
==== Front
Biomed J
Biomed J
Biomedical Journal
2319-4170
2320-2890
Chang Gung University

S2319-4170(23)00117-8
10.1016/j.bj.2023.100680
100680
Original Article
Clinical impact of therapeutic drug monitoring for newer anti-seizure medications in patients with epilepsy: A real-world observation study
Lim Siew-Na siewna@adm.cgmh.org.tw
ab∗
Wu Tony ab
Chang Chun-Wei ab
Johnny Tseng Wei-En abc
Cheng Mei-Yun ab
Hsieh Hsiang-Yao ab
Lee Chih-Hong ab
Lin Wey-Ran bd
Liu Chun-Jing a
Chen Po-Ru a
Lin Chia-Ni ef
a Section of Epilepsy, Department of Neurology, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taiwan
b College of Medicine, Chang Gung University, Taoyuan, Taiwan
c PhD Program in Biomedical Engineering, Chang Gung University, Taoyuan, Taiwan
d Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taiwan
e Department of Laboratory Medicine, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taiwan
f Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan
∗ Corresponding author. Section of Epilepsy, Department of Neurology, Chang Gung Memorial Hospital at Linkou Medical Center, No. 5, Fuxing St., Guishan Dist., Taoyuan City, 33305, Taiwan. siewna@adm.cgmh.org.tw
29 11 2023
10 2024
29 11 2023
47 5 10068021 8 2023
18 10 2023
24 11 2023
© 2023 The Authors
2023
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

The clinical value of therapeutic drug monitoring (TDM) for newer anti-seizure medications (ASMs) remains uncertain. This study aimed to assess the impact of newer ASM TDM on clinical decision making in patients with epilepsy.

Methods

We retrospectively identified all plasma requests for newer ASM level measurement as part of routine clinical management in the outpatient departments of seven medical institutes across Taiwan between September 2016 and May 2019. Data collected from reviewed medical records included clinical and medication details, indications for TDM requests, test results, interpretation, and impact on patient management.

Results

A total of 682 visits with 1051 plasma samples were included. The most frequently analyzed ASMs were levetiracetam (36.1%), oxcarbazepine (18.4%), and lamotrigine (12.0%). Reasons for TDM included poorly controlled seizures (55.3%), concerns about drug-drug interactions (12.3%), and suspicion of drug overdose (10.6%). 68.8% of samples were within the orienting therapeutic range, even for patients with poorly controlled seizures. TDM for non-adherence concerns showed 54.3% below the orienting therapeutic range, while ASM-related adverse events assessment only 8.9% showed levels exceeding the orienting therapeutic range. Following TDM results, 64.2% of cases had medication adjustments, mainly dosage increases. Overall, 55.9% of newer ASM TDM visits showed improved outcomes, including reduced seizures (47.5%) and fewer ASM-related side effects (8.4%).

Conclusions

These findings suggest that appropriate utilization of TDM for newer ASMs provides clinical benefits in adjunct to complement clinical decision making in the management of epilepsy patients in a real-world clinical setting.

Highlights

• Therapeutic drug monitoring (TDM) for newer antiseizure medications (ASMs) was ultilized across diverse situations.

• Overall, 55.9% of the TDM visits led to improved outcomes, including reduced seizures and decreased ASM-related side effects.

• Incorporating TDM for newer ASMs can offer substantial clinical benefits.

Keywords

Antiseizure medications
Therapeutic drug monitoring
Epilepsy
Drug-drug interactions
Adherence
Overdose
==== Body
pmc1 Introduction

Epilepsy is one of the most prevalent neurological disorders, affecting approximately 0.6–1% of the population in developed countries [1]. Over the years, advancements in understanding the neurochemistry and mechanisms of anti-seizure medications (ASMs) have led to a more rational approach to drug treatment [2]. However, the ability to predict individual patient response and potential adverse effects to specific ASMs remains challenging. The only practical way to determine whether a drug will work in a particular patient is to try it [3]. Therapeutic drug monitoring (TDM), which involves measuring drug concentrations in biological fluids and combining it with clinical pharmacology, may therefore be an important and valuable tool in guiding and optimizing ASM therapy [2].

Older ASMs (i.e., first generation), such as phenytoin (PHT), carbamazepine (CBZ), and valproic acid (VPA), are characterized by a narrow therapeutic range and exhibit significant variability in their pharmacokinetics [4]. Thus, monitoring the levels of these older ASMs has become widely accepted in clinical practice due to the established correlation between drug concentration, therapeutic target, and toxic effects.

