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

Abstract

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.

The pharmacokinetic, safety, and tolerability profiles of eslicarbazepine acetate are comparable between Korean and White subjects

“…In previous PK studies, including a population PK analysis, patient body weight and co‐administered drugs (phenytoin, phenobarbital, and carbamazepine) significantly influenced the PK of eslicarbazepine 4,12 . However, the exposure to eslicarbazepine was not significantly different between the various ethnic groups 10,12,15 . As ESL is highly converted to eslicarbazepine by hydrolase in the intestine and liver, the hydrolase activity was similar between the different ethnic groups 15–17 .…”

“…ESL exhibits high bioavailability (90%) and low protein binding (<40%) 8,9 . The PKs of ESL is not significantly affected by co‐administration, including gabapentin, topiramate, and valproate, and dose adjustment of ESL is not required when ESL is co‐administered with other AEDs 4,6,10 . ESL has a systemic mode of action and little potential for inappropriate use.…”

“…The exposure–response relationship of ESL between plasma concentration and a reduction in seizure frequency is well‐established 12 . The population PK analysis suggested that ethnicity did not significantly affect the PKs of eslicarbazepine, whereas weight and renal function were identified as covariates of eslicarbazepine PKs 10 . Considering these characteristics of ESL, a PK study design was considered an appropriate bridging study method for ESL.…”

“… 8 , 9 The PKs of ESL is not significantly affected by co‐administration, including gabapentin, topiramate, and valproate, and dose adjustment of ESL is not required when ESL is co‐administered with other AEDs. 4 , 6 , 10 ESL has a systemic mode of action and little potential for inappropriate use. Therefore, ESL has been found to be safe and effective in White patients with refractory partial‐onset seizures.…”

Modeling and simulations to support dose selection for eslicarbazepine acetate therapy in pediatric patients with partial-onset seizures

“…A pediatric PPK model for subjects aged ≥ 2 years was developed using NONMEM, version 7, level 1.2 (2010; ICON Development Solutions, Ellicott City, MD) and KIWI, version 1.1 (2012; Cognigen Corporation, Buffalo, NY). Key steps of the PPK model development were: exploratory analysis of the data collected in Studies 202 and 305, application and refinement of the one-compartment model previously developed for adjunctive ESL therapy in adults [ 15 ], evaluation of covariate effects, final model refinement, and model evaluation.…”