Serum perampanel levels in patients with seizures are not affected by hemodialysis

Abstract

Perampanel belongs to a novel class of antiseizure medications (ASMs). Studies examining the effect of hemodialysis on perampanel serum levels in clinical settings are lacking. We aimed to evaluate the changes in serum perampanel levels during hemodialysis. We studied patients with seizures who received oral perampanel between April 2020 and March 2023 and whose serum concentration of perampanel was measured before and after hemodialysis. We analyzed the serum concentrations of levetiracetam and lacosamide for comparison. Fourteen patients, with a mean age of 76.1 ± 7.88 years, were included. The dose of perampanel was 2.14 ± 1.27 mg. The hemodialysis clearance rate of perampanel, levetiracetam, and lacosamide was 0 ± 13%, 69 ± 11%, and 59.6 ± 8.2%, respectively. The post-dialysis CD ratio decreased significantly with levetiracetam but not with perampanel. Adverse but acceptable effects of perampanel were observed in two patients. The serum concentrations of several ASMs have been shown to be reduced during hemodialysis. Our study revealed that the serum perampanel concentration does not decrease during hemodialysis. Owing to the low rate of adverse effects and the stability of perampanel serum concentration during hemodialysis, perampanel could be a favorable choice as an ASM for patients with seizures undergoing hemodialysis.

Plain Language summary

Our study looked at how hemodialysis affects the serum levels of perampanel, a new type of medication for seizures. In 14 patients who started treatment between April 2020 and March 2023, perampanel serum levels did not decrease during hemodialysis, unlike other seizure medications. This shows that perampanel can be a good option for patients with seizures who need hemodialysis, with fewer side effects compared to other medications.

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Key points

• The pre- and post-dialysis serum concentration of perampanel was measured in 14 patients with seizure episodes.
• Serum perampanel levels remain stable during hemodialysis, contrasting with other seizure medications.
• This stability suggests perampanel as a favorable option for seizure patients undergoing hemodialysis.

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INTRODUCTION

The prevalence of epilepsy is increasing among older adults,¹ who also have a higher frequency of comorbidities, particularly renal dysfunction.² The prevalence of epilepsy is notably high among patients with end-stage renal disease, with a concomitantly elevated mortality rate.³ Hence, the appropriate use of antiseizure medications (ASMs) is crucial for patients with epilepsy and renal dysfunction. Novel ASMs with minimal drug interactions and adverse effects are frequently employed.⁴ However, the efficacy of these novel ASMs in patients undergoing dialysis remains unclear.

Perampanel is a novel, unique antiepileptic agent that selectively and non-competitively inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, thereby suppressing neuronal hyperexcitability.⁵ Perampanel possesses characteristics that make it less prone to clearance by hemodialysis, suggesting its potential effectiveness in patients susceptible to seizure induction owing to decreased serum concentrations following hemodialysis. However, data regarding the pre- and post-dialysis changes in perampanel serum levels in clinical settings are lacking. Therefore, this study aimed to analyze the dynamics of perampanel serum concentrations in patients undergoing hemodialysis by extracting cases of perampanel use.

MATERIALS AND METHODS Study design

We retrospectively extracted data from patients on hemodialysis treatment admitted to our stroke center between April 2020 and March 2023. Patients with cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, subdural/epidural hematoma, head trauma, or brain tumors were included in the study. We included cases in which seizure episodes occurred during hospitalization, leading to the initiation of novel ASMs, including perampanel, levetiracetam, lamotrigine, and lacosamide. Seizure diagnoses were made by the attending neurologist or neurosurgeon who decided to initiate ASM treatment. The ASM types and combinations were selected according to the severity of the seizures. This study was approved by the Ethics Committee of Kokura Memorial Hospital (approval number: 24011701). Informed consent was obtained through an opt-out process.

Data collection

From the patient records, we collected the clinical characteristics and serum concentrations of ASMs pre- and post-dialysis after at least 1 week of ASM administration. We excluded patients with insufficient data; peritoneal dialysis; severe hepatic dysfunction; CYP3A inducer or inhibitor use, which interacts with perampanel; and those who initiated ASMs within 1 week or who refused to be included in this study.

