OC period), subjects received ESL 800mg QD in one study and ESL 1200mg QD in the other study, for 15 days; concomitantly with the Day 14 ESL dose, an oral single dose of 30μg ethinylestradiol and 150μg levonorgestrel was administered. In the other period (OC alone), a single dose of 30μg ethinylestradiol and 150μg levonorgestrel was administered. Three weeks or more separated the periods. An analysis of variance (ANOVA) was used to test for differences between pharmacokinetic parameters of 30μg ethinylestradiol and 150μg levonorgestrel following ESL+OC and OC alone, and 90% confidence intervals (90%CI) for the ESL+OC/OC alone geometric mean ratio (GMR) were calculated. Results ESL significantly decreased the systemic exposure to both ethinylestradiol and levonorgestrel. GMR (90%CI) for AUC 0–24 of ethinylestradiol were 68% (64%; 71%) following 1200mg ESL and 75% (71%; 79%) following 800mg ESL. GMR (90%CI) for AUC 0–24 of levonorgestrel were 76% (68%; 86%) following 1200mg ESL and 89% (82%; 97%) following 800mg ESL. Conclusions A clinically relevant dose-dependent effect of ESL administration on the pharmacokinetics of ethinylestradiol and levonorgestrel was observed. Therefore, to avoid inadvertent pregnancy, women of childbearing potential should use other adequate methods of contraception during treatment with ESL, and, in case ESL treatment is discontinued, until CYP3A4 activity returns to normal.

  • efficacy and safety of Eslicarbazepine Acetate as add on treatment in patients with focal onset seizures integrated analysis of pooled data from double blind phase iii clinical studies
    Epilepsia, 2013
    Co-Authors: Antonio Gilnagel, Amilcar Falcao, Christian E. Elger, Luís Pereira De Almeida, Teresa G. Nunes, Elinor Benmenachem, Alberto Alain Gabbai, J Lopeslima, Peter Halasz, Patricio Soares Dasilva
    Abstract:

    Summary Purpose:  To evaluate the efficacy and safety profile of Eslicarbazepine Acetate (ESL) added to stable antiepileptic therapy in adults with partial-onset seizures. Methods:  Data from 1,049 patients enrolled from 125 centers, in 23 countries, in three phase III double-blind, randomized, placebo-controlled studies were pooled and analyzed. Following a 2-week titration period, ESL was administered at 400 mg, 800 mg, and 1,200 mg once-daily doses for 12 weeks. Key Findings:  Seizure frequency was significantly reduced with ESL 800 mg (p  10% patients) were dizziness, somnolence, and headache. The incidence of AEs in ESL groups compared to placebo was generally consistent among different subpopulations. Significance:  Once-daily ESL 800 mg and 1,200 mg showed consistent results across all efficacy and safety end points. Results were independent of study population characteristics and type and number of concomitant AEDs.

David Blum - One of the best experts on this subject based on the ideXlab platform.

  • long term safety and tolerability of adjunctive Eslicarbazepine Acetate in children with focal seizures
    Epilepsy & Behavior, 2020
    Co-Authors: Raman Sankar, Helena Gama, Joana Moreira, David Cantu, Fenella J Kirkham, Gregory L Holmes, Eric J Pinagarza, James W Wheless, Robert Tosiello, David Blum
    Abstract:

    Abstract Objective The objective of this study was to evaluate long-term safety and tolerability outcomes in two open-label extension (OLE) studies of adjunctive Eslicarbazepine Acetate (ESL) in children with focal seizures. Methods Safety data from patients aged 4–17 years in OLEs of Studies 2093-208 and -305 were pooled and analyzed. Studies 208 and 305 were randomized, double-blind, placebo-controlled studies of adjunctive treatment with ESL in children with focal seizures refractory to treatment with 1–2 antiseizure drugs; patients could continue into uncontrolled OLEs (up to 5 years total duration). The OLEs evaluated the safety and tolerability of ESL (10–30 mg/kg/day; maximum 1200 mg/day). Results The 1-year OLE and post-1-year OLE safety populations comprised 337 and 177 ESL-treated patients, respectively. The overall incidence of treatment-emergent adverse events (TEAEs) with ESL was 64.1% during the 1-year OLE and 52.5% during the post-1-year OLE. Nasopharyngitis, partial seizures, vomiting, pyrexia, headache, somnolence, and respiratory tract infection were the most frequently reported TEAEs during the 1-year OLE. The overall incidence of serious adverse events (AEs) was 8.9% during the 1-year OLE and 10.2% during the post-1-year OLE. Partial seizures (1.2%) and pneumonia (1.2%) were the most frequently reported serious AEs during the 1-year OLE. The overall incidence of TEAEs leading to discontinuation was 4.2% during the 1-year OLE and 0.6% during the post-1-year OLE. Partial seizures (1.5%) was the most frequently reported TEAE leading to discontinuation during the 1-year OLE. Conclusions Overall, long-term treatment with ESL was generally well tolerated in pediatric patients aged 4–17 years with focal seizures. TEAEs were comparable to those observed in adults with no new events of concern.

