Sejung Hwang (1), (2), Soyoung Lee (1), (3), Enwoo Kim (1), Inyoung Hwang (1), Joo-Youn Cho (1), (4), Jae-Yong Chung ¬(1), (2), (5), In-Jin Jang (1), Jaeseong Oh (1)
(1) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea, (2) Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea, (3) Kidney Research Institute, Seoul National University Medical Research Center, Seoul, Republic of Korea, (4) Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea, (5) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of Korea.
Objectives: Eslicarbazepine acetate (ESL) is an antiseizure medicationfor monotherapy or adjunctive therapy for focal seizures. ESL is extensively hydrolyzed primarily in the liver to its major active metabolite, eslicarbazepine. The sensitivity of ESL to ethnic factor was expected to be low considering the known pharmacokinetic (PK), pharmacodynamic (PD) characteristics and PK-PD relationships. However, the PK characteristics were evaluated to extrapolate the efficacy and safety data from Caucasian to Korean patients. The study aimed to establish the population PK model of ESL and investigated the impact of ethnicity on PK of ESL.
Methods: A population PK model was developed from a Phase I, randomized, double-blind, placebo-controlled, single and multiple dose-escalation study conducted in healthy adult Korean and Caucasian subjects. Korean subjects were assigned to 3 dose groups (400, 800, and 1600 mg once daily) and Caucasian subjects assigned to 2 dose groups (400 and 1600 mg once daily) receiving a single dose of ESL and multiple doses once daily for 7 days[FG1] [JM2] [HS3] according to assigned treatment. A total of 1331 plasma observations from 39 subjects were used to construct the PK model implementing the first-order conditional estimation method with interaction (FOCE-I) methos by nonlinear mixed-effect modeling (NONMEM) software (version 7.4). The interindividual variability (IIV) of PK parameters were described as an exponential model and a proportional error model was used for the residual variability. Subjects’ ethnicity, age, height, weight, and body mass index (BMI) were assessed as potential covariates to investigate the effects on variability in PK parameters. Covariate analysis using the forward-addition and backward-elimination methods were conducted. The final model was evaluated by assessing goodness-of-fit (GOF) plots, and prediction-corrected visual prediction checks (pcVPC).
Results: The PK of eslicarbazepine[JM1] [HS2] was well described by a two-compartment model with first-order absorption, and first-order elimination. The population PK parameter estimates (relative standard error, RSE) of first-order absorption rate constant (KA), apparent clearance (CL/F), apparent the volume of distribution of central compartment (Vc/F), apparent peripheral compartment (Vp/F), and apparent inter-compartmental clearance (Q/F) were 0.65 h-1 (14.3%), 2.78 L/h (2.3%), 45.5 L (6.6%), 11 L (32.7%), and 4.74 L/h (30.4%), respectively. The IIV (coefficient of variation, CV%) on KA and CL/F improved the PK model estimation, and estimated as 76% and 12%, respectively. The effect of ethnicity was investigated as a covariate but no significant impact on the PK parameters was found. No other covariates were also significant to describe the variability of the PK parameters.[RS3] [HS4] The model evaluation by GOF plot, and pcVPC suggested that the population PK model was robust and adequate with good precision.
Conclusions: The population PK model identified that the ethnicity was not a significant factor for describing the variability of the eslicarbazepine PK.
References:
[1] Almeida L, et al. The Treatment of Epilepsia (2009), 485-498.
[2] Bialer M, Soares-da-Silva P. Epilepsia (2012) 53, 935-46.
[3] Elger C, et al. Epilepsia (2013) 54, 1453-61.
[4] Galiana GL, et al. Drugs R D (2017) 44, 329-39.
[5] Trinka E, et al. Epilepsia (2018) 59, 479-91.
Reference: PAGE 30 (2022) Abstr 10090 [www.page-meeting.org/?abstract=10090]
Poster: Drug/Disease Modelling - Other Topics