Impact of the superoxide dismutase 2 Val16Ala polymorphism on the relationship between valproic acid exposure and elevation of γ-glutamyltransferase in patients with epilepsy: a population pharmacokinetic-pharmacodynamic analysis

Abstract

Background: There has been accumulating evidence that there are associations among γ-glutamyltransferase (γ-GT) elevation and all-cause mortality, cardiovascular diseases and metabolic diseases, including nonalcoholic fatty liver disease. The primary objective of this study was to evaluate the impact of the most common and potentially functional polymorphisms of antioxidant enzyme genes, i.e. superoxide dismutase 2 (SOD2), glutathione S-transferase M1 and glutathione S-transferase T1, on the γ-GT elevation during valproic acid (VPA) therapy.

Methods and findings: This retrospective study included 237 and 169 VPA-treated Japanese patients with epilepsy for population pharmacokinetic and pharmacokinetic-pharmacodynamic analyses, respectively. A nonlinear mixed-effect model represented the pharmacokinetics of VPA and the relationships between VPA exposure and γ-GT elevation. A one-compartment model of the pharmacokinetic parameters of VPA adequately described the data; while the model for the probability of the γ-GT elevation was fitted using a logistic regression model, in which the logit function of the probability was a linear function of VPA exposure. The SOD2 Val16Ala polymorphism and complication with intellectual disability were found to be significant covariates influencing the intercept of the logit function for the probability of an elevated γ-GT level. The predicted mean percentages of the subjects with γ-GT elevation were about 2- to 3-fold, 3- to 4-fold and 4- to 8-fold greater in patients with the SOD2 Val/Val genotype but without any intellectual disability, those with the SOD2 Val/Ala or Ala/Ala genotype and intellectual disability and those with the SOD2 Val/Val genotype and intellectual disability, respectively, compared to those with the SOD2 Val/Ala or Ala/Ala genotype without intellectual disability.

Conclusion: Our results showed that the SOD2 Val16Ala polymorphism has an impact on the relationship between VPA exposure and γ-GT elevation in patients with epilepsy. These results suggest that determining the SOD2 genotype could be helpful for preventing the VPA-induced γ-GT elevation.

Figure 1. The visual predictive check of the PK-PD model in patients with the SOD2 Ala/Ala or Val/Ala genotype (A), those with SOD2 Val/Val genotype (B), those without intellectual disability (C) and those with intellectual disability (D), using the dataset of the study patients aged 30 years old or younger who were treated with 100 to 1,300 mg/day of VPA.

The solid line represents the observed proportion of γ-GT elevation and the solid area represents the 90% prediction interval. PK = pharmacokinetic; PD = pharmacodynamics; SOD2 = superoxide dismutase 2; VPA = valproic acid γ-GT: γ-glutamyltransferase.

Figure 2. The relationships evaluated in the framework for the γ-GT elevation during VPA therapy.

The solid lines indicate the relationships included in the final population PK and PK-PD models. Black letters indicate relationships included in the final models, and grey letters indicate relationships investigated, but not included, in the final models. PK = pharmacokinetic; PD = pharmacodynamics; VPA = valproic acid γ-GT: γ-glutamyltransferase.