Intravenous perampanel as an alternative to the oral formulations in Japanese patients with epilepsy

Abstract

Objective

Perampanel is an oral anti-seizure medication, which is approved in Japan for focal-onset seizures, with/without focal to bilateral tonic–clonic seizures, as monotherapy/adjunctive therapy in patients aged 4 years and older. Treatment for generalized tonic–clonic seizures as adjunctive therapy in patients aged 12 years and older is approved as well. We evaluated the feasibility of intravenous (IV) administration of perampanel as an alternative to oral administration.

Methods

Study 240 (NCT03754582) was an uncontrolled, open-label study of IV perampanel, conducted in 21 Japanese patients with epilepsy who received a stable dose of 8–12 mg/day of oral perampanel. Patients received 30-minute IV infusions at equivalent daily doses of oral perampanel for 4 days, then were switched back to oral perampanel. Safety, tolerability, plasma concentration, and maintenance of efficacy throughout the transition between IV and oral dosing of perampanel were assessed. As supportive data, a subgroup analysis was also conducted using data from healthy Japanese subjects (n = 18) who were enrolled in Study 050 (NCT03376997) investigating the pharmacokinetics and safety of IV perampanel in healthy subjects who received an IV infusion (30-, 60-, or 90-minute) of perampanel 12 mg and a single oral administration of perampanel 12-mg tablet.

Results

In Study 240, the transition between 30-minute IV and oral perampanel dosing was associated with a ≤1.4-fold increase in the mean change in maximum observed concentration of perampanel. Seizure outcomes demonstrated no considerable changes in efficacy before, during, or after 30-minute IV dosing of perampanel. The safety profiles were similar between IV and oral formulations. In Study 050, the pharmacokinetics of 30- or 60-minute IV infusion of perampanel further support the interchangeability between oral and IV formulations in the Japanese subjects.

Significance

These results support that 30-minute IV perampanel may be a potential short-term alternative to oral formulations for patients with epilepsy.

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Key Points

• Intravenous (IV) anti-seizure medications are recommended to be used when oral dosing is not feasible in patients with epilepsy.
• The safety profiles were similar between 30-minute IV perampanel vs oral dosing, supporting the use of IV perampanel for short-term dosing.
• Thirty-minute IV perampanel could maintain seizure control after transition from oral tablets in patients with epilepsy.
• A 30-minute IV perampanel dosing is acceptable based on the pharmacokinetics and safety in healthy subjects and patients with epilepsy.
• IV perampanel may be a potential alternative to oral formulations for patients with epilepsy.

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INTRODUCTION

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, a key modulator of glutamate-mediated excitatory signaling in the central nervous system, plays a critical role in epileptic synchronization leading to epileptic seizures.^1–3 Perampanel, a selective, non-competitive AMPA receptor antagonist, is an oral anti-seizure medication (ASM) for focal-onset seizures (FOS) and generalized tonic–clonic seizures (GTCS).^1,2 Currently, for example, perampanel is approved in the United States and Japan for FOS, with or without focal to bilateral tonic–clonic seizures (FBTCS), as monotherapy and adjunctive therapy in patients aged 4 years and older, and as adjunctive therapy for GTCS in patients aged 12 years and older.^4,5

For patients with epilepsy, ASMs are critical to maintain seizure control and to lower the risks of injury or sudden unexpected death in epilepsy (SUDEP).^6–9 Patients with impaired consciousness due to illness, including status epilepticus, and patients who were in a fasting period following surgery may not be able to take oral formulations of ASMs. Uninterrupted treatment with ASMs is recommended in these scenarios to sustain seizure control without the risk of experiencing seizure rebound or status epilepticus.^10–16 Hence, we evaluated the safety and tolerability of intravenous (IV) infusion of perampanel (IV perampanel) as a short-term replacement treatment to oral dosing in Study 240 (NCT03754582), and a subgroup analysis of Study 050 (NCT03376997) was conducted as supportive evidence. Study 240 evaluated the safety, pharmacokinetics (PK), and maintenance of efficacy of 30-minute IV perampanel (8, 10, or 12 mg/day) as an alternative to oral perampanel in 21 Japanese patients with epilepsy who were receiving marketed perampanel oral tablets. Study 050 assessed the bioavailability of a single 12-mg dose of IV perampanel of different durations (30-, 60-, and 90-minute) relative to a single 12-mg dose of perampanel tablets in healthy subjects of mixed ethnicity,¹⁷ where we conducted a subgroup analysis in Japanese subjects. This analysis aimed to evaluate IV perampanel as an alternative to oral perampanel for treatment initiation and/or maintenance, based on data from Studies 240 and 050.