In the past 20 years, newer generations of ASMs (i.e., second or third generation) have been introduced to the market, including nine new compounds: gabapentin (GBP), lacosamide (LCM), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), perampanel (PER), pregabalin (PGB), topiramate (TPM), and zonisamide (ZNS) launched in Taiwan. In general, these newer ASMs are often claimed to have advantages over the older ASMs, such as more predictable pharmacokinetics, fewer drug-drug interactions, and less need for TDM [5]. However, the value of monitoring drug levels for these newer ASMs is yet to be established, as regulatory trials did not focus on blood concentration control or investigating the relationship between drug level and effects. A recent randomized and controlled trial comparing systematic (ASM plasma levels were available at each appointment) and rescue TDM (levels were known only if the study endpoint was reached) of seven newer ASMs found no difference in treatment efficacy and tolerability [6]. Consequently, the authors concluded that systematic drug-level monitoring for newer ASMS does not provide significant benefits in managing epilepsy. However, evidence from nonrandomized studies and clinical experience suggests that measuring plasma concentrations of newer ASMs can be valuable if concentrations are measured with a clear indication and interpreted critically, considering the whole clinical context [14].

A study of ASM level determinations at a tertiary care center revealed that only 27 % were appropriately indicated, and of those, one-half were sampled incorrectly [7]. Such indiscriminate utilization of TDM is undesirable as it may result in unnecessary therapeutic interventions and potential treatment misadventures. In Taiwan, TDM for newer ASM is not covered by the National Health Insurance, resulting that patients pay for these services only when there are clear indications. This situation provides a unique opportunity to study the plasma concentration of newer ASMs in various clinical circumstances. To the best of our knowledge, no previous study has endeavored the clinical indications, corresponding drug levels, action taken, and clinical outcomes associated with TDM of newer ASMs. To bridge this knowledge gap, our study aims to describe the practice of the TDM for newer ASMs in an epilepsy center. Specifically, our objectives are to (i) describe the indications for ordering plasma drug level measurements for newer ASMs in accordance with the recommendations of the International League Against Epilepsy (ILAE); (ii) report the subsequent actions taken following the availability of TDM results; and (iii) investigate the impact of providing TDM for these newer ASMs on the treatment outcome of epilepsy in a real-world clinical setting.

2 Methods

2.1 Subjects and study design

We searched the electronic medical record and Chang Gung Research Database (CGRD) [8] of Chang Gung Memorial Hospital (CGMH), Taiwan, in order to identify all plasma newer ASM level measurement requests sent for analysis as part of routine clinical management in the outpatient departments of seven medical institutes located from the northeast to southern regions of Taiwan, during the period September 2016 and May 2019. The study protocol was approved by the Institutional Review Board (IRB)/Ethics Committee of Chang Gung Memorial Hospital, Linkou, Taiwan (IRB No. 201900786B0), and all procedures followed were in accordance with the Helsinki Declaration of 1975, as revised in 2008.

2.2 Demographic and clinical data collection

Data was collected from reviewed medical records, including medication details (ASM types and dose), epilepsy syndrome, seizure types, age at epilepsy onset, body weight, monthly seizure frequency before and after TDM, adverse effects, co-medications, and laboratory test results. Additionally, documentation of indications and test results, their interpretation, and their impact on patient management were recorded.

The indications for requesting TDM of newer ASMs were thoroughly reviewed in the medical records and categorized as follows: (1) establishing baseline information or optimizing dosage, (2) managing uncontrolled seizures, (3) suspicion of ASM toxicity, (4) suspicion of non-adherence to ASM regimen, (5) managing drug-drug interactions, (6) addressing renal or hepatic comorbidities, (7) managing epilepsy during pregnancy, (8) managing epilepsy while breast-feeding, and (9) addressing the specific needs of elderly patients.

Following TDM, clinical physicians in charge made management decisions based on clinical judgment, ASM levels, or a combination of both, with the goal of achieving optimal seizure control: (1) increasing the target or co-ASM dosage, (2) decreasing the target or co-ASM dosage, (3) adjusting ASM dosing schedule, (4) adding an additional ASM, (5) substituting another ASM, (6) discontinuing the target or co-ASM, (7) educating the patient regarding medication compliance, (8) maintaining treatment without changing regimens, and (9) utilizing other strategies as deemed appropriate.

Clinical outcomes during the subsequent outpatient clinic follow-up visits after the aforementioned TDM-related clinical decision making, were retrospective reviewed on the medical record. The outcomes were classified as follows: (1) seizure-free, (2) seizure reduction, (3) decrease in adverse effects, (4) worsening of seizure control, (5) no significant changes observed, (6) loss of follow-up, and (7) other notable outcomes.