Outcomes

During this period, 432 patients undergoing dialysis were admitted to our stroke center. Among them, 72 patients who experienced seizures were screened. Forty-two of the 72 patients who were initiated on a novel ASM were included in the study. Twenty-eight patients were excluded from the dialysis based on the exclusion criteria, leaving a final sample size of 14 patients (Figure 1). During dialysis sessions, blood samples were collected from the shunt cannulas to determine ASM serum concentrations. We compared the pre- and post-dialysis serum concentrations of perampanel and other novel ASMs in the 14 patients, with 28 samples for perampanel, 12 samples for levetiracetam, four samples for lacosamide, and zero samples for lamotrigine. Dialysis clearance rates were then calculated for each ASM. In hemodialysis, the clearance rate refers to the percentage of substances removed from the blood during a dialysis session.⁶ This was calculated by dividing the difference between the pre- and post-dialysis blood concentrations by the pre-dialysis blood concentration. To compare the weight-adjusted ASM dosing, we calculated the concentration-to-dose (CD) ratio.⁷ The CD ratio represents the ratio of the serum concentration to the weight-adjusted dose. We determined the concentration reference range of the ASMs as follows: perampanel, 86–1000 ng/mL⁸; levetiracetam, 12–46 μg/mL⁹; lacosamide, 2.2–20 μg/mL.¹⁰ The adverse effects of ASMs during hospitalization were also evaluated. The symptoms according to the Liverpool Adverse Event Profile (LAEP)¹¹ and the biochemical abnormalities associated with ASMs were collected from clinical records.

FIGURE 1. Flow chart of the selection process for the enrolment of patients in the study. A total of 432 patients undergoing dialysis were newly admitted to our stroke center. Of these, 72 experienced seizures. Novel ASMs (perampanel, levetiracetam, lacosamide, and lamotrigine) were initiated in 42 of 72 patients. Subsequently, 28 patients were excluded from the dialysis based on the exclusion criteria, leaving a final sample size of 14 patients. ASM, antiseizure medication.

Statistical analysis

All data are presented as the mean ± standard deviation. Statistical significance based on the CD ratio of ASMs was determined using the one-sample Student's t-test with pre- and post-dialysis values. All reported p-values are two-tailed, and statistical significance was set at p < 0.05. All statistical analyses were conducted using JMP Pro 12 (SAS Institute, Cary, NC, USA). Graphical images were constructed using PRISM 9 (GraphPad Software, San Diego, CA, USA).

RESULTS Patient characteristics

The characteristics of the 14 patients are shown in Table 1. The mean age was 76.1 ± 7.88 years, with seven males and seven females. Five patients had arterial fibrillation, and four of them were taking warfarin. Diabetes and hypertension were the most frequent etiologies for hemodialysis. The mean age at the initiation of HD was 66 ± 18.46 years. All patients underwent hemodialysis three times weekly for approximately 3–4 h per session. Perampanel was initiated in 14 patients, levetiracetam in six, and lacosamide in two. Lamotrigine was not initiated in any case. The primary causes of seizures were cerebral infarction in five cases, acute subdural hematoma in five cases, intracerebral hemorrhage in three cases, and subarachnoid hemorrhage in one case. The mean dose of perampanel was 2.14 ± 1.27 mg.

TABLE 1 Clinical characteristics of patients and the serum concentrations of ASMs.

Patient	Age/sex	BW (kg)	Comorbidity and medication	Etiology of HD	Age at initiation of HD	Seizure etiology	ASM dose	Dialysis clearance rate of PER	Dialysis clearance rate of LEV	Dialysis clearance rate of LCM
#1	72 F	48.3	Hypothyroidism Thyroxine	DM	69	CI	PER 2 mg LEV 500 mg	20.30%	76.00%	n.e.
#2	73 F	44.7	n.p.	DM	64	ASDH	PER 6 mg LEV 1000 mg	−15.80%	66.50%	n.e.
#3	73 F	55.8	n.p.	DM	66	ASDH	PER 2 mg LEV 500 mg	−1.30%	68.10%	n.e.
#4	81 M	53.5	AF Warfarin	HT	81	CI	PER 2 mg LEV 500 mg	7.40%	62.60%	n.e.
#5	70 F	51.3	AF Warfarin	HT	68	ICH	PER 2 mg LEV 500 mg	−3.20%	86.70%	n.e.
#6	73 F	37.9	n.p.	HT	65	ICH	PER 2 mg	15.70%	n.e.	n.e.
#7	88 M	45.3	n.p.	DM	87	ASDH	PER 2 mg	8.30%	n.e.	n.e.
#8	64 F	39.7	SLE Prednisolone	SLE	15	CI	PER 1 mg	1.70%	n.e.	n.e.
#9	90 F	39.6	AS	HT	75	CI	PER 2 mg	−1.80%	n.e.	n.e.
#10	83 M	53.5	MR, AF Warfarin	HT	78	ASDH	PER 2 mg LEV 1000 mg	−4.70%	56.10%	n.e.
#11	82 M	53	AF Aspirin	DM	81	CI	PER 2 mg	−24.10%	n.e.	n.e.
#12	72 M	54.4	MR, AF Warfarin	HT	60	SAH	PER 4 mg	10.30%	n.e.	n.e.
#13	79 M	50	HBV, HCV	DM	79	ASDH	PER 2 mg LCM 100 mg	−6.90%	n.e.	53.80%
#14	65 M	64	ICH	ADPKD	46	ICH	PER 2 mg LCM 100 mg	−12.20%	n.e.	65.40%

Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; AF, atrial fibrillation; AS, aortic stenosis; ASDH, acute subdural hematoma; ASM, antiseizure medication; BW, body weight; CI, cerebral infarction; DM, diabetes mellitus; HBV, hepatitis B virus; HCV, hepatitis C virus; HD, hemodialysis; HT, hypertension; ICH, intracranial hemorrhage; LCM, lacosamide; LEV, levetiracetam; MR, mitral regurgitation; n.e., not examined; n.p., not particular; PER, perampanel; SAH, subarachnoid hemorrhage; SLE, systemic lupus erythematosus.

ASM serum concentration during hemodialysis

In all patients, the serum concentrations of each ASM were measured before and after dialysis. The dialysis clearance rate of perampanel was 0 ± 13%, whereas that of levetiracetam was 69 ± 11% (Figure 2A). There was no significant change in the CD ratio of perampanel pre- and post-dialysis [pre-hemodialysis CD ratio vs. post-hemodialysis CD ratio: 5.74 ± 2.77 vs. 5.66 ± 2.60 (μg/mL)/(mg/kg), p = 0.96], but a significant CD ratio decrease was observed in the levetiracetam group [pre-hemodialysis CD ratio vs. post-hemodialysis CD ratio: 3.19 ± 0.69 vs. 0.99 ± 0.41 (μg/mL)/(mg/kg), p = 0.016, Figure 2B]. The dialysis clearance rate of lacosamide was 59.6 ± 8.2%, and a CD ratio decrease was observed between pre- and post-hemodialysis. Among these 14 patients, there were no cases of seizure recurrence during hospitalization.

FIGURE 2. Dialysis clearance rate and CDr of perampanel and levetiracetam. (A) The dialysis clearance rate of perampanel was 0 ± 13%, whereas that of levetiracetam was 69 ± 11%. (B) The CDr of perampanel shows no significant differences between pre- and post-hemodialysis (B1). The CDr of levetiracetam shows a significant decrease post-hemodialysis (B2). CDr, concentration-to-dose ratio.

Analysis of adverse effects

Two patients experienced mild hepatic dysfunction as an adverse effect of perampanel during treatment; both improved after dose reduction.

DISCUSSION

Perampanel is less prone to clearance by hemodialysis than other ASMs, suggesting its potential effectiveness in patients susceptible to seizure induction owing to decreased serum concentrations following hemodialysis. However, clinical data examining pre- and post-dialysis serum concentrations of peranpanel are lacking. Here, we examined changes in the serum concentrations of novel ASMs during hemodialysis. Notably, we found that the serum perampanel concentration was maintained during hemodialysis. To the best of our knowledge, this is the first study to verify the hemodialysis clearance rate of perampanel in real-world practice.

Therapeutic drug monitoring (TDM) of ASMs is important in patients with epilepsy undergoing hemodialysis.⁹ Previous studies have found that levetiracetam, a frequently prescribed novel ASM, has the highest clearance rate (65%)¹² among the ASMs administered during dialysis. As levetiracetam is a low-protein-bound ASM, renal excretion eliminates most of the unbound levetiracetam. High renal excretion is associated with a high dialysis clearance rate.¹³ Additionally, the serum concentrations of other novel ASMs, such as lacosamide and lamotrigine, decrease following hemodialysis.¹⁴ The dialysis clearance rate of lacosamide is approximately 50%, whereas that of lamotrigine is approximately 30%.¹⁵ On the contrary, valproic acid,¹² phenytoin,¹⁶ and carbamazepine,¹⁴ known as classical ASMs, are characterized by their high plasma-protein binding capability. Highly protein-bound ASMs are generally eliminated via hepatic metabolism and are removed to a lesser degree by dialysis.⁹ However, Araki et al. reported that the CD ratios of valproic acid, phenytoin, and carbamazepine are significantly reduced by hemodialysis.⁶ These findings demonstrate the necessity of TDM to ensure appropriate dosing for patients undergoing hemodialysis and using ASMs. However, frequent measurements of serum concentrations before and after dialysis are burdensome in daily clinical practice. Therefore, drugs with fewer concentration changes due to hemodialysis may be more convenient for clinical practice.