  • analysis of cutaneous allergic reactions in clinical trials of Eslicarbazepine Acetate
    Acta Neurologica Scandinavica, 2020
    Co-Authors: Joanne Rogin, Patricio Soaresdasilva, David Blum, Helena Gama, Elinor Benmenachem, Laura Strom, Trevor Resnick, Silvia Kochen, Todd Grinnell
    Abstract:

    Objectives To evaluate cutaneous allergic reactions in clinical trials of adjunctive Eslicarbazepine Acetate (ESL) for focal seizures. Materials and methods Data were analyzed from three phase III randomized, double-blind, placebo-controlled studies of adjunctive ESL in adults (placebo, n = 426; ESL, n = 1021) and two randomized, double-blind, placebo-controlled studies (and open-label extensions [OLEs]) of adjunctive ESL in children aged 4-17 years (placebo, n = 160; ESL, n = 202; OLE, n = 337). Results Adult studies: Rash (ESL 1.9%, placebo 0.9%) and pruritus (ESL 1.2%, placebo 0.9%) were the most frequent rash-related treatment-emergent adverse events (TEAEs). Most rash-related TEAEs were mild or moderate in severity. Incidence of rash increased with increasing ESL dose, but was not higher for patients who initiated treatment with higher ESL doses. Pediatric studies: Allergic dermatitis (ESL 3.0%, placebo 0) and rash (controlled studies: ESL 1.0%, placebo 1.3%; OLE periods: ESL ≤1.2%) were the most frequent rash-related TEAEs. There was one case of DRESS in the ESL group. Most rash-related TEAEs were mild or moderate in severity and judged as not related to treatment with ESL. Conclusions Serious skin rashes were rare during adult and pediatric clinical trials of ESL. Although the incidence of rash with ESL was low, it is important for patients/caregivers to be made aware of the potential signs and symptoms associated with serious skin rashes.

  • serum sodium levels and related treatment emergent adverse events during Eslicarbazepine Acetate use in adults with epilepsy
    Epilepsia, 2019
    Co-Authors: Robert T Wechsler, David Blum, Todd Grinnell, Hailong Cheng, Eugen Trinka, Laura Strom, David G Vossler, Rodney A Radtke, Michael C Smith, Mariana Vieira
    Abstract:

    OBJECTIVE To examine the frequency of hyponatremia and potentially related symptoms in clinical trials of Eslicarbazepine Acetate (ESL) in adults with focal- (partial-) onset seizures. METHODS This post hoc, exploratory analysis included data from three controlled phase 3 trials of adjunctive ESL (400-1200 mg once daily), two phase 3 trials of ESL monotherapy (1200-1600 mg once daily), and their open-label extension studies. Exploratory endpoints included clinical laboratory measurements of serum sodium concentrations ([Na+ ]), incidences of hyponatremia-related treatment-emergent adverse events (TEAEs), and incidences of TEAEs that are potential symptoms of hyponatremia. RESULTS The controlled trials of adjunctive ESL and ESL monotherapy included 1447 (placebo, n = 426; ESL, n = 1021) and 365 (ESL, n = 365) patients, respectively; 639 and 274 patients continued onto uncontrolled, open-label extensions. In the controlled and uncontrolled trials ≤3.3% of patients taking ESL had a minimum postdose [Na+ ] measurement ≤125 mEq/L, 10 mEq/L decrease in [Na+ ] from baseline, <6% had a hyponatremia-related TEAE, and <2% discontinued the controlled trials due to a hyponatremia-related TEAE. Hyponatremia appeared to be more frequent in the monotherapy (vs adjunctive therapy) trials; in the controlled trials of adjunctive ESL and ESL monotherapy, incidence generally increased with increasing ESL dose. The majority of patients with an investigator-reported TEAE of "hyponatremia" or "blood sodium decreased" did not have a corresponding laboratory [Na+ ] measurement ≤125 mEq/L. Some symptoms potentially related to hyponatremia (including nausea and vomiting) were more frequent in patients with a minimum postdose [Na+ ] measurement ≤125 mEq/L. SIGNIFICANCE Reductions in serum sodium concentrations and hyponatremia-related TEAEs occurred in a small number of patients taking ESL. Suspected hyponatremia should be confirmed and monitored via [Na+ ] measurements.

