Chao-Yang Chen1, Ying Zhou1,2, Yi-Min Cui1,2, Ting Yang1, Xia Zhao1,2, Ye Wu3. 1. Department of Pharmacy, Peking University First Hospital, Beijing, China. 2. School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China. 3. Department of Pediatrics, Peking University First Hospital, Beijing, China.
Abstract
WHAT IS KNOWN AND OBJECTIVES: Oxcarbazepine (OXC) is a widely used antiepileptic drug whose effect mainly depends on its active metabolite 10-hydroxycarbazepine (MHD). This study established a population pharmacokinetic (PPK) model of MHD in Chinese children with epilepsy and conducted a dosage simulation in order to provide support for individualized OXC treatment. METHODS: Ninety-one plasma sampling points from 88 paediatric patients were retrospective collected. MHD concentrations were detected, and patients' clinical data were recorded. PPK analysis was performed using a non-linear, mixed-effect modelling approach. The goodness-of-fit (GOF) plots, bootstrap method, prediction-corrected visual predictive check (pcVPC) and normalized prediction distribution errors (NPDE) were performed to evaluate the final model. External model validations by an independent group of paediatric patients (10 patients, 10 blood samples) were conducted. The steady-state trough concentrations of MHD were determined by Monte Carlo simulations for doses ranging from 8 to 60 mg/kg/day. RESULTS: A one-compartment model with first-order elimination successfully described the data. The typical values for MHD clearance (CL/F), distribution volume (V/F) and absorption rate constant (Ka) were 3.25 L/h/70 kg, 151.41 L/70 kg and 0.598 h-1 , respectively. The CL/F and V/F of MHD were related to body weight (WT) via an empirical allometric model. Internal and external validations demonstrated a good predictability of the final model. Monte Carlo simulations revealed that for most paediatric patients, a dosing regimen of 20-30 mg/kg/d bid maybe sufficient to reach MHD therapeutic range. WHAT IS NEW AND CONCLUSION: A PPK model of MHD in Chinese paediatric patients was successfully established. A priori dosing guideline was proposed considering WT and MHD plasma concentrations, providing a basis for OXC dosage calculations and adjustments in Chinese epileptic children.
WHAT IS KNOWN AND OBJECTIVES: Oxcarbazepine (OXC) is a widely used antiepileptic drug whose effect mainly depends on its active metabolite 10-hydroxycarbazepine (MHD). This study established a population pharmacokinetic (PPK) model of MHD in Chinese children with epilepsy and conducted a dosage simulation in order to provide support for individualized OXC treatment. METHODS: Ninety-one plasma sampling points from 88 paediatric patients were retrospective collected. MHD concentrations were detected, and patients' clinical data were recorded. PPK analysis was performed using a non-linear, mixed-effect modelling approach. The goodness-of-fit (GOF) plots, bootstrap method, prediction-corrected visual predictive check (pcVPC) and normalized prediction distribution errors (NPDE) were performed to evaluate the final model. External model validations by an independent group of paediatric patients (10 patients, 10 blood samples) were conducted. The steady-state trough concentrations of MHD were determined by Monte Carlo simulations for doses ranging from 8 to 60 mg/kg/day. RESULTS: A one-compartment model with first-order elimination successfully described the data. The typical values for MHD clearance (CL/F), distribution volume (V/F) and absorption rate constant (Ka) were 3.25 L/h/70 kg, 151.41 L/70 kg and 0.598 h-1 , respectively. The CL/F and V/F of MHD were related to body weight (WT) via an empirical allometric model. Internal and external validations demonstrated a good predictability of the final model. Monte Carlo simulations revealed that for most paediatric patients, a dosing regimen of 20-30 mg/kg/d bid maybe sufficient to reach MHD therapeutic range. WHAT IS NEW AND CONCLUSION: A PPK model of MHD in Chinese paediatric patients was successfully established. A priori dosing guideline was proposed considering WT and MHD plasma concentrations, providing a basis for OXC dosage calculations and adjustments in Chinese epileptic children.