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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1423411

Combined carbapenem resulted in a 4.48-fold increase in valproic acid clearance: A population pharmacokinetics model in Chinese children and adults with epilepsy or after neurosurgery

Provisionally accepted
Luofei Zhang Luofei Zhang 1,2Ruoyun Wu Ruoyun Wu 1,2Xingmeng Li Xingmeng Li 3Weixing Feng Weixing Feng 3*Zhigang Zhao Zhigang Zhao 1,2*Shenghui Mei Shenghui Mei 1,2*
  • 1 Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
  • 2 Department of Clinical Pharmacology, Capital Medical University, Beijing, Beijing Municipality, China
  • 3 Department of Neurology, Beijing Children’s Hospital, Capital Medical University, Beijing, Beijing Municipality, China

The final, formatted version of the article will be published soon.

    Our study aims to explore the pharmacokinetics of VPA (valproic acid) in Chinese patients with epilepsy or after neurosurgery and establish a robust population pharmacokinetics (PPK) model. The PPK model was developed using nonlinear mixedeffects modeling, incorporating a total of 615 VPA plasma concentration data points from 443 Chinese epilepsy or after neurosurgery patients. A one-compartment model with an additive residual model was established. Forward addition and backward elimination strategies were used to assess the impact of covariates on the model parameters. Goodness-of-fit plots, bootstrap, visual predict check and normalized prediction distribution errors were used for model validation. In the final model, the apparent clearance (CL) was estimated using the following formula: CL (L/h) = 0.430 × (BW 60 ⁄ ) 0.787 × (Cr/50.3) -0.253 × (ALB/39) -0.873 × e gender × e CBP × e IND2 × e η CL (gender = 0.121 when is female, otherwise = 0; CBP = 1.50 when combined with carbapenems, otherwise = 0; IND2 = 0.15 when combined with oxcarbazepine, carbamazepine, phenobarbital, or phenytoin, otherwise = 0). The volume of distribution (Vd) was estimated using the formula: Vd (L) = 8.66 × (BW 60 ⁄ ) 0.751 . Comedication with carbapenems could increase VPA clearance by 4.48 times, and comedication with oxcarbazepine could enhance VPA clearance by 116%. Besides, creatinine and albumin could affect VPA clearance. Goodness-of-fit plots, bootstrap, visual predict check and normalized prediction distribution showed acceptable data fit, stability, and predictability of the model. In our study, a PPK model was utilized to attain a more comprehensive insight into these variables, improving the accuracy and individualization of VPA therapy in Chinese patients with epilepsy or after neurosurgery.

    Keywords: Valproic Acid, Population pharmacokinetic models, Nonlinear mixed effects modeling, Epilepsy, Carbapenem

    Received: 26 Apr 2024; Accepted: 28 Oct 2024.

    Copyright: © 2024 Zhang, Wu, Li, Feng, Zhao and Mei. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Weixing Feng, Department of Neurology, Beijing Children’s Hospital, Capital Medical University, Beijing, 100045, Beijing Municipality, China
    Zhigang Zhao, Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
    Shenghui Mei, Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.