Population pharmacokinetics of oxcarbazepine and its monohydroxy derivative in epileptic children

Rodrigues, Christelle; Chiron, Catherine; Rey, Elisabeth; Dulac, Olivier; Comets, Emmanuelle; Pons, Gérard; Jullien, Vincent

doi:10.1111/bcp.13392

Cited by 19 publications

(48 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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 …”

Section: Methodsmentioning

confidence: 99%

“…Children with a WT of 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 and 70 kg were simulated, and daily doses of 8, 10, 20, 30, 40, 50 and 60 mg/kg administered as a bid regimen were investigated. The dosing regimen was considered rational if the median and 95% percentile interval (PI) of the simulated MHD concentrations were within the therapeutic range (3‐35 mg/L, according to the 2008 ILEA TDM guideline for AEDs, and related PPK study by Rodrigues C et al in epileptic children. ).…”

Section: Methodsmentioning

confidence: 99%

“…Oxcarbazepine (10,11‐dihydro‐10‐oxo‐5H‐dibenz [b,f] azepine‐5‐carboxamide, OXC) is a second‐generation antiepileptic drug (AED) that is indicated as monotherapy or adjunctive therapy for partial and generalized tonic‐clonic seizures in children and adults . OXC is a 10‐hydroxy derivative of carbamazepine (CBZ) that has better tolerance and fewer adverse reactions than the parent compound .…”

Section: What Is Known and Objectivesmentioning

confidence: 99%

“…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.…”

Section: What Is Known and Objectivesmentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2019

View full text Add to dashboard Cite

Summary 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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: What Is Known and Objectivesmentioning

confidence: 99%

Section: What Is Known and Objectivesmentioning

confidence: 99%

See 3 more Smart Citations