MATERIALS AND METHODS Standard protocol approvals, registrations, and patient consents

As Study 050 was completed earlier than Study 240, we describe these two studies in the order of Study 050 and Study 240 chronologically. Study 050 was conducted at a single site in the United States, and Study 240 was conducted at 12 sites in Japan. Studies 050 and 240 were conducted in accordance with the International Conference on Harmonization Good Clinical Practice (GCP) guidelines as required by the Principles of the World Medical Association Declaration of Helsinki (in both studies), the US Code of Federal Regulations Title 21 (in Study 050), Japan's GCP (J-GCP) guidelines (in Study 240), and other applicable regulatory authorities' requirements or directives. The study protocol, amendments, and informed consent in Studies 050 and 240 were approved by Institutional Review Boards for each site prior to the initiation of the study. All patients provided written informed consent before trial participation.

Study participants Study 050

Healthy adult subjects aged 20-55 years with a body mass index of 18-32 kg/m² were eligible to participate in this study. Briefly, key exclusion criteria included pregnancy, clinically significant illness requiring medical treatment within 8 weeks of dosing, clinically significant infection or disease that may influence the outcome of the study within 4 weeks of dosing, a history of gastrointestinal surgery that may affect PK profiles of perampanel, and any clinically abnormal symptom found at screening via medical history and physical examination.¹⁷

Study 240

Patients aged 12 years and older with FOS, with or without FBTCS, or GTCS as defined by the 2017 International League Against Epilepsy (ILAE) Classification of Epileptic Seizures were included. Eligible patients received a stable dose (8, 10, or 12 mg/day) of perampanel oral tablets as an adjunctive therapy with up to three marketed concomitant ASMs for at least 28 days before the first IV perampanel. Only one enzyme-inducing ASM (EIASM; such as carbamazepine, phenobarbital, and phenytoin) was allowed for concomitant use during the study. Key exclusion criteria included pregnancy, clinically problematic psychological or neurological disorder, clinically significant disease that may influence the outcome of the study, a history of status epilepticus within 6 months of treatment initiation, unsuitability for venipuncture and IV administration, and a history of multiple drug allergies or a severe drug reaction to an ASM.

Study design Study 050

The design of Study 050 has been previously described.¹⁷ Briefly, Study 050 comprised a Prerandomization/Pretreatment Phase (including a Screening and a Baseline Period) and a Randomization/Treatment Phase (including Treatment Periods 1 and 2). Healthy subjects were randomized to receive either a 30-, 60-, or 90-minute IV perampanel or an oral tablet on Day 1 of Treatment Period 1. Subjects were transitioned to the alternative treatment (IV or oral perampanel) on the first day of Treatment Period 2 (Day 43). A Washout Period of 6 weeks or more was introduced between the two treatment periods (Figure 1A).¹⁷

Study 240

As shown in Figure 1B, Study 240 consisted of the three following phases: a Pretreatment Phase (up to 29 days; oral perampanel), a Treatment Phase (4 days; IV perampanel), and a Follow-up Phase (up to 14 days; oral perampanel). Informed consent/assent was obtained before screening, and by Day −7 at the latest, after which protocol eligibility was established. Eligible patients were hospitalized on Day −1. Hospitalized patients were transitioned from perampanel tablets to IV perampanel at a dose equivalent to the oral dosing on Day 1. Patients received 30-minute infusions of IV perampanel once daily for 4 days during the Treatment Phase. Patients were transitioned back to oral perampanel at the equivalent daily dose of IV perampanel after completing the course of IV infusions. A follow-up visit occurred 7 days (allowance window: +7 days) after the last IV infusion.

Treatment

The IV formulation of perampanel, used in Study 050 and Study 240, was a lyophilized powder containing 8-mg perampanel (anhydrate) with 4000-mg solubilizing agent sodium sulphobutylether-beta-cyclodextrin (SBECD) in a vial. The lyophilized product was reconstituted with 14.0 mL of water or normal saline for injection and the reconstituted solution was further diluted in normal saline in a 100-mL infusion bag. The final solution for IV administration contains 4%-6% of SBECD for perampanel doses of 8 to 12 mg.

