Epilepsy is a chronic neurological disorder with a long history and extremely high prevalence. It affects approximately 50 million people worldwide, with 1% to 3% of the global population suffering from the condition, which is characterized by recurrent seizures ^[1].

Epilepsy is treated with a long-term regimen involving three main approaches: medication, surgery and the ketogenic diet. There is a wide variety of antiepileptic drugs (AEDs), the most widely used first-line medications of which are valproic acid (VPA) and carbamazepine. Both drugs have applications beyond the treatment of epilepsy. Valproic acid is approved for treating complex partial seizures in adults and children aged 10 years and over. It can be used as a single treatment or alongside other medications to treat various types of seizures, including absence seizures ^[2, 3].

The two drugs have distinct mechanisms of action: carbamazepine blocks voltage-gated sodium channels, while valproic acid inhibits GABA metabolism and reduces levels of the excitatory neurotransmitter aspartate. It also increases levels of the inhibitory neurotransmitter glycine and acts as a sodium channel blocker and a calcium-activated potassium channel agonist. Due to the complexity of these mechanisms and the significant impact of individual differences on drug efficacy, therapeutic drug monitoring (TDM) is essential to ensure therapeutic efficacy and medication safety.

The therapeutic efficacy of these two drugs is influenced by various factors, including age, gender, liver and kidney function, genetics, pregnancy, other health conditions and other medications being taken, all of which can alter the way the drugs are processed by the body and affect their concentration in the blood. Therapeutic drug monitoring (TDM) can improve seizure control, help avoid adverse drug reactions and guide individualized dose adjustments ^[4].

This retrospective study ^[5] analyzed serum drug concentrations in patients with epilepsy who were treated with valproic acid or carbamazepine in the Emergency Department of the Kırklareli Training and Research Hospital in Turkey between 1 January and 31 December 2023. The study also examined the associations between drug levels and demographic characteristics, as well as concomitant medications.

Method and Result

This was a single-centre, retrospective study. Patients were included if they had been clinically diagnosed with epilepsy, were being treated with valproic acid or carbamazepine (either as monotherapy or in combination) and had completed blood drug concentration testing. They also had to be aged 18 years or over and have presented to the emergency department. A total of 440 patients with epilepsy were included: Of these, 378 were treated with valproic acid and 62 with carbamazepine. Plasma drug concentrations were measured using the immunoassay method on a Roche COBAS C503 fully automated biochemical analyzer. The clinically effective therapeutic range was defined as 8–12 μg/mL for carbamazepine and 50–100 μg/mL for valproic acid.

This study used the Drugs.com database to identify drug-drug interactions, which were categorized by severity as none, mild, moderate or severe. SPSS 24 was used for statistical analysis; the Shapiro–Wilk test was used to assess normality in continuous variables and the Mann–Whitney U test was used for non-normal data. The chi-squared test or Fisher's exact test was used for categorical data and a P-value of less than 0.05 was considered statistically significant.

The demographic analysis of the 440 enrolled patients is shown in Table 1.

Table 1. Demographic profile of the participants

There were no statistically significant differences in the age distribution or gender composition of the two groups. There was also no significant association between age and plasma drug concentration.

Table 2. Therapeutic blood drug levels in patients using valproic acid and carbamazepine

There is a statistically significant difference in the rates of therapeutic levels between the drugs valproic acid and carbamazepine (p<0.001, Fisher’s Exact test)

Table 3. Distributions of therapeutic levels of valproic acid and carbamazepine

No statistically significant differences were observed in the stratification of plasma drug concentrations for either drug between men and women. The mean valproic acid plasma concentration was 68.15 μg/ml. The mean concentration in the low-concentration group was 35.51 μg/ml and the mean concentration outside the therapeutic range was 152.9 μg/ml. For carbamazepine, the mean concentration within the therapeutic range was 10.07 μg/ml, below the therapeutic range was 5.17 μg/ml and outside the therapeutic range was 15.75 μg/ml.

Table 4. Association between therapeutic drug levels and potential drug interactions in the carbamazepine and valproic acid groups

Carbamazepine group: A greater number of concomitant drug interactions was associated with a higher probability of subtherapeutic plasma concentrations (P=0.0393). No such association was observed in the valproic acid group (P=0.1354). There was a significantly higher probability of drug interactions affecting plasma drug concentrations with carbamazepine than with valproic acid (P = 0.0048), and patients with carbamazepine-related interactions were predominantly female.

TDM (therapeutic drug monitoring), which uses pharmacokinetics and modern testing technologies to optimize therapeutic efficacy and reduce adverse reactions by accounting for individual differences, is the standard approach to managing antiepileptic drugs ^[6]. Factors such as pregnancy, liver and kidney disease, polypharmacy and ageing can interfere with the metabolism of antiepileptic drugs. Regular monitoring can guide dose adjustments to achieve seizure-free treatment ^[7].

This study shows that the volume of clinical prescriptions for valproic acid is significantly higher than for carbamazepine, and the rate at which therapeutic concentrations are attained for valproic acid (62.16%) is significantly higher than for carbamazepine (27.42%). These findings contradict those of some previous studies. For example, Sharma et al. ^[8] reported therapeutic concentration attainment rates of 63% for carbamazepine and 45.99% for valproic acid, while studies published in 2020 ^[9, 10] reported rates of 75.5% and 54.87%, respectively. Analysis of the reasons for these differences: Valproic acid has a weaker liver enzyme-inducing effect and more stable pharmacokinetics, resulting in more predictable plasma drug concentrations ^[11]. In contrast, carbamazepine metabolism varies greatly among individuals, resulting in plasma drug concentrations that deviate from the therapeutic window and are subject to interference from multiple factors.

Drug-drug interactions are the primary cause of subtherapeutic carbamazepine plasma concentrations. The literature confirms that carbamazepine can interact with approximately 760 drugs, including 240 severe and 487 moderate interactions ^[12]; valproic acid, however, has a much narrower spectrum of interactions. In this study, patients taking carbamazepine alongside other medications or those taking interacting drugs were more likely to have low blood concentrations. Furthermore, the group experiencing carbamazepine interactions was predominantly female. It is hypothesized that women, who tend to have more comorbidities and take a greater variety of concomitant medications, experience an amplification of blood concentration fluctuations to a greater extent. In contrast, valproic acid blood concentrations remained stable even with polypharmacy, without a significant decline, and the impact of drug interactions on valproic acid was not statistically significant ^[13].

As shown above, the probability of patients with epilepsy achieving therapeutic serum concentrations of valproic acid is significantly higher than that of carbamazepine. Low carbamazepine plasma concentrations are associated with drug-drug interactions and female gender. For patients receiving carbamazepine therapy, particularly female patients, the importance of routine plasma concentration monitoring and individualized dose adjustments must be emphasized. Further multicentre, large-sample, prospective studies are required to validate these findings and refine personalized treatment strategies for antiepileptic drugs.