
==== Front
Ther Drug Monit
Ther Drug Monit
tdm
Therapeutic Drug Monitoring
0163-4356
1536-3694
Therapeutic Drug Monitoring

38648661
TDM23-182
10.1097/FTD.0000000000001199
00014
3
Original Article
Retrospective Analysis of Steady-State Sodium Valproate Plasma Concentrations in Chinese Patients With Bipolar Disorder: Impact of Demographic and Clinical Characteristics
Qiming Qian BS *†
Ping Zheng MM *†
Huiqi Li BS *
Leyu Xu BS *
LIren Li BS *
Ming Lei MM *
* Clinical Pharmacy Center, Naufans Hospital, Southern Medical University, Guangzhou, China; and
† Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Correspondence: Zheng Ping, MM, No. 1838, North Guangzhou Avenue, Baiyun District, Guangzhou, China (e-mail: zpm321@126.com).
10 2024
19 4 2024
46 5 658663
09 10 2023
26 12 2023
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Supplemental Digital Content is Available in the Text.

Background:

This study comprehensively examined the demographic and clinical characteristics of patients undergoing valproic acid therapy and explored their potential impact on plasma valproic acid concentrations. All enrolled patients were administered the extended-release formulation. An in-depth investigation of factors, including dose, age, sex, body mass index, co-administered medications, and laboratory test findings, was conducted to evaluate their potential influence on study outcomes.

Methods:

In total, 164 patients met the inclusion criteria and were included in the analysis. The patient age ranged from 13 to 60 years, with a median age of 25.71 years. Most patients (89%) received a daily dose of 1 g valproic acid. Co-administered psychiatric medications included aripiprazole, quetiapine, and lorazepam. Laboratory test results, such as hemoglobin and transaminase levels, were also collected as part of the study.

Results:

The average plasma valproic acid plasma concentration was 79.8 mg/L. The dose significantly affected valproic acid concentrations, as a higher percentage of measurements exceeded the therapeutic range at a daily dose of 1 g. Furthermore, females exhibited significantly higher valproic acid concentrations compared with males at the same dose (P < 0.05). However, different age groups showed no statistically significant differences in valproic acid concentrations (P > 0.05). The co-administered antipsychotic and antidepressant medications significantly affected valproate concentrations, as reflected in the multiple regression model (P < 0.01).

Conclusions:

This study offers valuable insights into the demographic and clinical characteristics of patients undergoing valproic acid therapy. It highlights the influence of dose, sex, and concomitant medications on plasma valproic acid concentrations. Overall, these findings can help guide dose adjustments and implement personalized treatment strategies in valproic acid therapy.

Key Words:

valproic acid
plasma concentration
therapeutic drug monitoring
concomitant medication
Guangdong Pharmaceutical Society2022JZ03 Ping ZhengKey Technologies Research and Development Program2020YFC2005501 Ping ZhengOPEN-ACCESSTRUE
SDCT
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pmcINTRODUCTION

Bipolar disorder is a severe and chronic mental illness characterized by a complex array of symptoms. These symptoms include low mood, slowed thinking, poor sleep quality, elevated or pessimistic mood, racing thoughts, increased speech, and uncontrolled behavior.1 Valproic acid (VPA) is a well-established antiepileptic drug that has also been used for treating multiple psychiatric disorders. Although the precise mechanism of action of VPA in psychiatric disorders remains unclear, several studies have supported its efficacy in managing bipolar disorder.2 VPA functions as a mood stabilizer in treating bipolar disorder, exerting antimanic, antidepressant, and anti-suicidal effects.

In a study examining the monitoring of antiepileptic drugs, Patsalos et al3 emphasized the saturation of valproic acid binding to plasma proteins and the nonlinearity of its pharmacokinetics. These factors contribute to notable variations in the relationship between dosage and plasma concentration among individuals. The International College of Neuropsychopharmacology has issued guidelines recommending therapeutic drug concentrations based on different clinical conditions. For acute manic episodes, the suggested concentration ranges from 75 to 150 mg/L, whereas for maintenance monotherapy, the recommended range is 45–100 mg/L.4 The guidelines issued by the International Society for Bipolar Disorders recommend a target plasma level of 50–100 mg/L for valproic acid during acute manic episodes.5 In a study by Marco, data from 12,294 patients with bipolar disorder who were treated with valproic acid at the clinical center of the University of Pisa in Italy between 2016 and 2020 were analyzed. The findings revealed that approximately 50% of patients attained effective valproic acid concentrations within the therapeutic range of 50–100 mg/L, whereas 35% had concentrations below 40 mg/L.6 Therefore, implementation of therapeutic drug monitoring (TDM) for patients receiving valproic acid may help achieve an optimal balance between clinical effectiveness and the occurrence of adverse reactions.