  • health related quality of life in patients treated with Eslicarbazepine Acetate monotherapy pooled analysis from two registered clinical trials
    Epilepsy & Behavior, 2019
    Co-Authors: Joyce A Cramer, Kathryn Anastassopoulos, Krithika Rajagopalan, David Blum
    Abstract:

    Abstract Purpose While antiepileptic drug (AED) treatment effectiveness is traditionally assessed based on seizure frequency reduction (SFR), the overall value of AEDs in managing epilepsy and associated sequelae may be best assessed by how patients feel and function in terms of overall health-related quality of life (HRQoL). We conducted a pooled analysis of the Quality of Life in Epilepsy-31 (QOLIE-31) questionnaire from two phase 3 trials to explore the effect of response to conversion to Eslicarbazepine Acetate (ESL) monotherapy on HRQoL. Methods Data were pooled from two multicenter, randomized, double-blind, historical control phase 3 trials examining conversion to ESL monotherapy in adults with inadequately controlled partial-onset seizures (POS). The relationship between HRQoL and ESL treatment response was examined through the analysis of week 18 QOLIE-31 scores between patients who met the SFR ≥ 50% threshold (responders) and patients with SFR Results In the efficacy population, week 18 QOLIE-31 total score least squares mean (LSM) was significantly higher for responders with ≥ 50% SFR (LSM difference: 3.0; 95% confidence interval (CI): 0.2–5.8; p = 0.037) and with ≥ 75% SFR (LSM difference: 7.0; 95% CI: 3.6–10.3; p  Conclusions This analysis of data from the phase 3 trials demonstrated significantly higher HRQoL among ESL responders with SFR of ≥ 75% and also at the lower SFR threshold of ≥ 50% compared with nonresponders.

  • 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.

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.

  • 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.

  • efficacy and safety of Eslicarbazepine Acetate as add on treatment in patients with focal onset seizures integrated analysis of pooled data from double blind phase iii clinical studies
    Epilepsia, 2013
    Co-Authors: Antonio Gilnagel, Amilcar Falcao, Christian E. Elger, Luís Pereira De Almeida, Teresa G. Nunes, Elinor Benmenachem, Alberto Alain Gabbai, J Lopeslima, Peter Halasz, Patricio Soares Dasilva
    Abstract:

    Summary Purpose:  To evaluate the efficacy and safety profile of Eslicarbazepine Acetate (ESL) added to stable antiepileptic therapy in adults with partial-onset seizures. Methods:  Data from 1,049 patients enrolled from 125 centers, in 23 countries, in three phase III double-blind, randomized, placebo-controlled studies were pooled and analyzed. Following a 2-week titration period, ESL was administered at 400 mg, 800 mg, and 1,200 mg once-daily doses for 12 weeks. Key Findings:  Seizure frequency was significantly reduced with ESL 800 mg (p  10% patients) were dizziness, somnolence, and headache. The incidence of AEs in ESL groups compared to placebo was generally consistent among different subpopulations. Significance:  Once-daily ESL 800 mg and 1,200 mg showed consistent results across all efficacy and safety end points. Results were independent of study population characteristics and type and number of concomitant AEDs.

  • 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.

  • pharmacokinetic interaction study between Eslicarbazepine Acetate and topiramate in healthy subjects
    Current Medical Research and Opinion, 2010
    Co-Authors: Teresa G. Nunes, Amilcar Falcao, José Francisco Rocha, Luís Pereira De Almeida, Eric Sicard, Jeansebastien Brunet, Marc Lefebvre, Patricio Soaresdasilva
    Abstract:

    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...