Adjunctive eslicarbazepine acetate: A pooled analysis of three phase III trials

Biton, Victor; Rogin, Joanne; Krauss, Gregory L.; Abou‐Khalil, Bassel; Rocha, José; Moreira, Joana; Gama, Helena; Trinka, Eugen; Elger, Christian E.; Cheng, Hailong; Grinnell, Todd; Blum, David

doi:10.1016/j.yebeh.2017.04.019

Cited by 38 publications

(45 citation statements)

References 16 publications

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“…However, as the current study was not designed to evaluate differences between populations, a future study would be required to further investigate this effect. The CBZ‐related predictions from this exposure‐efficacy response analysis are a valuable confirmation of the findings obtained in previous post hoc exploratory analyses of clinical trials of adjunctive ESL and ESL monotherapy, where patients not taking CBZ at baseline had better efficacy outcomes than those taking CBZ at baseline 19, 24. The predicted relationship between exposure and SSF was shallow over the range of concentrations included in this analysis.…”

Section: Discussionsupporting

confidence: 81%

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Exposure-safety and efficacy response relationships and population pharmacokinetics of eslicarbazepine acetate

et al. 2018

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ObjectivesEslicarbazepine 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.MethodsEslicarbazepine (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.ResultsEslicarbazepine 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.ConclusionsPharmacokinetic 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.

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Section: Discussionsupporting

confidence: 81%

“…Some adverse events occur more frequently when patients take ESL with CBZ 19 (potentially due to a PD interaction); lowering the CBZ dose may therefore be necessary to improve the tolerability of the combination. 8 Use of ESL concomitantly with CBZ also had an impact on carbamazepine PK, leading to reductions in carbamazepine AUC.…”

Section: Discussionmentioning

confidence: 99%

Exposure-safety and efficacy response relationships and population pharmacokinetics of eslicarbazepine acetate

et al. 2018

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“…Eslicarbazepine acetate (ESL) is a once‐daily, oral AED for the treatment of focal (partial‐onset) seizures in patients aged 4 years and older in the USA . Double‐blind, fixed‐duration clinical trials of adjunctive ESL have demonstrated that ESL is an effective and well‐tolerated treatment for focal seizures in both adults and children . ESL is a dibenzazepine carboxamide derivative.…”

Section: Introductionmentioning

confidence: 99%

“…5 Double-blind, fixed-duration clinical trials of adjunctive ESL have demonstrated that ESL is an effective and well-tolerated treatment for focal seizures in both adults and children. [6][7][8][9][10][11] ESL is a dibenzazepine carboxamide derivative. Relatively high rates of rash have previously been observed with phenytoin and lamotrigine (LTG), and other dibenzazepine carboxamides such as carbamazepine (CBZ) and oxcarbazepine (OXC), 1,2,[12][13][14][15][16][17][18][19] and so it is relevant to examine to what extent allergic reactions also occur with ESL, and whether there may be any identifiable risk factors.…”

Section: Introductionmentioning

confidence: 99%

Analysis of cutaneous allergic reactions in clinical trials of eslicarbazepine acetate

Rogin¹,

Resnick

Strom

et al. 2020

Acta Neurol Scand

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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.

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“…Hyponatremia (ie, low blood sodium) may occur with the use of dibenzazepine carboxamide AEDs, [2][3][4][5][6][7][8][9] selective serotonin reuptake inhibitors (SSRIs), 10 thiazide diuretics, 11 or tricyclic antidepressants. 12 The risk of developing hyponatremia with dibenzazepine carboxamides may be greater with increased fluid intake, older age, AED polypharmacy, or concurrent use of sodium-wasting medications.…”

Section: Introductionmentioning

confidence: 99%

Serum sodium levels and related treatment‐emergent adverse events during eslicarbazepine acetate use in adults with epilepsy

et al. 2019

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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, <9% had a >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.

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Adjunctive eslicarbazepine acetate: A pooled analysis of three phase III trials

Abstract: ESL (800 and 1200mg QD) was effective and well tolerated as adjunctive therapy for adults with refractory POS.

Cited by 38 publications

References 16 publications

Exposure-safety and efficacy response relationships and population pharmacokinetics of eslicarbazepine acetate

Exposure-safety and efficacy response relationships and population pharmacokinetics of eslicarbazepine acetate

Analysis of cutaneous allergic reactions in clinical trials of eslicarbazepine acetate

Serum sodium levels and related treatment‐emergent adverse events during eslicarbazepine acetate use in adults with epilepsy

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