Most existing studies on the TDM and analysis of valproic acid primarily focus on patients with epilepsy, leaving limited research specifically addressing patients with bipolar disorder. Although some observational studies have explored the impact of sex and weight on valproic acid concentrations in Chinese patients with bipolar disorder, they do not provide sufficient comprehensive information.7 Patients with bipolar disorder frequently require combination therapy involving antipsychotics and antidepressants. However, limited research examining the influence of newer antipsychotics on VPA drug metabolism is available.8 Multiple studies have indicated a commonality in metabolic pathways between valproic acid and drugs such as olanzapine, quetiapine, and risperidone.9,10 However, the available data primarily stems from Western populations, with limited representation from Chinese populations. Notably, Sun et al9 demonstrated that olanzapine does not exert an impact on the pharmacokinetics of lithium or valproic acid salts. Nevertheless, the impact of combination medications on valproic acid concentrations in Chinese patients with bipolar disorder remain to be fully elucidated.

Thus, this study aimed to examine the potential impact of various factors, such as dosage, age, sex, body mass index (BMI), and concomitant medications, on serum valproic acid concentrations in Chinese patients with bipolar disorder through TDM. The outcomes of this investigation can provide vital insights for appropriately modifying the valproic acid dosage in clinical settings.

METHODS

Data Source

Our research involved the collection of retrospective data from patients diagnosed with bipolar disorder who underwent sodium valproate treatment at Nanfang Hospital, affiliated with the Southern Medical University, from July 17, 2018, to October 1, 2021. The comprehensive dataset encompassed various patient demographics, including sex, age, height, and weight. In addition, medication details such as dosage and concurrent drug usage were recorded, along with laboratory parameters including alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, creatinine (Cr), bilirubin, and uric acid levels. The study inclusion criteria were as follows: (1) patients clinically diagnosed with bipolar disorder, (2) patients undergoing valproic acid treatment and subjected to medication monitoring, (3) patients demonstrating normal hepatic and renal function (AST and ALT values within the accepted reference range of 0–40 U/L; total bilirubin level below the threshold of 17 µmol/L, blood urea nitrogen levels ranging from 9 to 7.1 mmol/L, and blood Cr levels within 45–133 µmol/L), and (4) patients on long-term valproic acid therapy, with blood medication concentrations measured at least 7 days after consistent dosing; further, (5) only blood medication concentration data from the final time point for each patient and dosage regimen were considered for inclusion. The following exclusion criteria were applied: (1) pregnant women and (2) patients with substantial missing research data, including important identifiers and study variables. To ensure accurate and appropriate data, we excluded medication records without TDM measurements, those from pregnant or breastfeeding women, and only retained the primary medication record for each patient. We carefully removed the medication records with significant missing laboratory test results to enhance data quality, reliability, and robust interpretation. Finally, we obtained the final data set for statistical analysis. This research protocol was approved by The Medical Ethics Committee of NanFang Hospital of Southern Medical University (Approval No: [2022] No. 450), with a waiver for patient consent after evaluating its compliance with the requirements.

Valproic Acid Determination

We collected plasma samples from 2 dosing regimens of VPA: 0.5 g daily and 0.5 g twice daily. Blood samples were collected to assess steady-state trough concentrations of VPA after administering a consistent dosage for 7 days, immediately preceding the final maintenance dose. Peripheral blood samples (2–3 mL) were collected from each patient using ethylenediaminetetraacetic acid (EDTA) anticoagulant tubes, identified by purple caps, to analyze plasma drug concentrations. Clinical blood samples were then centrifuged at 3000g for 5 minutes to isolate plasma. Afterward, 200 μL of the plasma sample was precisely transferred into a 1.5-mL centrifuge tube, and 500 μL of acetonitrile was added. The mixture was mixed vigorously for 40 seconds and then centrifuged at 14,000 rpm for 10 minutes. A 2-μL fraction of the supernatant was subjected to liquid chromatography–mass spectrometry analysis at the Precision Medicine Laboratory, which serves as a crucial aspect of the patient's ongoing clinical monitoring. The VPA calibration range was 1–150 mg/L with a coefficient of variation ranging from 10% to 15%. All patients included in the study were administered sodium valproate extended-release tablets (trade name: Depakine), with a dosage of 0.5 g per tablet, manufactured by Sanofi (Hangzhou) Pharmaceutical Co., Ltd.

