文章基本信息

标题：Population pharmacokinetic model development and its relationship with adverse events of oxcarbazepine in adult patients with epilepsy
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作者：Yoonhyuk Jang ; Seonghae Yoon ; Tae-Joon Kim 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2021
卷号：11
期号：1
页码：6370
DOI：10.1038/s41598-021-85920-0
出版社：Springer Nature
摘要：Abstract This study aimed to develop a pharmacokinetic (PK) model of oxcarbazepine (OXC) and analyse the relationship between monohydroxylated derivative (MHD), an active metabolite of OXC, and the adverse events of OXC. We obtained 711 OXC samples from 618 patients with epilepsy who were enrolled in the Epilepsy Registry Cohort of Seoul National University Hospital from February 2011 to January 2014. The plasma PK model was developed using a nonlinear mixed-effect modelling method with NONMEM (ver 7.3). A one-compartment model with a first-order absorption model and proportional residual error adequately described the MHD concentration–time profiles. The only covariate incorporated for CL/F and V/F was body weight. Of the 447 patients analysed, 28 (6.26%) had dose-related adverse events (DRAEs), which were dizziness, somnolence, headache, and diplopia. For DRAE occurrence, the cut-off values of the MHD trough and AUC were 12.27 mg/L (specificity 0.570, sensitivity 0.643) and 698.5 mg h/L (specificity, sensitivity 0.571), respectively. Multivariate analysis showed the sole dizziness symptom was significantly associated with both the MHD trough and the AUC ( p = 0.013, p = 0.038, respectively). We newly developed a population PK model using sparse sampling data from patients with epilepsy, and the model better reflects the actual clinical situation.
其他摘要：Abstract This study aimed to develop a pharmacokinetic (PK) model of oxcarbazepine (OXC) and analyse the relationship between monohydroxylated derivative (MHD), an active metabolite of OXC, and the adverse events of OXC. We obtained 711 OXC samples from 618 patients with epilepsy who were enrolled in the Epilepsy Registry Cohort of Seoul National University Hospital from February 2011 to January 2014. The plasma PK model was developed using a nonlinear mixed-effect modelling method with NONMEM (ver 7.3). A one-compartment model with a first-order absorption model and proportional residual error adequately described the MHD concentration–time profiles. The only covariate incorporated for CL/F and V/F was body weight. Of the 447 patients analysed, 28 (6.26%) had dose-related adverse events (DRAEs), which were dizziness, somnolence, headache, and diplopia. For DRAE occurrence, the cut-off values of the MHD trough and AUC were 12.27 mg/L (specificity 0.570, sensitivity 0.643) and 698.5 mg h/L (specificity, sensitivity 0.571), respectively. Multivariate analysis showed the sole dizziness symptom was significantly associated with both the MHD trough and the AUC ( p = 0.013, p = 0.038, respectively). We newly developed a population PK model using sparse sampling data from patients with epilepsy, and the model better reflects the actual clinical situation.