Glomerular Filtration Rate Is a Major Predictor of Clearance of Oxcarbazepine Active Metabolite in Adult Chinese Epileptic Patients: A Population Pharmacokinetic Analysis

Abstract

Background: Oxcarbazepine (OXC) is almost completely metabolized to its10-monohydroxy derivative (MHD), which is responsible for the pharmacological effects of the drug. Several studies have described the population pharmacokinetics (PPK) of MHD in pediatric patients, but little is known about its pharmacokinetics in adult patients. In addition, no study to date has proposed a model to investigate the influence of genetic polymorphisms on MHD pharmacokinetics. The aim of this study was to establish a PPK model of MHD to investigate the effects of genetic polymorphisms in UGT2B7, UGT1A9, ABCB1, and ABCB2 in adult Chinese patients with epilepsy and to develop a new dosage guideline for OXC. Methods: Data were prospectively collected from 187 adult patients with epilepsy who were taking OXC. MHD trough concentrations were detected by enzyme-multiplied immunoassay. Patients were genotyped for 4 single nucleotide polymorphisms (UGT2B7 802T>C, UGT1A9 I399C>T, ABCB1 3435C>T, and ABCB2 1249G>A). Other covariates included sex, age, body weight (BW), hepato-renal function, and concomitant medications. Data were analyzed using the nonlinear mixed effects modelling software. Results: The apparent clearance (CL) of MHD was significantly influenced by glomerular filtration rate and BW, and was unrelated to other covariates such as genetic polymorphisms and coadministration with levetiracetam, lamotrigine, and topiramate. Moreover, a new dosage guideline was proposed based on the final model to individualize OXC regimens for adult patients with varying BW and renal function. Conclusions: Glomerular filtration rate was first found as an important covariate influencing MHD CL. A PPK model was established to estimate the individual MHD CL for adult patients taking OXC and may be applied for individualizing doses in the target population.

Population Pharmacokinetics of Oxcarbazepine: A Systematic Review

“…It was found that eGFR significantly affected MHD CL, according to the observations from Lin et al [29]. In patients with impaired renal function (eGFR: 20–80 mL/min), the CL was 34.8% (9.4%–64.2%) lower than those with normal renal function.…”

“…Most PPK analysis was performed in patients with epilepsy [24,26-33], and only Antunes et al [34] enrolled healthy subjects. One study was conducted only in infants [25], seven studies were conducted in children [24,25,27,28,30-32], two studies included both children and adults [26,33], and two studies only enrolled adults [29,34]. Subjects in all the included studies were administered OXC orally, with doses ranging from 75 to 1800 mg/d.…”

“…The PPK analyses were all conducted using population modelling software, including NONMEM (Icon, Dublin, Ireland) [24-26,29-31,34,35], Phoenix NLME (Certara L.P. Pharsight, St. Louis, MO, USA) [26–28], and Monolix (Lixoft, Antony, France) [32]. The most commonly used algorithm was first-order conditional estimation with the η - ε interaction.…”

“…The commonly method of external evaluation is the goodness-of-fit plot, while the second popular method was the visual predictive check. Although a normalised prediction distribution error (NPDE) has better properties [36], it is not commonly used [29,30,32,34]. Four studies performed an external evaluation using an independent dataset, all of which showed acceptable predictability [28,30,31,33].…”

“…Co-administration with EIAEDs also significantly affected CL in children and adults, which approximately increased 1.17 to 1.63 times [24-26,28,32]; in four studies, the clinical significance of the impact of EIAED co-administration on CL was more than 20% [24-26,32]. eGFR was identified to significantly affect the CL of adults with a range of 0.33 to 1.24 times [29] compared to a typical patient with an eGFR of 90 mL/min. ALT was also found to have a significant impact on CL in children, with a range of 0.73 to 1.35 times compared to a typical patient with an ALT level of 30 U/L [33].…”