Statistical Analysis

Statistical analysis was performed using SPSS V19.0 software (IBM Corporation, Armonk, NY). Normally distributed data were presented as mean ± SD, whereas nonnormally distributed data were presented as the median (interquartile range, P25–P75); the mean values of each group were compared. Between-group comparisons of mean values for 2 samples were conducted using the Mann–Whitney U test, and between-group comparisons of mean values for multiple samples were performed using the Kruskal–Wallis test. The χ2 test was used to evaluate the influence of various factors on the distribution of valproic acid therapeutic ranges. Multiple linear regression analysis was conducted to assess the correlation between plasma valproic acid levels and factors such as dosage, age, sex, BMI, and co-medications. A P-value <0.05 was considered statistically significant.

RESULTS

Demographic and Clinical Characteristics

Table 1 displays the demographic and clinical characteristics of the patient population involved in this study. In total, 218 patients underwent screening for plasma valproic acid concentrations, resulting in 342 measurements. After implementing the inclusion criteria, data from 164 individual patient measurements met the inclusion criteria and were included in the final analysis. The mean measured concentration of valproic acid in the plasma of these patients was 79.8 mg/L. Daily doses of 0.5 g and 1 g were collected, with most patients (89.1%) receiving a daily dose of 1 g. The age range of the patient population involved in this study was between 13 and 60 years, with a median age of 25.7 years. The patient population comprised 76 male patients and 88 female patients. The median values for height, weight, and BMI were 165.4 cm, 61.2 kg, and 22.3 kg/m2, respectively. Among patients with bipolar disorder, the most frequently co-administered psychiatric medications were aripiprazole (n = 88), quetiapine (n = 83), and lorazepam (n = 50). We also gathered laboratory indices including hemoglobin (Hb), transaminase, and bilirubin because these may be connected with plasma valproic acid concentrations. Among the measurements analyzed, 112 were within the therapeutic range, 19 were below the therapeutic range, and 33 were above the therapeutic range.

TABLE 1. Demographic and Clinical Data of Patients

Categories	Variables	Cases (N = 164)	
VPA information	VPA TDM, mg/L, median (IQR)	79.8 (62.8–95.5)	
	VPA daily dose, g, n (%)		
	0.5	18 (11.0%)	
	1	146 (89.0%)	
Demographic information	Age, yr, median (IQR)	25.7 (18.0–29.0)	
	Sex, n (%)		
	Male	76 (46.3%)	
	Female	88 (53.7%)	
	Height, cm, median (IQR)	165.4 (159.0–170.3)	
	Weight, kg, median (IQR)	61.2 (52.0–71.3)	
	BMI, kg/m2, median (IQR)	22.3 (19.3–24.7)	
Combination, n (%)	Olanzapine	88 (53.7)	
	Quetiapine	83 (50.6)	
	Lorazepam	50 (30.5)	
	Sertraline	30 (18.3)	
	Aripiprazole	22 (13.4)	
	Risperidone	15 (9.2)	
	Lamotrigine	13 (7.9)	
Essay index	Hb, g/L, median (IQR)	134.4 (123.0–145.0)	
	AST, U/L, median (IQR)	21.8 (13.0–21.5)	
	Albumin, g/L, median (IQR)	40.6 (38.4–42.9)	
	Total bilirubin, μmol/L, median (IQR)	8.3 (5.8–9.7)	
	Direct bilirubin, μmol/L, median (IQR)	3.1 (2.0–3.8)	
	Indirect bilirubin, μmol/L, median (IQR)	5.2 (3.7–6.5)	
	Cr, μmol/L, median (IQR)	68.3 (55.0–75.0)	
IQR, interquartile range; Hb, hemoglobin; Cr, creatinine.

