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CYP2C9*3/*3 Gene Expression Affects the Total and Free Concentrations of Valproic Acid in Pediatric Patients with

Xikun Wu1, Weichong Dong1, Haoran Li1

  • 1The Second Hospital of Hebei Medical University, Shijiazhuang City, People's Republic of China.

Pharmacogenomics and Personalized Medicine
|April 16, 2021
PubMed

Insights

Therapeutic drug monitoring of valproic acid (VPA) in children with epilepsy is crucial. Factors like CYP2C9 genotype and drug interactions significantly impact VPA levels, necessitating TDM and caution with certain antibiotics.

Area of Science:

  • Pharmacology
  • Clinical Pharmacy
  • Pediatric Neurology

Background:

  • Epilepsy management in children requires precise dosing of antiepileptic drugs.
  • Valproic acid (VPA) is a commonly used antiepileptic, but its therapeutic range necessitates careful monitoring.
  • Individual patient factors and drug interactions can significantly alter VPA pharmacokinetics.

Purpose of the Study:

  • To conduct therapeutic drug monitoring (TDM) of total and free plasma valproic acid (VPA) concentrations in pediatric epilepsy patients.
  • To identify factors influencing VPA concentrations, including genetics and co-administered medications.

Main Methods:

  • Assessed pediatric epileptic patients from 2015-2019.
  • Measured total and free plasma VPA using UPLC and LC-MS/MS.
  • Employed regression analysis and examined effects of CYP2C9 genotype and drug combinations.

Main Results:

  • 81 of 251 patients had sub-therapeutic total VPA levels.
  • CYP2C9 *3/*3 genotype was associated with lower VPA doses and free concentrations.
  • Concomitant use of phenobarbital, meropenem, or biapenem significantly decreased VPA concentrations, leading to therapeutic failure with meropenem/biapenem.

Conclusions:

  • Nonlinear relationships exist between total VPA, free VPA, and protein binding in pediatric epilepsy.
  • CYP2C9 *3/*3 genotype impacts VPA metabolism.
  • TDM is recommended due to phenobarbital's effect on VPA metabolism; co-administration of VPA with carbapenems should be avoided.
Abstract

Keywords:
CYP2C9 gene expressionTDMfree concentrationpediatric patientvalproic acid

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