The use of perampanel, a novel ASM frequently used to treat focal-onset seizures because of its minimal drug interactions, is particularly prevalent among older patients with comorbidities.¹⁷ However, to the best of our knowledge, the available literature lacks comprehensive data on the hemodialysis clearance rate of perampanel. In this study, the dialysis clearance rate of perampanel was almost 0%, indicating that hemodialysis had no influence on its serum concentration. In a phase III population pharmacokinetics analysis of perampanel, its clearance was lower in patients with renal impairment; however, the difference was not statistically significant.¹⁸ Generally, the clearance rate of ASMs during dialysis is affected by the molecular size, water solubility, protein binding, volume distribution, and dialysis conditions.¹⁹ Notably, perampanel has a relatively large molecular weight (349.39 g/mol)²⁰ compared with other ASMs investigated in this study (levetiracetam, 170.21 g/mol²¹; lacosamide, 250.29 g/mol²²; and lamotrigine, 256.09 g/mol²³). Furthermore, perampanel exhibits a high degree of protein binding (95%) to albumin and α1-acid glycoprotein, with extensive hepatic metabolism.²⁰ These unique characteristics of perampanel may contribute to its low dialysis clearance rate.

Previous case reports have shown the risk of temporary exacerbation of seizures during the clearance of ASMs by dialysis.²⁴ Levetiracetam is a renally metabolized ASM with low plasma-protein binding. There have been reports of seizure risk due to a temporary decrease in serum concentrations during hemodialysis.²⁵ From this perspective, perampanel, which shows stable serum concentrations owing to its minimal removal by dialysis, may prove to be a stable ASM for patients undergoing hemodialysis.

However, owing to its resistance to removal in patients with renal impairment undergoing hemodialysis, the serum concentration of perampanel may increase, potentially resulting in adverse effects. The CD ratio of perampanel has been reported to be markedly higher in patients with renal impairment,²⁶ suggesting a potential need for dose adjustment based on TDM in these patients. In this study, a few transient adverse effects were observed in the patients receiving perampanel, all of which were mild, and none of the patients discontinued perampanel. Previous reports have indicated an increased risk of adverse effects in older patients with perampanel doses exceeding 8 mg,²⁷ suggesting that the low dosage used in this study (2.14 mg) may have reduced the occurrence of adverse effects. Conversely, careful dose adjustments may lead to stable serum concentrations in patients with epilepsy undergoing hemodialysis. Additionally, clinical studies have demonstrated the efficacy of perampanel at low doses (<6 mg).^28,29 These data also support our results showing that low-dose perampanel is effective for seizure suppression in patients undergoing hemodialysis without any crucial adverse effects.

The limitations of this study include its small sample size, single-center design limited to Asian patients, short duration of perampanel administration, limited types of ASMs, and retrospective design. Further prospective studies with larger numbers of patients are needed.

CONCLUSIONS

Here, we studied the changes in the serum concentrations of perampanel and other ASMs during hemodialysis. The measurement of serum perampanel concentrations before and after dialysis in 14 patients revealed a dialysis clearance rate of approximately 0%, with no significant changes observed in the CD ratio before and after dialysis. Perampanel, a novel ASM characterized by high plasma protein binding, may maintain stable serum concentrations during dialysis, potentially offering efficacy for patients with epilepsy undergoing hemodialysis. To the best of our knowledge, this is the first clinical study to observe the evolution of perampanel blood levels in patients undergoing dialysis treatment. However, cautious TDM and dose adjustments are warranted to reduce the risk of elevated serum concentrations and avoid adverse effects.

AUTHOR CONTRIBUTIONS

Wataru Shiraishi: writing—review & editing, and supervision. Ayano Matsuyoshi: data curation. Yukiko Inamori: data curation. Koki Mitani: formal analysis. Narutada Ando: formal analysis. Koji Shiomi: writing—review & editing. Takao Morita: writing—review & editing. Noriyuki Koga: resources. Yuji Agawa: methodology. Takeshi Miyata: software and validation. Takenori Ogura: supervision. Taketo Hatano: supervision.

ACKNOWLEDGMENTS

We would like to thank Editage (www.editage.jp) for English language editing. This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

CONFLICT OF INTEREST STATEMENT

None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved with ethical publication and affirm that their report is consistent with those guidelines.