Effect of Dose, Age, Sex, and BMI on Plasma Valproic Acid Concentrations

The distribution of plasma valproic acid concentrations is outlined in Supplemental Digital Content 1 (see Table, http://links.lww.com/TDM/A737). None of the measurements associated with a daily dose of 0.5 g exceeded the therapeutic range. However, 33 measurements (22.6%) associated with a daily dose of 1 g registered values that surpassed the therapeutic range (S1). Consequently, we analyzed the impact of age and sex on plasma valproic acid concentrations at the equivalent dosage. The comparison of valproic acid parameters across various age, sex, and BMI groups is shown in Tables 2–4. For measurements associated with a daily dose of 1 g, the average concentration of valproic acid in females was significantly higher than that in males (P < 0.001). We further divided the age groups into 3 categories: <20, 20–40, and >40 years and evaluated the mean concentrations of valproic acid TDM within each group, using the same daily dose. However, the observed differences were not significant (P > 0.05; Tables 2 and 3).

TABLE 2. Effect of Sex on Plasma VPA-Na Concentrations in 0.5 and 1 g Daily Doses

VPA Daily Dose (g)	Male	Female	Z	P	
N	C (mg/L)	N	C (mg/L)	
0.5	6	53.8 ± 18.0	12	48.9 ± 13.7	−0.56	0.574	
1	69	73.0 ± 24.2	77	92.6 ± 25.2	−4.47	<0.001	
C, plasma VPA-NA concentrations.

TABLE 3. Effect of Age on Plasma VPA-Na Concentrations in 0.5 and 1 g Daily Doses

VPA Daily Dose (g)	<20 yrs	20–40 yrs	>40 yrs	H	P	
N	C (mg/L)	N	C (mg/L)	N	C (mg/L)	
0.5	7	49.5 ± 18.5	11	53.2 ± 13.6	0	0	—	0.751	
1	43	89.6 ± 26.6	87	80.1 ± 25.7	16	83.9 ± 29.7	5.41	0.067	
C, plasma VPA-NA concentrations.

TABLE 4. Univariate Analysis of the Factors Influencing Plasma VPA-Na concentrations (Lower, Within, or Higher Than the Therapeutic Window)

Factors	Distribution of Plasma VPA-NA Concentrations/N	χ2	P	
<50 mg/L	50–100 mg/L	>100 mg/L	
Sex						
 Male	11	56	8	7.34	0.025	
 Female	8	57	24			
Age, yr						
 <20	6	30	14	2.95	0.228	
 ≥20	13	82	19			
BMI, kg/m2						
 <24	10	62	27	7.91	0.019	
 ≥24	7	34	3			
Combination						
 Antipsychotics	11	81	26	2.63	0.268	
 No combined	8	31	7			
 Antidepressants	6	15	1	8.46	0.015	
 No combined	13	97	32			

The χ2 test was used to examine the distribution of valproic acid TDM measurements within the therapeutic range, considering the variables of sex, age, and BMI. The findings revealed that most of the valproic acid TDM measurements were within the therapeutic range. Nonetheless, when examining the proportions of valproic acid TDM within different therapeutic ranges across various sex and BMI groups, statistically significant differences were identified (P < 0.05). Conversely, no statistically significant differences were found in the proportions of valproic acid TDM within different therapeutic ranges among various age groups (P > 0.05; Table 4).

Effects of Concomitant Medication and Test Index on Valproic Acid Parameters

The plasma concentrations of valproic acid in the context of combined antipsychotics and antidepressants are provided in Table 4 and Supplemental Digital Content 1 (see Table, http://links.lww.com/TDM/A737). We examined the average plasma concentrations of valproic acid when used in conjunction with sodium valproate, aripiprazole, quetiapine, lorazepam, escitalopram, and olanzapine at equivalent daily doses. However, no statistically significant differences were observed (P > 0.05). The valproic acid concentrations were lower when combined with antipsychotics compared with those when administered alone. Conversely, the valproic acid concentrations were higher when co-administered with antidepressants. However, these differences were not statistically significant (P > 0.05) (S2). We conducted a χ2 test to examine the distribution of valproic acid TDM measurements within the therapeutic range, considering the influence of antipsychotic and antidepressant medications. Within the antidepressant group, the proportions of valproic acid TDM within various therapeutic ranges demonstrated statistical significance (P < 0.05). Conversely, in the antipsychotic medication group, no statistically significant differences were observed (P > 0.05) (Table 4). In addition, we collected data on Hb, aspartate aminotransferase, albumin, and various types of bilirubin from patients during the monitoring of plasma valproic acid concentrations. The results indicated that for both the 0.5 and the 1 g daily doses, no statistically significant differences were observed in the different test indexes of valproic acid therapeutic drug monitoring within the therapeutic range (P > 0.05) (S3).