Study 050

Subjects received a single 12-mg dose of IV or oral perampanel after an overnight fast of at least 10 hours; no food was permitted for at least 4 hours post-dose. IV infusion durations were 30, 60, or 90 minutes. In each IV infusion arm, subjects were randomly and equally allocated to one of the two treatment sequences (ie, oral dosing followed by IV infusion or IV infusion followed by oral dosing). Each IV infusion arm was stratified by Japanese and non-Japanese subjects to ensure a balanced allocation.

Study 240

During the Pretreatment Phase, patients were maintained on oral perampanel at a stable dose of 8, 10, or 12 mg/day that were approved as maintenance dose in Japan in 2018. On Day 1, patients were transitioned from oral tablets to a 30-minute infusion of IV perampanel at the individual's equivalent daily doses during the Treatment Phase for four consecutive days. The IV infusion time on Days 1-4 was designed to align with the administration time of oral perampanel on Day −1, with an allowance window of ±1 hour. Patients were discharged the next day following the last IV perampanel after the treatment was transitioned back to oral tablets at the same daily dose.

Safety assessments

Safety evaluation was a secondary objective in Study 050 and the primary objective in Study 240. In both studies, safety measurements comprised monitoring and recording of all adverse events (AEs), treatment-emergent AEs (TEAEs), and serious TEAEs; laboratory evaluations for biochemistry, hematology, and urine values; periodic measurements of vital signs, weight, and 12-lead electrocardiography; and the performance of physical examinations. In Study 050, a TEAE was defined as an AE that emerged at any time between the first perampanel administration and 28 days after the patient's last perampanel dose. In Study 240, a TEAE was defined as an AE that emerged at any time between the first IV perampanel and 28 days after the patient's last IV dose, including the Follow-up Phase with oral perampanel.

Pharmacokinetic assessments

Perampanel plasma concentrations were measured by a validated liquid chromatography with tandem mass spectrometry (LC/MS/MS) assay. Blood samples for PK analyses were collected at the time as outlined below.

Study 050

Blood samples were collected pre-dose and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 120, 168, 336, and 504 hours following the dosing initiation in each treatment period. PK parameters for perampanel were calculated via non-compartmental analysis using Phoenix WinNonlin version 6.3 (Certara) and included maximum observed drug concentration (C_max), time of maximum concentration (t_max), area under the plasma concentration–time curve (AUC), terminal elimination phase half-life (t_1/2), total clearance (CL), and volume of distribution at terminal phase (V_d).

Study 240

Blood samples were collected pre-dose and at 0.5, 1, and 1.5 hours after the oral dosing of perampanel on Day −1 to assess the trough concentration (C_trough) and C_max after oral administration. Blood samples were also collected pre-dose and upon the completion of 30-minute IV infusions on Days 1-4 to assess C_trough and C_max after IV infusion. The maximum plasma concentration among 0.5, 1, and 1.5 hours after an oral administration on Day −1 was defined as C_max,po. Ratios of C_max on Days 1-4 to C_max,po were calculated in each patient.

Assessment of efficacy maintenance

In Study 240, seizure frequency was assessed throughout the study to compare the efficacy of perampanel between the Pretreatment Phase (oral dosing), Treatment Phase (IV infusion), and Follow-up Phase (oral dosing), and to determine the interchangeability of IV and oral formulations. The maintenance of efficacy of perampanel was assessed by seizure counts and types as recorded in patients' diaries. Diaries were completed by patients, caregivers, clinical nurses, or other site staff to record the counts and types of seizures, as well as medication adherence.

Statistical analyses

The Safety Analysis Set included healthy subjects who received at least one dose of oral or IV perampanel in Study 050, and patients who received IV infusion in Study 240. The Efficacy Analysis Set included patients who received IV infusion and had at least one post-dose efficacy measurement in Study 240. The PK Analysis Set included healthy subjects who had sufficient PK data to derive at least one specified PK parameter in Study 050, and patients who received IV infusion and had at least one evaluable measurement of plasma perampanel concentration in Study 240.

In Study 050, the sample size for Japanese subjects enrolled in the IV infusion treatment arm was not based on statistical power analyses. The number of enrolled subjects was deemed sufficient to provide overall comparability of perampanel PK between Japanese and non-Japanese subjects following IV dosing. PK parameters after IV infusions were summarized by infusion duration (30-, 60-, and 90-minute) and race (Japanese and non-Japanese).

