Factors Influencing Sodium Valproate Serum Concentrations in Patients with Epilepsy Based on Logistic Regression Analysis

Background

Valproic acid (VPA), which is prepared as an injection, oral solution, sustained-release tablet, and ordinary tablet, is widely used to treat seizures, bipolar disorder, migraine, and other psychiatric illnesses or neuropathies [1]. Its mechanism of action involves the interruption of γ-aminobutyric acid (GABA) transferase decomposition, which causes an increase in the concentration of GABA in the brain and inhibits neuronal excitement by weakening the neuronal response to N-methyl-D-aspartic acid. Therapeutic drug monitoring of VPA is a key aspect of the drug treatment of epilepsy because the therapeutic window of VPA is relatively narrow and there are many factors that affect the serum drug concentration. The current reference treatment range of VPA for epilepsy recommended by existing guidelines is 50 to 100 mg/L [2,3]. When the serum drug concentration is lower than required for treatment, the symptoms of epilepsy are not well controlled, and when the concentration is exceeded, the risk of adverse drug reactions increases, including those of the digestive system, nervous system, and hematological system [4]. This study aimed to provide an individualized reference for rational clinical drug use based on the monitoring of clinical therapeutic drugs to explore the influence of various factors on the serum concentration of VPA. We collected relevant clinical data of patients treated with sodium valproate (VPA-Na) and analyzed them by logistic regression analysis.

Material and Methods

GENERAL INFORMATION:

This study protocol was reviewed and approved by the Ethics Committee of the First People’s Hospital of Nanning. Data were collected on 109 hospitalized patients who received oral VPA-Na medication and serum concentration monitoring in a class-A tertiary hospital in Guangxi from January 2018 to December 2019. Collected data included basic patient characteristics (sex, age), drug use information (dosage, dosage form, combination of drugs), and liver and kidney function, measured by alanine transaminase (ALT), aspartate transaminase (AST) albumin, creatinine, urea, uric acid, and cystatin C levels.

INCLUSION CRITERIA:

The patients met the diagnostic criteria for epilepsy in the “Guidelines for Clinical Diagnosis and Treatment - Epilepsy Volume” (2015 revised edition). After the patients had taken 5 to 6 doses of VPA-Na, blood samples were collected within the following 30 min.

EXCLUSION CRITERIA:

Patients were excluded from the study for incomplete clinical medical records; poor compliance with the prescribed medications; steady-state concentration not reached; blood sampling monitoring after the patients took VPA-Na; serum concentration monitoring not performed; and pregnancy or lactation.

INSTRUMENTS AND REAGENTS:

The following instruments and reagents were used: VPA detection kit (Siemens, USA) and Viva-E automatic biochemical analyzer (Siemens, USA).

METHODS:

After the VPA-Na serum concentration reached a steady state in patients treated with VPA-Na by the oral route, 5 mL of fasting venous blood was collected before the patients took the medication the next morning. Blood samples were centrifuged at 4000 rpm to collect the serum. The drug concentration of VPA-Na was determined by enzyme-multiplied immunoassay with the Viva-E analysis system. The treatment window of VPA-Na ranged from 50 to 100 mg/L. If the result was within the treatment window, it was classified as reaching standard requirements; otherwise, it was classified as failing to meet standard requirements.

STATISTICAL ANALYSIS:

Data with a normal distribution were shown as mean±standard deviation, while non-normally distributed data were represented by median of the interquartile range (IQR, P25, P75), and the means of each group were compared. The independent samples were analyzed using the t test, and count data were expressed as a rate (%) and were analyzed using the chi-squared test. A P value of <0.05 was considered statistically significant. To screen and analyze the factors affecting the serum concentration of VPA-Na, we used logistic regression analysis. All statistical analyses were performed using SPSS version 16.0 (IBM Corp, Armonk, NY, USA).

Results

GENERAL DATA:

Therapeutic drug monitoring data were collected from 109 patients, including 83 male patients and 26 female patients. The patients’ ages ranged from 3 months to 91 years, with an average age of 47.46±29.29 years. The daily dose of the patients was 0.2 to 1.8 g, so that the average serum concentration of VPA-Na was 52.47±26.26 μg/mL. The serum drug concentration of 56 patients (51.38%) was within the reference range; the serum drug concentration of 51 patients (46.79%) was below the lower limit of the reference value; and the remaining 2 patients had serum concentrations above the upper limit of the reference value (Table 1).

CLINICAL DATA:

First, we carried out univariate analysis. To facilitate the discussion and accurate conclusions, the data of the 2 patients exceeding the upper limit of the reference value were eliminated, and the chi-squared test was used to calculate the difference of the standard-reaching rate under the influence of a single factor. The chi-squared test results showed no significant differences in the standard-reaching rate of serum drug concentrations in groups divided by sex, dosage form, liver function, kidney function, and combined enzyme inducer. However, there were significant differences in the standard-reaching rate of serum drug concentration in other groups, such as the juvenile and high-dose groups. The standard-reaching rate in the juvenile group was higher than that in the mature group and elderly group; the rate was lower in the low-dose group and intermediate-dose group than in the high-dose group; and in the group receiving carbapenems in combination, the standard-reaching rate was lower than that in the non-combination group (Table 2).

The second part of the study used multiple logistic regression to analyze VPA-Na serum concentrations lower than the standard. According to the results of the influence of a single factor and after excluding the data of the 2 patients whose concentrations exceeded the upper limit of the reference value, the variables mentioned above were analyzed by binary logistic regression. We showed that the combination of carbapenems and enzyme inducers was an independent risk factor for VPA-Na serum concentration below the target level (P<0.05). The results indicated a goodness of fit of 0.882 by the Hosmer-Lemeshow test (Table 3).

Discussion

LIMITATIONS AND PROBLEMS:

There were some limitations in our study. First, the sample size was relatively small, with only 2 patients having serum drug concentration greater than the upper limit of the treatment window, which led us to study only the factors leading to substandard concentration in the multivariate regression analysis. Second, the therapeutic effects and toxicities of VPA-Na were affected by the target receptors, effector pathways, absorption, metabolism, and polymorphisms of transporter-related genes [17,18], but the polymorphisms of genes [19] were not included in this study. Studies [20,21] have shown that the genetic polymorphisms of CYP450ABCB1 and UGT genes are significantly related to the serum concentration of epilepsy patients treated with VPA-Na. Third, the effective therapeutic concentration of VPA-Na remains controversial; in this study, 50 to 100 μg/mL was considered the target value. However, some studies have shown that the type of disease onset should be considered in the selection of effective therapeutic concentrations because sometimes patients’ conditions could be well controlled even with the concentration lower than 50 μg/mL, whereas some patients can need excessive drug concentration to control the disease, but with careful monitoring of liver function and routine blood parameters.

Conclusions

Considering the serum concentration in hospitalized patients is often lower than the standard concentration, clinical pharmacists may benefit from our study by adjusting the serum concentration of VPA-Na. For patients with a low dose or combined use of an enzyme inducer, a dose increase can be used to reach the standard drug concentration. Meanwhile, it is necessary to continuously monitor drug concentrations after the adjustment of the medication regimen to avoid great fluctuations. When possible, patients using non-sustained-release dosage forms should switch to sustained-release dosage forms. For patients who must be fed nasally, oral liquids or plain tablets are recommended, as grinding can destroy the special structure of the sustained-release tablets. The combined use of carbapenems should be avoided as much as possible. If the combined use of carbapenems is necessary, clinical pharmacists should select drugs other than VPA-Na, according to the type and frequency of seizure attacks.