Effect of Covariates on Plasma Valproic Acid Sodium Parameters: Multiple Regression Analysis

In the multiple linear regression analysis, daily dose (standardized r coefficient β = 0.3; P < 0.001), sex (β = −0.4; P < 0.001), BMI (β = −0.2; P < 0.001), antipsychotics (beta = 0.2; P < 0.01), and antidepressants (β = −0.2; P < 0.01) had significant effects on plasma concentrations of VPA-Na. However, age had no influence. The analysis could account for 29.9% of the observed variation in the plasma concentrations of VPA-Na (R2 = 0.299, Table 5).

TABLE 5. Effect of Covariates on Plasma VPA-Na Parameters: Multiple Regression Analysis*

Factors	B	Beta	t	95% CI	P	
Daily dose (0 = 0.5 g, 1 = 1.0 g)	33.3	0.3	6.0	22.3 to 44.2	<0.001	
Sex (0 = male, 1 = female)	−19.3	−0.4	−7.2	−24.6 to −14.1	<0.001	
Age (yr)		0.0	−1.0		0.3	
BMI (kg/m2)	−1.8	−0.2	−4.9	−2.5 to −1.1	<0.001	
Antipsychotics	10.7	0.2	3.5	4.6 to 16.8	<0.01	
Antidepressants	−12.4	−0.2	−3.1	−20.2 to −4.6	<0.01	
* R2 = 0.299.

DISCUSSION

In this retrospective study, we analyzed the plasma concentration of sodium valproate (VPA-Na) among patients diagnosed with bipolar disorder. Our results revealed that at daily doses of 0.5 and 1 g, 61% and 70% of the plasma VPA-Na concentrations were within the range of 50–100 mg/L, respectively. Moreover, at a daily dose of 1 g, 22.6% of the concentrations surpassed the threshold of 100 mg/L. In a separate analysis involving 5087 VPA samples collected from the psychiatry unit, a distinct distribution pattern was identified. Among these samples, 44.6% were within the range of 50–100 mg/L, whereas only 1.2% exceeded the threshold of 100 mg/L.6 The results of our study showed a higher adherence rate to target VPA-Na concentrations. However, we also noted a significantly higher proportion of concentrations exceeding the therapeutic range at a daily dose of 1 g. This discrepancy could be attributed to the smaller sample size in our study, making it more susceptible to individual variations. Alternatively, the higher frequency of TDM in our hospital for patients taking higher doses of VPA owing to suboptimal therapeutic effects, demonstrated by the larger proportion under monitoring at a 1 g daily dose, may also account for this observation.

In the context of sex differences, our study uncovered a significant discrepancy in VPA-Na plasma levels between male and female patients. Notably, male patients exhibited lower plasma levels compared with those of their female counterparts. This finding aligns with previous research, which indicated that the variation in clearance (CL/F) attributable to sex may stem from disparities in weight between males and females.11,12 In our multiple regression model, sex was incorporated as a covariate. Despite adjusting for BMI, our analysis indicated that sex retained a significant impact on the model (P < 0.05). This strongly indicates that the influence of sex on valproic acid concentration parameters may be influenced by various other factors, such as differences in fat distribution, hepatic blood flow, and genetically determined transporter pathways.13,14 Several studies have consistently demonstrated that females typically exhibit lower levels of UGT (UDP glucuronosyl transferase) activity in comparison with males. This disparity may help elucidate the observed sex-related differences in VPA clearance.15,16 Regarding age differences, our study did not show any significant variations in valproic acid parameters between adolescent and adult patients. Notably, most patients with bipolar disorder patients included in our study were below 40 years old, aligning with the decreasing age of onset for bipolar disorder. However, it is important to acknowledge that our study did not incorporate blood concentration monitoring in older patients, which may have impacted our research findings. Older patients often present multiple comorbidities and frequently receive multiple medications, which could potentially affect the absorption and metabolism of VPA-Na within their bodies. To further investigate this matter, future research should focus on analyzing a larger sample of older patients.