2.3 Measurement of plasma ASM concentrations

The plasma concentrations of the newer ASMs listed were measured with ultra-performance liquid chromatography/mass spectroscopy (UPLC-MS/MS) (Waters XEVO TQ-S, Mundelein, IL) in the Therapeutic Drug Monitoring Unit at CGMH, Taiwan. This UPLC-MS/MS method has been fully validated and is routinely employed for newer ASM analysis. The validation process followed the guidelines outlined in the Clinical Laboratory Standards Institute guideline C62-A for liquid chromatography-mass spectrometry. It is important to note that OXC is a prodrug that exerts its primary action through the active metabolite, 10-hydroxycarbazepine metabolite. Therefore, during TDM, the primary focus lies in monitoring the concentrations of this particular metabolite [9].

In our laboratory, the orienting therapeutic ranges for these newer ASMs are as follows: GBP, 2 to 20 μg/mL; LCM, 1 to 10 μg/mL; LTG, 2.5 to 15 μg/mL; LEV, 12 to 46 μg/mL, OXC, 3 to 35 μg/mL; PER, 180 to 980 ng/mL; PGB, 2 to 8 μg/mL; TPM, 5-20 μg/mL, and ZNS, 10 to 40 μg/mL. The delineation of the orienting therapeutic range for most of these studied ASMs adheres to the recommendations by the ILAE [9]. It is worth noting that for LCM, we refer to the range suggested by the Task Force on TDM within the Association of Neuropsychopharmacology and Pharmacopsychiatry (AGNP) [10], taking into account the updated 10-20 μg/mL range recommended by the ILAE in 2018 increased toxicity in patients treated with LCM [11]. The plasma concentrations of these newer ASMs were further categorized as within, below, and above the designated orienting therapeutic range, using the terminology recommended by the ILAE's best practice guidelines for TDM of ASMs [12].

2.4 Statistical analysis

Descriptive statistics were used to summarize baseline characteristics. Categorical data were presented as numbers (%), and continuous data were presented as mean ± standard deviation (SD). Student's t-tests were performed for comparisons between subgroups. P ≤ 0.05 was considered statistically significant. All statistical analyses were performed with SPSS Statistics version 23 (IBM, Chicago, IL, USA).

3 Results

3.1 Baseline demographic and clinical characteristics of patients

During the study period, routine TDM was conducted for the newer ASMs listed in a cohort of 539 patients with epilepsy, including pediatric, adolescent, and adult individuals in the outpatient department. The baseline clinical characteristics of the patients are summarized in [Table 1]. The distribution of sex was approximately equal, with 283 female patients (52.5%). The mean age was 39.9 ± 16.9 years (range: 1.7-95.2 years). The majority of patients (393, 72.9%) were receiving more than two ASMs at the time of TDM. Most patients (429, 79.6%) underwent TDM only once, while the remaining patients were sampled on multiple occasions as deemed clinically necessary. This resulted in a total of 682 visits being included for analysis. In total, 1051 plasma samples were assayed, with the most commonly analyzed ASMs being LEV (379 samples, 36.1%), followed by OXC (193 samples, 18.4%), and LTG (126 samples, 12.0%) [Fig. 1A].Table 1 Clinical characteristics of patients received therapeutic drug monitoring for newer anti-seizure medications.

Table 1	Total n = 539 (%)	
Gender, female	283 (52.5)	
Age, y, mean ± SD	39.9 ± 16.9	
Body weight, kg, mean ± SD	63.5 ± 14.7	
Seizure onset age, y, mean ± SD	25.6 ± 19.5	
Seizure type		
Focal motor seizure with aware	34 (6.3)	
Focal motor seizure with impaired awareness	12 (2.2)	
Focal motor seizures with aware to bilateral tonic-clonic	28 (5.2)	
Focal motor seizures with impaired awareness to bilateral tonic-clonic	32 (5.9)	
Focal non-motor seizures with aware	3 (0.6)	
Focal non-motor seizure with impaired awareness	58 (10.8)	
Focal non-motor seizures with aware to bilateral tonic-clonic	11 (2.0)	
Focal non-motor seizures with impaired awareness to bilateral tonic-clonic	239 (44.3)	
Generalized motor	117 (21.7)	
Generalized absence	3 (0.6)	
Unknown onset	2 (0.4)	
Number of current ASMs	2 (1-7)	
Monotherapy	146 (27.1)	
Polytherapy	393 (72.9)	
Abbreviations: ASM: antiseizure medications; SD: standard deviation.