In Study 240, the sample size of patients for the safety assessments of IV perampanel was not based on statistical power analyses. It was based on the premise that a sufficient number of patients could be obtained for the safety assessments if the sample size was at least 20 according to the IV levetiracetam study in Japan (NCT01407523). Safety data, PK data, and efficacy data were summarized using descriptive statistics.

RESULTS Study participants Study 050

Forty-eight healthy subjects were enrolled and included in the Safety and PK Analysis Sets, which consisted of 18 Japanese and 30 non-Japanese subjects. The demographics of healthy subjects were generally similar across IV infusion arms. Overall, 52.1% of the healthy subjects were male, with a mean (standard deviation [SD]) age of 39.0 (9.4) years.¹⁷ Demographics and baseline clinical characteristics of healthy subjects stratified by race, are shown in Table S1.

Study 240

Twenty-one Japanese patients were enrolled and included in the Safety, PK, and Efficacy Analysis Sets. Mean (SD) age was 40.7 (12.8) years, and 42.9% of patients were male (Table 1). Twenty patients had a diagnosis of epilepsy with FOS and one patient had both FOS and GTCS. Most patients (52.4%) received oral tablets of perampanel 8 mg/day, and the remaining patients received perampanel 10 or 12 mg/day (23.8%, each) during the Pretreatment Phase. Concomitant use of carbamazepine, an EIASM, was reported by 42.9% of patients. Of the 21 patients, only one patient discontinued during the Treatment Phase (Day 1) due to a TEAE of delusion, which was deemed not related to IV perampanel. The timing of IV infusions varied across patients ranging between 2 and 8 p.m.; three patients received IV infusions between 2 and 3 p.m., 11 patients between 3 and 4 p.m., three patients between 4 and 5 p.m., one patient between 5 and 6 p.m., and three patients between 7 and 8 p.m.

TABLE 1 Baseline demographics and disease characteristics in Study 240.

Category	Total (n = 21)
Age, years
Mean (SD)	40.7 (12.8)
Min, max	18, 62
Sex, n (%)
Male	9 (42.9)
Female	12 (57.1)
Seizure type, n (%)
Focal-onset seizures	21 (100.0)
Focal aware seizures without motor signs	12 (57.1)
Focal aware seizures with motor signs	1 (4.8)
Focal impaired awareness seizures	18 (85.7)
Focal seizures with focal to bilateral tonic–clonic seizures	12 (57.1)
Generalized-onset seizures	1 (4.8)
Generalized absence seizures	1 (4.8)
Generalized tonic–clonic seizures	1 (4.8)
Dose of perampanel, n (%)
8 mg	11 (52.4)
10 mg	5 (23.8)
12 mg	5 (23.8)
ASMs during the Pretreatment Phase, n (%)
EIASM	9 (42.9)
Non-EIASM	12 (57.1)
Number of ASMs except for perampanel, n (%)
1 ASM	4 (19.0)
2 ASMs	8 (38.1)
3 ASMs	9 (42.9)

Note: EIASMs include carbamazepine, phenytoin, and phenobarbital. All other ASMs are non-EIASMs.

Abbreviations: ASM, anti-seizure medication; EIASM, enzyme-inducing ASM; max, maximum; min, minimum; SD, standard deviation.

Safety outcomes Study 050

All TEAEs were classified as mild or moderate in severity, and the majority (70.8%) of TEAEs were reported to be related to study drug, which could be either oral or IV perampanel.¹⁷ The most common TEAEs were dizziness (24 events reported by 17 Japanese subjects, and 15 events reported by 12 non-Japanese subjects), lethargy (seven events reported by seven Japanese subjects, and four events reported by four non-Japanese subjects), and nausea (two events reported by one Japanese subject, and four events reported by three non-Japanese subjects). No TEAEs leading to discontinuation or deaths were reported during the study. No TEAEs with higher incidence were identified after a single infusion of IV perampanel among Japanese subjects relative to non-Japanese subjects.

TEAEs related to renal dysfunction need to be carefully observed since the IV formulation of perampanel included the solubilizing agent SBECD, which is reported to be potentially associated with renal impairment but the strong evidence for the association was not established.^18,19 There was no clinically relevant change in renal function markers (blood urea/blood urea nitrogen, creatinine) reported in Study 050.

