Population pharmacokinetics modeling of oxcarbazepine to characterize drug interactions in Chinese children with epilepsy

Abstract

Aim: To develop a population pharmacokinetics model of oxcarbazepine in Chinese pediatric patients with epilepsy, and to study the interactions between oxcarbazepine and other antiepileptic drugs (AEDs). Methods: A total of 688 patients with epilepsy aged 2 months to 18 years were divided into model (n=573) and valid (n=115) groups. Serum concentrations of the main active metabolite of oxcarbazepine, 10-hydroxycarbazepine (MHD), were determined 0.5-48 h after the last dosage. A population pharmacokinetics (PPK) model was constructed using NLME software. This model was internally evaluated using Bootstrapping and goodness-of-fit plots inspection. The data of the valid group were used to calculate the mean prediction error (MPE), mean absolute prediction error (MAE), mean squared prediction error (MSE) and the 95% confidence intervals (95% CI) to externally evaluate the model.

Population pharmacokinetics and dose simulation of oxcarbazepine in Chinese paediatric patients with epilepsy

“…TVCL in this study was within the range calculated in the existing models (2.37‐4.11 L/h/70 kg) and was very close to those found in the researches by Rodrigues et al (3.18 L/h/70 kg for children not taking EI) and Sallas et al (3.2 L/h/70 kg), while TVV was similar to those of Sugiyama et al (171.5 L/70 kg). Ka was fixed according to studies by Park et al and Sallas et al, consistent with previous models (0.41‐0.83 h −1 ) . Studies of Wang et al and Peng et al were all conducted in Chinese epileptic children, and selected the same basic model with this study.…”

“…Although several studies have established OXC and MHD PPK models, some were conducted in healthy subjects who could not fully reflect the clinical situation, some lacked complete model assessments, and only a few were conducted in paediatric patients. This study explored the PPK characteristics of MHD in Chinese epileptic children, investigated the influence of patients’ demographic factors, biological factors and medication information on MHD PK, and confirmed WT as a significant covariate for the CL/F of MHD.…”

“…A one‐compartment model with first‐order elimination was selected as the basic structural model, corresponding to the previous studies . The typical population values of the PK parameters of the final model were as follows: TVCL = 3.25 L/h/70 kg, TVV = 151.41 L/70 kg, and Ka = 0.598 h −1 .…”

“…Most concentrations in this study were steady trough concentration data, which could not fully reflect the characteristics of the distribution phase. Considering the type of sampling points and information from the literature, a one‐compartment structural kinetic model with first‐order elimination was selected as the basic model. The absorption rate constant (Ka) was fixed to 0.598 h −1 according to previous researches …”

“…Traditional PK method makes it difficult to calculate MHD PK parameters through clinically obtained sparse blood samples; therefore, it is essential to establish the population pharmacokinetic (PPK) model of MHD, so as to investigate its PK characteristics in Chinese paediatric patients. Previous PPK studies showed that weight (WT), age, height (HT), blood urea nitrogen (BUN), haemoglobin (HGB) and co‐medications had significant influences on MHD PK parameters . However, few PPK studies have been performed on Chinese paediatric patients.…”