Fig. 1 (A) Distribution of anti-seizure medications plasma samples; (B) Reasons for requesting therapeutic drug monitoring for antiseizure medications. Abbreviations:ASM: antiseizure medication; TDM: therapeutic drug monitoring; GBP: gabapentin; LCM: lacosamide; LTG: lamotrigine; LEV: levetiracetam; OXC MHD: oxcarbazepine monohydroxy derivative; PER: perampanel; PGB: pregabalin; TPM: topiramate; ZNS: zonisamide.

Fig. 1

3.2 Reasons for requesting TDM of newer ASMs

Among the 682 visits, the majority of TDM assays (377, 55.3%) were performed due to poorly controlled seizures, followed by concerns about potential drug-drug interactions (84, 12.3%), and suspicion of drug overdose (72, 10.6%) [Fig. 1B].

3.3 ASM dosages and distribution of TDM range

When evaluating the ASM plasma levels in relation to their therapeutic reference range as mentioned above [9,10], a significant percentage (68.8%) of the samples fell within the orienting therapeutic range (Fig. 2), even among those with poorly controlled seizures [Fig. 3]. In contrast, 26.9% were below the orienting therapeutic range, while 4.3% above it. It is worth noting that among the TDM assays carried out to investigate non-adherence concerns, 54.3% of the measured levels were below the orienting therapeutic range. However, in cases where TDM was conducted to assess potential ASM-related adverse events, only 8.9% exhibited drug overdose with TDM results exceeding the therapeutic dose.Fig. 2 Plasma concentrations of newer antiseizure medications. (A) The overall plasma concentration of the nine newer ASMs; (B) plasma concentration distribution of different ASMs. The plasma levels of these ASMs were interpreted as within, below, and above the orienting therapeutic range recommended by the ILAE [9], and the TDM Task Force of the Association of Neuropsychopharmacology and Pharmacopsychiatry (AGNP) [10]. Abbreviations:ASM: antiseizure medication; GBP: gabapentin; LCM: lacosamide; LTG: lamotrigine; LEV: levetiracetam; OXC MHD: oxcarbazepine monohydroxy derivative; PER: perampanel; PGB: pregabalin; TPM: topiramate; ZNS: zonisamide.

Fig. 2

Fig. 3 Distribution of drug levels among 1051 assays across different indications. Abbreviations: ASM: antiseizure medication; GBP: gabapentin; LCM: lacosamide; LTG: lamotrigine; LEV: levetiracetam; OXC MHD: oxcarbazepine monohydroxy derivative; PER: perampanel; PGB: pregabalin; TPM: topiramate; ZNS: zonisamide.

Fig. 3

The concentrations measured in patients receiving monotherapy or polytherapy are presented in [Table 2]. Patients treated with LEV, LTG, and OXC as part of polytherapy exhibited significantly higher drug dosage and concentration levels compared to those on monotherapy (p < 0.05). No significant differences in plasma concentrations were observed for the remaining ASMs, regardless of whether they were used in monotherapy or combination therapy.Table 2 Anti-seizure medications doses and plasma concentration in patients received monotherapy and polytherapy.

