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

Artikel i vetenskaplig tidskrift
Författare B. E. Gidal
M. P. Jacobson
Elinor Ben-Menachem
M. Carreno
D. Blum
P. Soares-da-Silva
A. Falcao
F. Rocha
J. Moreira
T. Grinnell
E. Ludwig
J. Fiedler-Kelly
J. Passarell
S. Sunkaraneni
Publicerad i Acta Neurologica Scandinavica
Volym 138
Nummer/häfte 3
Sidor 203-211
ISSN 0001-6314
Publiceringsår 2018
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för klinisk neurovetenskap
Sidor 203-211
Språk en
Länkar dx.doi.org/10.1111/ane.12950
Ämnesord antiepileptic, epilepsy, eslicarbazepine, pharmacodynamics, pharmacokinetics, partial-onset seizures, adjunctive treatment, labeling decisions, adult, patients, drug approval, double-blind, phase-iii, tolerability, oxcarbazepine, carbamazepine
Ämneskategorier Neurovetenskaper

Sammanfattning

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 1200mg. 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 800mg than with an initial dose of ESL 400mg 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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