Genetic and Non-genetic Factors Contributing to the Significant Variation in the Plasma Trough Concentration-to-Dose Ratio of Valproic Acid in Children With Epilepsy

Abstract

Objective: This study was conducted to evaluate the potential genetic and non-genetic factors contributing to plasma trough concentration-to-dose (C0/D) ratio of valproic acid (VPA) in pediatric patients with epilepsy.Study Design: A single-center, retrospective cohort study was performed by collecting data from 194 children aged 1–14 years between May 2018 and November 2018. The oral solution (n = 135) group and the sustained-release (SR) tablet group (n = 59) were defined, and the plasma VPA C0 was measured. Twenty-six single-nucleotide polymorphisms (SNPs) were chosen for genotyping with the MassARRAY system. A multiple logistic regression model was used for data analysis.Results: Body weight (BW) and age were positively correlated with the C0/D ratio in 194 patients, but the positive correlation disappeared after the patients were divided into oral solution and SR tablet subgroups. The average C0/D ratio was significantly increased by 2.11-fold (P = 0.000) in children who took VPA SR tablets compared with children who were administered VPA oral solutions. No significant association between genetic variants and the C0/D ratio was found, even for the five well-studied SNPs, namely UGT2B7 G211T, C802T, C161T, T125C, and CYP2C9*3 A1075C. However, a significant association between the C0/D ratio and UGT1A6/9 Del>A (rs144486213) was observed in the VPA oral solution group, but not in the VPA SR tablet group.Conclusions: The dosage forms of sodium valproate, rather than BW, age, or genetic polymorphisms, significantly affected the VPA C0/D ratios in pediatric patients with epilepsy. Based on our findings, switching the dosage form between solution and SR tablet should be performed cautiously. Total daily dose adjustment should be considered, and the plasma concentration, seizure-control effect, and adverse drug reaction should also be monitored very closely.

Genetic Polymorphisms of UDP-Glucuronosyltransferases and Plasma Sodium Valproate Level

“…The current study showed no significant association between various genetic polymorphisms of UGT1A6 and UGT2B7 and plasma sodium valproate concentration. Almost similar findings were reported by Xu et al who studied various genetic and nongenetic factors affecting plasma trough concentration-to-dose (C 0 /D) ratio of valproic acid in pediatric patients with epilepsy [6]. No significant association was found between common single nucleotide polymorphisms (SNPs) of UGT2B7 but significant association between the C 0 /D ratio and UGT1A6/9 Del>A was observed in the valproate oral solution group.…”

Integrating metabolomics and lipidomics revealed a decrease in plasma fatty acids but an increase in triglycerides in children with drug‐refractory epilepsy

“…Blood was collected into tubes containing the anticoagulant EDTA, and plasma was separated by centrifugation at 4000 rpm for 8 min. After the plasma trough concentration of VPA was determined, the plasma was collected immediately and stored at −80°C until omics analysis 26 …”

“…After the plasma trough concentration of VPA was determined, the plasma was collected immediately and stored at −80°C until omics analysis. 26…”

Factors Influencing Plasma Concentrations of Valproic Acid in Pediatric Patients with Epilepsy and the Clinical Significance of CYP2C9 Genotypes in Personalized Valproic Acid Therapy

“…29 However, in clinical settings, there is ongoing debate regarding the influence of CYP2C9 polymorphisms on plasma VPA levels. 26,[30][31][32][33][34] The most common CYP2C9 mutations are CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910), which significantly affect the metabolism of numerous drugs. Studies have revealed that the CYP2C9*2 mutation is most prevalent in the Middle East (18.1%), followed by Southern Europe (16.0%).…”