Table 2	Monotherapy	Polytherapy	P-value	Orienting therapeutic range	
GBP	
Number of Patient	0	4			
Age		40.9 ± 2.1			
Daily Dose (mg/day), mean ± SD		575 ± 685			
Plasma level, μg/mL, mean ± SD		3.2 ± 2.9		2-20a	
LCM	
Number of Patient	5	108			
Age	27.3 ± 13.1	36.3 ± 16.4	0.200		
Daily Dose (mg/day), mean ± SD	250 ± 100	275 ± 119.5	0.614		
Plasma level, μg/mL, mean ± SD	6.5 ± 3.5	5.9 ± 3.2	0.722	1-10b	
LEV	
Number of patients	85	294			
Age	41.1 ± 25.2	26.5 ± 20.7	0.000∗		
Daily dose, mg/day, mean ± SD	1450.0 ± 629.2	1825.6 ± 798.9	0.000∗		
Plasma level, μg/mL, mean ± SD	17.8 ± 13.0	21.2 ± 14.6	0.047∗	12-46a	
LTG	
Number of patients	34	92			
Age	34.5 ± 10.6	34.7 ± 11.6	0.942		
Daily dose, mg/day, mean ± SD	194.1 ± 101.3	250.4 ± 142.6	0.015∗		
Plasma level, μg/mL, mean ± SD	3.9 ± 1.9	7.2 ± 4.7	0.000∗	2.5-15a	
OXC	
Number of patients	29	164			
Age	35.5 ± 12.0	37.1 ± 14.3	0.517		
Daily dose, mg/day, mean ± SD	817.2 ± 449.3	1169.0 ± 531.7	0.000∗		
Plasma level, μg/mL, mean ± SD	14.3 ± 7.4	18.5 ± 8.0	0.007∗	3-35a	
PER	
Number of patients	2	58			
Age	52.7 ± 9.7	39.5 ± 15.9	0.286		
Daily dose, mg/day, mean ± SD	7.0 ± 7.1	5.9 ± 2.8	0.866		
Plasma level, ng/mL, mean ± SD	363.5 ± 359.8	173.4 ± 102.0	0.591	180-980a	
PGB	
Number of patients	1	18			
Age	51.1	35.7 ± 12.5			
Daily dose, mg/day, mean ± SD	450	316.7 ± 153.4			
Plasma level, μg/mL, mean ± SD	7.8	3.2 ± 1.9		2-8a	
TPM	
Number of patients	7	76			
Age	62.8 ± 12.7	69.7 ± 12.7	0.222		
Daily dose, mg/day, mean ± SD	192.9 ± 105.8	264.8 ± 105.	0.133		
Plasma level, mean ± SD	6.8 ± 3.8	5.8 ± 3.8	0.503	5-20a	
ZNS	
Number of patients	6	68			
Age	35.3 ± 18.2	40.8 ± 14.4	0.493		
Daily dose, mg/day, mean ± SD	216.7 ± 75.3	260.3 ± 102.4	0.231		
Plasma level, μg/mL, mean ± SD	15.1 ± 5.6	15.6 ± 8.8	0.836	10-40a	
Student's t-test, ∗p < 0.05.

Abbreviations: GBP: gabapentin; LCM" lacosamide; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine;PER: perampanel; PGB: pregabalin; TPM: topiramate; ZNS: zonisamide; SD: standard deviation.

a These specific orienting therapeutic ranges were in accordance with the recommendation provided by the International League Against Epilepsy (ILAE) [9].

b The recommended orientating therapeutic range for lacosamide was determined based on the advisory from the TDM Task Force of the Association of Neuropsychopharmacology and Pharmacopsychiatry (AGNP) [10].

3.4 Action after TDM

Out of the 682 visits, medication adjustments were made in 64.2% (n = 438) of the cases after obtaining the results of TDM in the subsequent outpatient clinic visit. Among these adjustments, the most common action was an increase in the dosage of ASM, which occurred in 208 visits (30.5%). However, in 33.0% of visits, no changes were made to the ASMs, including 11 visits (1.6%) fell into the “others” category, which involved adjustments of non-ASM co-medications, lifestyle modifications, surgical interventions, or ketogenic diet treatments [Fig. 4A].Fig. 4 Management after therapeutic drug monitoring of the newer antiseizure medications. (A) overall management; (B) management across different plasma level range. Abbreviations:ASM: antiseizure medication; TDM: therapeutic drug monitoring; GBP: gabapentin; LCM: lacosamide; LTG: lamotrigine; LEV: levetiracetam; OXC MHD: oxcarbazepine monohydroxy derivative; PER: perampanel; PGB: pregabalin; TPM: topiramate; ZNS: zonisamide.

Fig. 4

When the TDM results indicated subtherapeutic levels of ASMs, 37.5% had their ASM dosage increased, while 25.1% of them did not have any changes in their ASM dosage. Conversely, among those with TDM results within the therapeutic range, a larger proportion (32.2%) did not undergo any treatment modifications, while 29.7% of them still had their dosage increased. However, in cases where the TDM results indicated levels higher than the therapeutic range, the majority (53.3%) had their ASM dosage decreased, either for the target ASM or co-ASM [Fig. 4B].

3.5 Impact of TDM on seizure outcome

Overall, 381 visits (55.9%) in which newer ASMs blood level were determined showed improved outcomes. This included a decrease in the occurrence of seizures in 47.5% of visits and a reduction in ASM-related side effects in 8.4% of visits [Fig. 5]. On the other hand, 22.9% of the visits involved testing patients who were already seizure-free at baseline. These visits were conducted to establish baseline information, address concerns about drug-drug interactions, assess renal/hepatic impairment, manage pregnancy-related considerations, or address the specific needs of elderly patients. A small proportion of seven individuals (1.0%) underwent TDM due to suspected drug toxicity and adverse effects resulting from medication other than ASM; these particular patients were categorized under the “others” outcome groups.Fig. 5 Clinical implications of therapeutic drug monitoring for newer antiseizure medications. Abbreviations: ASM: antiseizure medication; TDM: therapeutic drug monitoring; GBP: gabapentin; LCM: lacosamide; LTG: lamotrigine; LEV: levetiracetam; OXC MHD: oxcarbazepine monohydroxy derivative; PER: perampanel; PGB: pregabalin; TPM: topiramate;ZNS: zonisamide.

