Evaluation of Factors Impacting the Efficacy of Single or Combination Therapies of Valproic Acid, Carbamazepine, and Oxcarbazepine: A Longitudinal Observation Study.

Objective: This study aimed to determine the efficacy and clinical factors related to the pharmacodynamics of single or combination therapies of valproic acid (VPA), carbamazepine (CBZ), and oxcarbazepine (OXC), three commonly used anti-epileptic drugs (AEDs) in China. Methods: The study evaluated the records of 2027 outpatients in a Changsha hospital, located in China, from December 23, 2015 to October 28, 2019. The baseline seizure frequency was assessed during the first visit. AED efficacy was determined based on the reduction in seizures from baseline at the subsequent visits. Multivariable ordinal regression analysis was used to determine the association between the clinical factors (demographic characteristics, clinical features, and medication situation) and AED efficacy. For validation, the clinical efficacies of AEDs were compared as both single agents and in combinations. Differences in adverse effect (AEs) categories were analyzed by Chi-square between AED groups. Results: Records of patients receiving VPA, CBZ, and OXC were evaluated. Serum concentrations of VPA and CBZ is significantly correlated with efficacy (OR 1.030 [1.024-1.037], p < 0 0.0001; OR 1.250 [1.146-1.63], p < 0.0001, respectively) and OXC efficacy correlated to the serum concentration of the metabolite 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD) serum concentrations (OR 1.060 [1.031-1.089], p < 0.0001). Significant differences existed between females and males in VPA efficacy (OR 1.318 [1.033-1.682], p = 0.027). After validation, VPA, in combination with OXC (OR 1.93 [1.38-2.70], p<0.001), or with VGB (Vigabatrin) (OR 2.36 [1.38-2.70], p = 0.002), showed significantly better efficacy than as a single agent. OXC efficacy was also affected by the duration of epilepsy (OR 0.965 [0.946-0.984], p < 0.001). Additionally, the efficacies of OXC and VPA were also affected by the seizure type. Seizure reduction improved significantly with an increasing number of pharmacists' educations in the first three visits period. There were no differences in AEs incidence among these 3 AEDs except for Psychiatric (0.02) and nervous system disorders (0.0001). Conclusion: Serum concentrations of VPA and CBZ may positively affect their efficacies, while OXC efficacies are correlated to MHD serum concentrations. The efficacy of VPA was higher in females compared to males. VPA-OXC and VPA-VGB combinations had higher efficacies compared to monotherapy. Besides, OXC efficacy is probably reducing by the duration of epilepsy. Additionally, VPA efficacy for focal or generalized seizures is superior to mixed-type seizures. OXC was more effective for focal seizures compared to mixed-type ones. Education provided by pharmacists improved the seizures to some extent, and there were no significant differences between most categories of adverse effects for the investigated AEDs.

Population pharmacokinetics of unbound valproic acid in pediatric epilepsy patients in China: a protein binding model.

PURPOSE: The purpose of this study was to establish a protein binding model of unbound valproic acid (VPA) based on Chinese pediatric patients with epilepsy and provide a reference for clinical medication. METHODS: A total of 313 patients were included and both their total and unbound VPA concentrations (375 pairs of concentrations) were measured. NONMEM software was used for population pharmacokinetic modeling. The stepwise method was used to screen the potential covariates. Goodness-of-fit plot, bootstrap, and visual predictive check were used for model evaluation. In addition, dose recommendations for typical patients aged 0 to 16 years were proposed by Monte Carlo simulations. RESULTS: A one-compartment model of first-order absorption and first-order elimination was used to describe the pharmacokinetic characteristics of unbound VPA, and the linear non-saturable binding equation was introduced to describe the protein binding. Body weight, age-based maturation, and co-medicated with lamotrigine could affect the CL/F of unbound and bound VPA. Model evaluation showed satisfactory robustness of the final model. The dosing regimens for children aged 0 to 16 years were proposed based on the final established model. CONCLUSION: We developed a population pharmacokinetic model of unbound and bound VPA that took account of protein binding. The VPA dosing regimen in pediatric patients with epilepsy needs to be optimized by the body weight, age, and co-medications.

Determination of unbound valproic acid in plasma using centrifugal ultrafiltration and gas chromatography:Application in TDM.

AIM: In order to monitor the free concentration of VPA in plasma, a simple and rapid method needs to be developed. METHODS: The free fraction of VPA in plasma was obtained by centrifugal ultrafiltration (CF-UF) devices. Cyclohexanecarboxylic acid was used as internal standard. Valproate in plasma was converted to VPA by sulphuric acid acidification, and dichloromethane was used as solvent for extraction. Nitrogen was the carrier gas, the samples were separated by capillary column, and the flame ionization detector was used to detect VPA fragment ions for quantitative analysis. RESULTS: The assay had good specificity and stability. The linear range of the assay was 0.56-28.11 mg/L. The intra-day and inter-day precision (RSDs) of the assay were all within 15%, and the accuracy (RE) was 2.58%. The recoveries of VPA with three different concentrations were 102.03 ±â€¯1.05, 101.45 ±â€¯2.08 and 102.58 ±â€¯3.38. The results of therapeutic drug monitoring (TDM) in pediatric inpatient group and outpatient group showed significant differences between the two groups (P < 0.001). CONCLUSION: This assay has low cost and good analytical performance, so it can be developed into a routine TDM method of unbound VPA. We recommend the monitoring of unbound VPA concentration in pediatric inpatients during clinical use of VPA.

Pharmacist impact on adherence of valproic acid therapy in pediatric patients with epilepsy using active education techniques.

There is limited information on the impact of active education by a pharmacist in the population of pediatric patients with epilepsy (PWE) in China. The objective of this study was to assess the effect of education by pharmacists on medication adherence and percentage of valproic acid (VPA) samples reaching therapeutic reference range in these patients. This study was conducted at two teaching hospitals in Changsha, China. Patients were retrospectively identified from January 2016 to December 2017. Active education by a pharmacist in both oral and written formats was provided at the intervention hospital whereas standard passive pharmacist service (dispensing and answering questions) was provided at the control hospital. Medication adherence was assessed by the simplified medication adherence questionnaire (SMAQ), and serum concentrations of VPA were collected. The correlation between pharmacist education and medication adherence and percentage of VPA samples reaching therapeutic reference range were analyzed. A total of 2165 patients and 4343 serum VPA concentrations were included in the analysis. For the first therapeutic drug monitoring (TDM) measurement, there was no statistical difference between the two hospitals: 41.3% of VPA samples reached therapeutic range at the intervention hospital compared with 45.4% at the control hospital (χ2 = 3.686, P > 0.05). After pharmacist intervention at the intervention hospital, however, there were significant differences in the percentage of therapeutic VPA samples reaching therapeutic range between the first and the second, third, fourth, and fifth TDM measurements (χ2 = 9.756, P < 0.01; χ2 = 22.840, P < 0.01; χ2 = 15.816, P < 0.01; χ2 = 27.613, P < 0.01). Based on the SMAQ adherence assessment, adherence increased from a minimum of 56.0% to a maximum of 73.9% with stabilization during the last six months of follow-up at the intervention hospital. Both the medication adherence rate and the percentage of VPA samples reaching therapeutic range increased as the result of active education by a pharmacist, suggesting that continuous pharmacist intervention had a positive impact in outpatient pediatric PWE.