Furthermore, our findings revealed that the CL/F of VPA remained unaffected by clinical factors such as liver function (ALT and AST) kidney function (serum creatinine, SCr) parameters. However, the concurrent usage of specific antiepileptic medications, namely phenobarbital, phenytoin, and carbamazepine, exerted a significant influence on VPA blood concentrations.17–19 Notably, none of the patients included in our dataset were concurrently receiving antiepileptic medications. However, individuals with bipolar disorder commonly undergo combination therapy involving antipsychotic agents and antidepressants. Although the impact of atypical antipsychotics on VPA drug metabolism remains unclear, some studies propose that VPA shares overlapping metabolic pathways with specific antipsychotics, such as olanzapine, quetiapine, and risperidone.8,10,20 We compared the blood concentrations of patients prescribed antipsychotic versus nonantipsychotic medications and those using antidepressant versus non-antidepressant medications. The results indicated significant differences in the multivariate regression model for both comparisons. However, when assessing the effects of individual combined medications, no significant differences were found. Notably, the study participants in this cohort mostly received two- to three-drug combinations, which may potentially affect valproic acid metabolism. Therefore, further investigations are imperative to elucidate the potential interactions between VPA and antidepressant or antipsychotic drugs.

We conducted a multiple linear regression analysis, which incorporated the variables of dose, sex, BMI, and concurrent medication use to evaluate their effects on VPA plasma concentrations. However, these factors could only explain approximately 30% of the variability in VPA concentrations. This implies that other parameters, such as individual differences in drug-metabolizing enzyme activity, liver function, and kidney function, may also play a critical role in determining VPA dosage requirements. Therefore, psychiatrists should consider the unique patient characteristics and incorporate various factors that influence VPA concentration to tailor the medication regimen accurately.

This study has several limitations that need to be acknowledged. First, the data used for the routine TDM of VPA were retrospective and lacked the prospective inclusion of patients in the study. Moreover, extraction of information regarding concomitant medications for the combination therapy analysis was not sufficiently comprehensive, particularly for limited samples of antidepressants; thus, the specific impact of individual combination drugs on VPA concentration remains unclear. Finally, this study did not examine genetic polymorphism, which is a crucial factor to consider in patients undergoing VPA-Na treatment. Notably, previous studies have highlighted a significant association between plasma concentrations and enzyme polymorphisms in VPA-metabolizing enzymes, including CYP2C9, CYP2C19, UGT1A4, and UGT2B7.14,21–23

This study also has several strengths. First, we comprehensively assessed blood concentrations of VPA in Chinese patients with bipolar disorder, contributing valuable insights, specifically within this population. Second, we extensively analyzed the influence of various factors on the attainment of therapeutic VPA concentration windows, providing a more nuanced understanding of how these factors impact treatment outcomes. This aspect has been lacking in previous research. Finally, we analyzed a diverse range of concomitant medications, such as antipsychotics and antidepressants, which is a significant contribution as previous studies have seldom explored these combinations.

CONCLUSIONS

Our study aimed to investigate the association between plasma concentrations of VPA and various factors, including age, sex, BMI, and concurrent medications, in Chinese patients diagnosed with bipolar disorder. Our findings demonstrated notable interindividual variability in VPA plasma levels within the Chinese bipolar disorder cohort, with only a partial explanation provided by dosage, BMI, sex, and concomitant medications. The factors accounting for most of this variability remain unclear, indicating the limited accuracy in predicting VPA plasma concentration. Further research is thus warranted to elucidate the impact of concomitant medications and metabolic enzyme genotypes on VPA and to enhance our understanding of combination therapies involving VPA.

Supplementary Material

SUPPLEMENTARY MATERIAL

ACKNOWLEDGMENTS

The authors thank Nanfang Hospital, Southern Medical University for support in data collection and acknowledge financial support from the Guangdong Provincial Pharmaceutical Association and the National Health Commission of China.

Supported by the National Key Research and Development Program (2020YFC2005501) and Clinical Drug Use Research project in Guangdong Province (2022JZ03).

Z. Ping leaded the research and provided medical support. Q. Qiming, L. Huiqi, X. Leyu, L. Ming, and L. LIren were involved in patient recruitment. Q. Qiming analyzed and interpreted data. Z. Ping wrote the manuscript.

The authors declare no conflict of interest.

The studies involving human participants were reviewed and approved by the Medical Ethics Committee, Nanfang Hospital, Southern Medical University. The ethics committee waived the requirement of written informed consent for participation.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.drug-monitoring.com).
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