Fig. 5

4 Discussion

TDM of the older generation ASMs has been routinely performed for decades, especially because of the complicated pharmacokinetics, high potential for drug-drug interactions, and narrow therapeutic indices of this class of medications. In contrast, the newer ASMs generally have wider therapeutic ranges, more predictable pharmacokinetics, and lower frequency of adverse effects. Thus, for newer ASMs, the role of TDM is assumed to be limited. In this retrospective study, we describe the utilization of TDM for newer ASM in a single epilepsy center. Our result demonstrated that after TDM with a clear indication, the majority of the patients had better seizure outcomes, including a decrease in seizure occurrence and side effects, indicating that newer ASM blood level monitoring remains a useful adjunct to complement clinical decision making in the management of patients with epilepsy.

Theoretically, TDM can be utilized to assess and adjust for pharmacokinetic variability and interactions, thus facilitating optimal dosing for individual patients with epilepsy. However, it is important to acknowledge that in clinical practice, there are some clinicians who use TDM as a routine without critical evaluation to resolve specific clinical problems [7,13]. This uncritical approach of TDM can be problematic as it may result in unnecessary therapeutic interventions and, in some cases, even lead to adverse treatment outcomes [9,14]. A Cochrane review found no conclusive evidence supporting the routine use of TDM for ASMs [15], and there is strong level A evidence suggesting that TDM for newer ASMs does not provide benefits for managing epilepsy patients in general [6]. Therefore, it is crucial to understand how to appropriately use TDM in relevant clinical scenarios. Nonetheless, there is limited robust evidence demonstrating its effectiveness in improving clinical outcomes. In our current study, TDM was predominantly ordered based on clear clinical indications, and adhering to this rational utilization approach led to improved outcomes in most patients. Our findings support the use of TDM in epilepsy patients, provided that it is employed in appropriate situations, accompanied by practical guidelines for its application within a clinical setting.

There has been a noticeable increase in the use of TDM for newer ASMs [16]. Several factors likely contribute to the growing demand for TDM of these newer ASMs. Prescription of these newer ASMs has been steadily increasing, with newer ASMs most compared with the older ASM in Taiwan [17]. Real-life studies that explore the clinical effectiveness and tolerability of ASMs in relation to blood concentrations have played a crucial role in enhancing TDM services for newer ASMs [[18], [19], [20], [21]]. In our study, most of the patients underwent TDM for newer ASMs due to poorly controlled seizures, and a significant number of these patients experienced improvements in seizure reduction or became seizure-free after TDM. Nevertheless, although it is important to highlight that the necessity for TDM is more pronounced in patients with drug-resistant epilepsy compared to those with new-onset seizures, there is a lack of high-level evidence supporting it use. Thus, investigating the impact of TDM on seizure control through randomized controlled trials is warranted, but it is not easily feasible. Blinding blood concentrations in patients is challenging, and it would be unethical to randomize vulnerable patients and exclude necessary measurements. Retrospective, uncontrolled studies may be a valuable supplement to prospective studies by the possibility of identifying rare adverse effects in subgroups of patients as they represent a real-life setting. Thus, adding to this body of real-world data, here we report the analysis of registry data of clinical outcomes after taking TDM as part of the comprehensive follow-up in patients with epilepsy.

The concern of potential drug overdose is another common indication for TDM for newer ASMs, since the increased therapeutic use of these drugs has also raised the possibility of accidental or intentional overdoses [[22], [23], [24]]. Various situations, such as acute medication overdose, drug-drug interactions, pharmacogenetic variation, or organ failure, can result in high blood concentrations of these newer ASMs, leading to symptoms that may be challenging to differentiate from the worsening of the underlying epilepsy syndrome [9,12]. In such cases, the availability of rapid drug-level testing can assist in making clinical decisions. This might explain why many laboratories continue to test for older ASMs, even if their use is declining; their potential toxicity profile might warrant on-site testing despite low volumes [16]. This practice is also applicable to newer ASMs. In the current study, TDM was conducted on 112 samples (10.6%) due to suspected drug overdose based on clinical judgment. However, only 8.9% surpassing the therapeutic dose, while 20.5% of them fell below the orienting therapeutic range. Following TDM, not only were target ASMs decreased, but a number of patients had their co-ASM adjusted or their dosing schedule modified.

