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Population pharmacokinetics of oxcarbazepine active metabolite in Chinese children with epilepsy

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Abstract

Oxcarbazepine (OXC) is an antiepileptic drug whose efficacy is largely attributed to its monohydroxy derivative metabolite (MHD). Nevertheless, there exists significant inter-individual variability in both the pharmacokinetics and therapeutic response of this drug. The objective of this study is to explore the impact of patients’ characteristics and genetic variants on MHD clearance in a population pharmacokinetic (PPK) model of Chinese pediatric patients with epilepsy. The PPK model was developed using a nonlinear mixed effects modeling method based on 231 MHD plasma concentrations obtained from 185 children with epilepsy. The one-compartment model and combined residual model were established to describe the pharmacokinetics of MHD. Forward addition and backward elimination were employed to evaluate the impact of covariates on the model parameters. The model was evaluated using goodness-of-fit, bootstrap, visual predictive checks, and normalized prediction distribution errors. In the two final PPK models, age, estimated glomerular filtration rate (eGFR), and a combined genotype of six variants (rs1045642, rs2032582, rs7668282, rs2396185, rs2304016, rs1128503) were found to significantly reduce inter-individual variability for MHD clearance. The inter-individual clearance equals to 1.38 × (Age/4.74)0.29 × (eGFR/128.66)0.25 × eθABCB-UGT-SCN-INSR for genetic variants included model and 1.30 × (Age/4.74)0.30 × (eGFR/128.66)0.23 for model without genetic variants. The precision of all parameters was deemed acceptable, and the model exhibited good predictability while remaining stable and effective.

   Conclusion: Age, eGFR, and genotype may play a significant role in MHD clearance in children with epilepsy. The developed PPK models hold potential utility in facilitating oxcarbazepine dose adjustment in pediatric patients.

What is Known:

• The adjustment of the oxcarbazepine regimen remains difficult due to the considerable inter- and intra-individual variability of oxcarbazepine pharmacokinetics.

• Body weight and co-administration with enzyme-inducing antiepileptic drugs emerge as the most influential factors contributing to the pharmacokinetics of MHD.

What is New:

• A positive correlation was observed between eGFR and the clearance of MHD in pediatric patients with epilepsy.

• We explored the influence of genetic polymorphisms on MHD clearance and identified a combined genotype (ABCB-UGT-SCN-INSR) that exhibited a significant association with MHD concentration.

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Data availability

The datasets generated during and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

Thanks are given to all patients and authors in our study.

Funding

This work was supported by the National Key Research and Development Program of China (2020YFC2008306).

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Author notes

  1. Xingmeng Li and Shifeng Wei are contributed equally to this work and should be considered co-first authors.

Authors and Affiliations

  1. Department of Neurology, Beijing Children’s Hospital, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing, 100045, People’s Republic of China

    Xingmeng Li, Weixing Feng & Yun Wu

  2. Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, 119 Nansihuan West Road, Fengtai District, Beijing, 100070, People’s Republic of China

    Shifeng Wei, Han Wu, Qiang Zhang, Zhigang Zhao & Shenghui Mei

  3. Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, People’s Republic of China

    Shifeng Wei, Han Wu, Qiang Zhang, Zhigang Zhao & Shenghui Mei

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  1. Xingmeng Li
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Contributions

S Mei, W Feng and Y Wu conceived and designed the study. X Li, W Feng, S Wei, H Wu and Q Zhang collected samples from patients and analyzed the data. S Wei and X Li performed the development of model and drafted the manuscript. S Mei, Y Wu, W Feng, and Z Zhao revised the manuscript. S Mei and Y Wu supervised the quality of the study. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Shenghui Mei, Weixing Feng or Yun Wu.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards, and approved by the Ethics Committee of Beijing Children’s Hospital (ID: 2019-k-150).

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Li, X., Wei, S., Wu, H. et al. Population pharmacokinetics of oxcarbazepine active metabolite in Chinese children with epilepsy. Eur J Pediatr 182, 4509–4521 (2023). https://doi.org/10.1007/s00431-023-05092-z

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