Seonghae Yoon (1) Su-jin Rhee (1), Tae-Joon Kim (2), Sang Kun Lee (2), Kon Chu (2) and In-jin Jang (1)
(1) Department of Clinical Pharamcology and Therapeutics, Seoul National University Hospital and College of Medicine, South Korea, (2) Department of Neurology, Laboratory of Neurotherapeutics, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital and College of Medicine, South Korea
Objectives: Oxcarbazpine is a widely used anticonvulsant drug to treat partial seizure as monotherapy or adjunctive therapy. The mono-hydroxylated derivative (MHD) is the main metabolite which is responsible for most of the anticonvulsant activity. The objectives of this study to develop a PK model of oxcarbazepine and to analyse the relationship between trough concentrations of the drug and occurrence of adverse event (AE) or seizure.
Methods: To develop a PK model of oxcarbazepine, the data from two studies were used; the data of 447 patients who had been enrolled in from Epilepsy Registry Cohort of Seoul National University Hospital since Feb 2011 and the data of PK study involving 40 patients evaluating oral loading of oxcarbazepine [1]. Plasma concentrations of MHD were analysed using nonlinear mixed-effect modelling in NONMEM (ver 7.3). The first-order conditional estimation (FOCE) with interaction method was used to fit the plasma concentration-time data. The trough concentrations (Cmin) of each patients were calculated using the final PK model. The relation between trough concentrations and occurrence of AE or seizure were analysed using Students’ t-test.
Results: A one-compartment model with first-order absorption, and a proportional error model describes oxcarbazepine PK adequately. The body weight was significant covariate for the clearance and the volume of distribution of the drug and the use of concomitant drugs including carbamazepine, phenytoin, and phenobarbital which are known to be enzyme-inducers increased the clearance 1.38-fold. The daily dose per body weight (DDPBW) and the Cmin of the drug were slightly higher in the patients group with AEs (mean ± SD; DDPBW 17.1 ± 5.0 mg/kg, Cmin 13.4 ± 7.8 ng/mL) or with seizure episodes more than once (16.4 ± 4.3 mg/kg, 13.9 ± 7.6 ng/mL) compared to the non-AE group (14.5 ± 4.6 mg/kg, 12.4 ± 6.8 ng/mL) or non-seizure group (15.4 ± 4.9 mg/kg, 12.7 ± 7.2 ng/mL) but the differences were not statistically significant.
Conclusion: The population PK model developed in this study adequately described oxcarbazepine PK in patients with epilepsy. The covariates selected in this study including body weight and the use of concomitant drug are expected to be used to choose appropriate dosage regimen in the patients.
References:
[1] Kim DW1, Gu N, Jang IJ, Chu K, Yu KS, Cho JY, Yoon SH, Kim HS, Oh J, Lee SK. Efficacy, tolerability, and pharmacokinetics of oxcarbazepine oral loading in patients with epilepsy. Epilepsia, 53(1):e9–e12, 2012
Reference: PAGE 25 () Abstr 5894 [www.page-meeting.org/?abstract=5894]
Poster: Drug/Disease modeling - CNS