In addition to inadequate seizure control and potential drug toxicity, TDM also plays a crucial role in various clinical scenarios, including pregnancy, breakthrough seizures with suspected non-adherence, and suspected treatment interactions. These indications have been effectively summarized by recommendations from the ILAE recommendations [9,12]. Our findings indicate that TDM can also contribute to the rational management of treatment in these patients. Among the patients included in our study, 4.3% were suspected to have poor drug compliance, in which a majority (53.3%) exhibited low therapeutic ASM levels, and the remaining 46.7% had levels within the orienting therapeutic range. After education intervention aimed at improving drug adherence, we observed a seizure reduction in 73.3% of patients, with 46.7% achieving seizure freedom (Data not shown). Hence, the measurements of ASM blood level provide a valuable tool for both enhancing patient monitoring and effectively managing compliance in individuals who may otherwise be considered “drug-resistant” due to poor response to treatment [23]. This approach allows patients with borderline or low ASM blood levels to increase their levels without altering the dosage through the implementation of intensified compliance measures and supervision [25].

The therapeutic reference range is defined as a range of drug concentrations that specifies a lower limit below which a therapeutic response is less likely to occur and an upper limit above which toxicity becomes more probable [9,10]. Due to substantial interindividual variations in epilepsy type and seizure severity, the effective concentration of ASMs can vary significantly among patients. As a result, some patients may experience therapeutic benefits at plasma concentrations outside of these specified therapeutic reference ranges. It is not uncommon for certain patients to achieve optimal seizure control with plasma concentrations below the lower limit of the therapeutic reference range, while others may require (and tolerate) concentrations above the upper limit. Consequently, the therapeutic reference range is an orienting, population-based range, which may not universally apply to all patients. Given that routine TDM for newer ASMs is not standard practice, a universally accepted orienting therapeutic range has yet to be established. The recommendations from the ILAE and the AGNP suggest orienting therapeutic ranges for these ASM plasma concentrations, with slight variations between them [9,10]. Notably, the drug levels assessed in this study largely fell within the proposed orienting therapeutic ranges established by the ILAE [9], except for LCM. In 2018, the ILAE updated the orienting therapeutic range for LCM from 1 to 10 μg/mL to 10 to 20 μg/mL [9]. Previously, the LCM range was defined based on trough-level measurements, but the revised ranges are derived from peak-level measurements. However, recent research has demonstrated that the 10 to 20 μg/mL therapeutic range notably increases toxicity in patients treated with LCM [11]. Thus, it is recommended to adjust the upper limit of the therapeutic range to 12 μg/mL with the implementation of a routine therapeutic drug monitoring program in order to attain a reasonable likelihood of efficacy while reducing the risk of toxicity. Hence, in the case of LCM, we refer to the advisory on the orienting therapeutic range of 1-10 μg/mL provided by the Task Force on TDM within the AGNP [10], an approach also employed in a recent randomized and controlled trial comparing systematic and rescue TDM of newer ASMs [6]. Table 3 provides a concise summary of the orienting therapeutic range for the studied newer ASMs as recommended by the ILAE and AGNP. It is of paramount importance to establish a globally recognized orienting therapeutic range for these newer ASMs.Table 3 Antiseizure medications and orienting therapeutic ranges recommended by International League Against Epilepsy and Therapeutic Drug Monitoring Task Force of the Association of Neuropsychopharmacology and Pharmacopsychiatry.

Table 3ASMs	Current study	ILAE 2018 [9]	AGNP 2018 [10]	
Gabapentin, μg/mL	2-20	2-20	2-20	
Lacosamide, μg/mL	1-10	10-20	1-10	
Lamotrigine, μg/mL	2.5-15	2.5-15	3-15	
Levetiracetam, μg/mL	12-46	12-46	10-40	
Oxcarbazepine, μg/mL	3-35	3-35	10-35	
Perampanel, ng/mL	180-980	180-980	180-980	
Pregabalin, μg/mL	2-8	2-8	2-5	
Topiramate, μg/mL	5-20	5-20	2-10	
Zonisamide, μg/mL	10-40	10-40	10-40	
Abbreviations: ASM, antiseizure medications; ILAE: International League Against Epilepsy; AGNP: Association of Neuropsychopharmacology and Pharmacopsychiatry.