Study 240

Overall, 76.2% of patients experienced TEAE(s). The incidences of AEs during the Pretreatment Phase, TEAEs during the Treatment Phase, and TEAEs during the Follow-up Phase were 14.3%, 71.4%, and 28.6%, respectively (Table 2). Overall, 61.9% of patients experienced TEAE(s) that were deemed related to the study drug, which could be either oral or IV perampanel. The incidences of treatment-related TEAEs during the Treatment Phase and Follow-up Phase were 61.9% and 4.8%, respectively (Table 2). The majority of TEAEs were classified as mild or moderate in severity, except for three events of serious TEAEs in two patients (one event of hypoesthesia during the Follow-up Phase [Days 24-53] in one patient, and one event each of delusion during the Treatment Phase [Days 1-3] and loss of consciousness during the Follow-up Phase [Days 25-26] in the other patient). All serious TEAEs resolved and were classified as not related to study drug. For the patient who reported delusion during the Treatment Phase, this TEAE subsided on the following day even though oral perampanel was administered. Therefore, the delusion event was likely to be attributable to factors other than the study drug, such as change in the environment. The most frequently reported TEAEs, which occurred in ≥10% of patients during the Treatment Phase, were dizziness (28.6%) and somnolence (14.3%), most of which occurred within an hour after initiation of IV infusions, and all were mild in severity and resolved prior to the Follow-up Phase. No TEAEs related to dizziness, such as falling, were observed. Of TEAEs reported in ≥2 patients during the Treatment Phase, dizziness and hypoesthesia were reported in one patient each (4.8%) during the Pretreatment Phase. Injection site pain, rash, and vesicles were reported in one patient each, which were all mild in severity and resolved at the time of study completion. No TEAEs related to renal dysfunction, clinical laboratory abnormalities, or worsening of renal functions (creatinine and urea nitrogen) were observed in patients with epilepsy.

TABLE 2 TEAEs reported in Study 240 (Safety Analysis Set).

[Table omitted. See PDF]

Abbreviations: IV, intravenous; TEAE, treatment-emergent adverse event.

^aOf the Safety Analysis Set, one patient who discontinued during the Treatment Phase and was evaluated at the follow-up visit was also included.

^bA TEAE related to study drug was defined as a TEAE considered by the investigator to be related to study drug (IV perampanel) or a TEAE with missing causality.

PK outcomes Study 050

Based on the results of the subgroup analysis, the similarity of PK profiles following 30- or 60-minute infusions of IV perampanel between Japanese subjects (n = 12) and non-Japanese (n = 26) healthy subjects was confirmed (Table 3). Despite differences being observed across races following 90-minute IV infusions, interpretations may be limited due to the small sample size (Japanese n = 3; non-Japanese n = 3).

TABLE 3 Summary of plasma PK parameters of perampanel by infusion durations for Japanese and non-Japanese subjects in Study 050 (PK Analysis Set).

	Arm 1		Arm 2		Arm 3
	30-minute IV infusion		60-minute IV infusion		90-minute IV infusion
	Japanese (n = 5)	Non-Japanese (n = 14)	Japanese (n = 7)	Non-Japanese (n = 12)	Japanese (n = 3)	Non-Japanese (n = 3)
Cmax, ng/mL	472 (108)	479 (176)	381 (58.8)	361 (58.3)	338 (87.5)	370 (66.5)
tmax, h	0.53 (0.53-0.55)	0.53 (0.53-0.75)	1.03 (1.03-1.03)	1.03 (0.75-1.03)	1.53 (1.25-1.53)	1.53 (1.25-1.53)
AUC(0-t), ng·h/mL	25 600 (10 200)	24 900 (9710)	22 800 (5430)	22 500 (8780)	19 900 (10 200)	25 800 (11 000)
AUC(0-inf), ng·h /mL	23 900 (9400)a	24 700 (11 000)b	24 100 (6290)	26 100 (9030)b	12 500, 16 100c	29 400 (15 700)
t1/2, h	127 (66.3)a	135 (55.3)b	105 (36.0)	123 (52.8)b	50.9, 52.5c	129 (76.7)
CL, L/h	0.557 (0.195)a	0.623 (0.431)b	0.532 (0.159)	0.519 (0.199)b	0.745, 0.958c	0.488 (0.231)
Vd, L	90.8 (20.7)a	96.8 (32.7)b	74.3 (12.5)	81.2 (21.8)b	54.7, 72.5c	73.4 (18.1)
	Oral administration		Oral administration		Oral administration
	Japanese (n = 6)	Non-Japanese (n = 14)	Japanese (n = 7)	Non-Japanese (n = 12)	Japanese (n = 5)	Non-Japanese (n = 3)
Cmax, ng/mL	322 (137)	285 (83.2)	303 (88.6)	269 (57.8)	305 (58.9)	373 (118)
tmax, h	1.38 (1.00-4.00)	0.75 (0.53-4.00)	1.25 (0.75-3.00)	1.00 (0.50-3.00)	0.75 (0.75-2.02)	2.00 (0.50-2.00)
AUC(0-t), ng·h/mL	25 100 (14 300)	27 200 (9830)	22 400 (5100)	25 400 (11 200)	25 600 (17 300)	26 700 (11 900)
AUC(0–inf), ng·h /mL	20 400 (4350)d	27 200 (11 500)e	23 700 (5460)	25 700 (9290)e	21 500 (14 300)a	14 200, 31 000c

