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. 2021 May;9(10):846.
doi: 10.21037/atm-21-1459.

The association of adjusted plasma valproic acid concentration with CYP2C9 gene polymorphism in patients with epilepsy: a systematic review and meta-analysis

Huihui Fang  1   2 , Xiaojuan Wang  2 , Kelu Hou  1 , Ying Zhang  1 , Shuai Shao  1 , Guijie Zhang  1 , Yufei Feng  1 , Lin Huang  1
Affiliations

The association of adjusted plasma valproic acid concentration with CYP2C9 gene polymorphism in patients with epilepsy: a systematic review and meta-analysis

Huihui Fang et al. Ann Transl Med. 2021 May.

Abstract

Background: Valproic acid (VPA) is a common antiepileptic drug used to treat both generalized and partial epilepsy. Although there is increasing evidence to suggest that CYP2C9 gene polymorphisms are associated with interindividual variability of VPA metabolism, the results are debatable. Therefore, in the present study, we conducted a meta-analysis to evaluate the correlation between CYP2C9 gene polymorphisms and adjusted plasma VPA concentration.

Methods: The EMBASE, MEDLINE, and Cochrane Library databases were searched to obtain relevant studies. Eligible articles were reviewed, and data extraction was performed. We calculated 95% confidence intervals (CIs) and mean differences (MDs) to assess the strength of the relationship of CYP2C9 gene polymorphisms with adjusted plasma VPA concentration.

Results: The meta-analysis included 6 studies involving 847 patients with epilepsy. The pooled analysis showed that the CYP2C9 A1075C (AA vs. AC) polymorphism was related to the adjusted plasma concentration of VPA (P=0.02, I2= 82%). Additionally, the AC phenotype statistically significantly increased the adjusted plasma VPA concentration in children compared with the mixed age subgroup (P=0.04, I2= 48%). A similar association was observed between the AC phenotype for Asians (P<0.00001, I2=0%) but not for Caucasians (P=0.34, I2=87%).

Discussion: Age might be a crucial covariate influencing the dosage-adjusted VPA concentration in patients with epilepsy. A reduced VPA dosage may be recommendable for children, particularly Asian children, who are CYP2C9 A1075C AC carriers. Further studies could provide high-quality evidence to confirm the correlation between VPA pharmacokinetics and CYP2C9 A1075C polymorphisms.

Keywords: CYP2C9; Valproic acid (VPA); genetic polymorphism; meta-analysis; pharmacokinetics.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-21-1459). The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Flow diagram of study selection.
Figure 2
Figure 2
Forest plots for association between CYP2C9 A1075C (AA versus AC) polymorphism and adjusted plasma concentration (µg/mL per mg/kg) of VPA. VPA, valproic acid.
Figure 3
Figure 3
Forest plot of CYP2C9 A1075C polymorphism (AA versus AC) associated with adjusted plasma concentration (µg/mL per mg/kg) of VPA according to the age. VPA, valproic acid.
Figure 4
Figure 4
Forest plot of CYP2C9 A1075C polymorphism (AA versus AC) associated with adjusted plasma concentration (µg/mL per mg/kg) of VPA according to the ethnicity. The squares and horizontal lines correspond to the study-specific MD and 95% CI. The area of the squares reflects the weight (inverse of the variance). The diamond represents the MD and 95% CI. VPA, valproic acid.
Figure 5
Figure 5
Sensitivity analysis of CYP2C9 A1075C polymorphism associated with adjusted plasma concentration (µg/mL per mg/kg) of VPA. VPA, valproic acid.
See this image and copyright information in PMC

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