Our findings indicate that the majority of the tested ASMs, including those used in patients with uncontrolled seizures, fell within the orienting therapeutic range. It is interesting to note that among the patients with uncontrolled seizures, only 152 (25.6%) had drug levels below the orienting therapeutic range, while 19 (3.2%) had levels above it. Despite being ongoing seizures, 13.1% in the poorly controlled seizure group kept their medication without changing the regimen; this might be due to the fact they appeared to derive some benefits in terms of tolerability, even though they were not completely seizure-free. We cannot definitively rule out the possibility that some patients with ongoing seizures could achieve seizure freedom with further up-titration of their treatment. However, it seemed that the treating physicians do not consider further titration to result in a meaningful improvement.

TDM were conducted on220 samples from patients who were initially seizure-free. Among these, 25% had drug levels below the orienting therapeutic range, while 70% fell within the range. Interestingly, a previous prospective study found a consistent association between plasma levels of newer ASMs and seizure freedom. In that study, nearly all patients who achieved long-term seizure freedom had blood levels in the lower half or even below the orienting therapeutic ranges [26], these results likely reflect the titration process carried out in both drug-responsive and drug-resistant patients. While patients with drug-responsive epilepsy can often achieve control at lower dosages, those with drug-resistant epilepsy may require further titration in an attempt to achieve at least a partial response.

Whether plasma drug levels are a better surrogate of treatment exposure compared with mere daily dosage (in mg/kg) constitutes the key argument for justifying TDM [26]. As mentioned earlier, the newer ASMs are generally considered to have wider therapeutic ranges, more predictable pharmacokinetics, and lower frequency of adverse effects [16]. Thus, the role of TDM is presumed to be limited for newer ASMs compared to older ASMs. It may be argued that regulatory agencies do not consider blood levels in deciding the efficacy of newer ASMs [27]. That is generally true, but it has more to do with the practicalities of running a clinical trial than with any scientific reason. Drugs which do not show a good step-wise relationship between dose and efficacy are unlikely to be approved. It would make more sense to assess the blood (or brain/cerebrospinal fluid) level-efficacy relationship. However, clinical trials provide important data for regulatory approval but do not provide all the information required for doctors to know how well the drug will work in clinical practice [28,29]. Thus, real-world experience provides clinical data that complement investigational data, providing valuable insight into epilepsy treatment in different patient populations and informing the use of newer ASMs. In any case, the drug blood level is the best pharmacokinetic marker to assess the patient's exposure to treatment, also integrating other aspects such as compliance, physiological changes, and potential drug-drug interactions [30].

The findings of this study should be interpreted within certain limitations. These include the observational study design and lack of randomized assignment. Although we did find improved outcomes after TDM for newer ASMs, the management is based on a combination of clinical response and TDM levels; thus, our observation can only implicate that the clinical utility of TDM for newer ASM could possibly facilitate ASM therapy. In this study, we only look at the utilization of TDM for newer ASMs in outpatient clinic settings; however, in hospital setting, there may be a desire to have a more comprehensive TDM for newer ASMs, in order to assess whether concentrations are adequate or possibly toxic when ASMs are administered in urgent cases. In addition, the studied ASM was heterogeneous, considering all newer generation ASMs together may also represent an oversimplification. Lastly, it is important to acknowledge that most of our patients only underwent a single TDM assessment, and we did not continue to monitor their drug levels following the management based on TDM results. Previous research has suggested that a single drug level measurement is insufficient unless compared with previous measurements from the same patient [24]. Therefore, there is a need for further studies focusing on specific patient populations and establishing homogeneous indications for TDM, with subsequent follow-up assessments after implementing management strategies. These efforts would contribute to a higher level of evidence and a better understanding of the benefits of TDM, leading to improve patient treatment and enhanced patient safety.

5 Conclusions

In our study, most of the patients with newer ASM blood level determination have a better outcome, both including seizure reduction and a decrease in side effects; the data indicated that the appropriate and rational utility of TDM for the newer generation ASMs has clinical benefits.

Funding

This work was supported in part by grants from the 10.13039/100012553 Chang Gung Memorial Hospital , Taiwan (Grant numbers CMRPG3M1401 and CMRPG3M1402 ) and the National Science and Technology Council, Taiwan (Grant numbers 110-2628-B-182A-012- , 111-2628-B-182A-017- and 112-2628-B-182A-005- ).

Availability of data and materials

The data used to support the findings of this study are included in the article.

Declaration of competing interest

The authors declare that they have no competing interests.

Acknowledgments

The authors wish to thank the patients and all members of the Epilepsy Section, Department of Neurology at Chang Gung Memorial Hospital, Linkou Medical Center.

Peer review under responsibility of Chang Gung University.
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