Note: All values are mean (standard deviation) except for t_max which is shown as median (range).

Abbreviations: AUC_(0-t), area under the plasma concentration–time curve from zero time to the last quantifiable concentration; AUC_(0-inf), area under the plasma concentration–time curve from zero time extrapolated to infinite time; CL, total clearance; C_max, maximum observed drug concentration; IV, intravenous; PK, pharmacokinetic; t_max, time of maximum concentration; t_1/2, terminal elimination phase half-life; V_d, volume of distribution at terminal phase.

^an = 4.

^bn = 11.

^cn = 2 (individual values are shown).

^dn = 5.

^en = 10.

Study 240

When transitioning from oral tablets to 30-minute IV infusion at steady state, the mean increase in C_max of perampanel ranged between 1.03- and 1.39-fold throughout the 4-day IV treatment and across the dose groups (Table 4). In the 10-mg dosing group, relatively high ratios (2.4-2.6) were observed in one patient who showed low plasma concentrations after the oral dosing on Day −1; the individual ratios in the other four patients were not higher than 1.2.

TABLE 4 Maximum plasma concentrations of perampanel after oral administration or IV infusion in Study 240 (PK Analysis Set).

Dose of Perampanel	Parameter	Statistic	Oral administration	IV infusion
			Day −1	Day 1	Day 2	Day 3	Day 4
8 mg (n = 11)	Cmax, ng/mL	Mean (SD)	574 (375)	609 (303)	614 (315)	557 (301)	554 (300)
	Ratio to Cmax,po	Mean (SD)	NA	1.16 (0.208)	1.16 (0.220)	1.03 (0.195)	1.04 (0.227)
		Median	NA	1.17	1.20	0.97	0.95
		Min, Max	NA	0.8, 1.5	0.9, 1.5	0.8, 1.3	0.8, 1.5
10 mg (n=5a)	Cmax, ng/mL	Mean (SD)	528 (228)	591 (172)	520 (184)	547 (169)	541 (209)
	Ratio to Cmax,po	Mean (SD)	NA	1.33 (0.647)	1.35 (0.836)	1.39 (0.779)	1.35 (0.739)
		Median	NA	1.14	1.04	1.10	1.07
		Min, Max	NA	0.8, 2.5	0.7, 2.6	0.8, 2.5	0.8, 2.4
12 mg (n = 5)	Cmax, ng/mL	Mean (SD)	678 (293)	837 (282)	760 (261)	815 (276)	841 (312)
	Ratio to Cmax,po	Mean (SD)	NA	1.35 (0.394)	1.21 (0.301)	1.30 (0.324)	1.31 (0.252)
		Median	NA	1.33	1.23	1.24	1.27
		Min, Max	NA	1.0, 2.0	0.9, 1.7	0.9, 1.8	0.9, 1.6
Total (n=21b)	Cmax, ng/mLc	Mean (SD)	509 (299)	564 (245)	548 (262)	530 (245)	532 (252)
	Ratio to Cmax,po	Mean (SD)	NA	1.25 (0.381)	1.21 (0.400)	1.17 (0.405)	1.17 (0.386)
		Median	NA	1.16	1.14	1.16	0.97
		Min, Max	NA	0.8, 2.5	0.7, 2.6	0.8, 2.5	0.8, 2.4

Note: C_max, maximum plasma concentrations among 0.5, 1, and 1.5 hours after oral administration (C_max,po) or plasma concentrations just after the completion of 30-minute IV infusion.

Abbreviations: IV, intravenous; Max, maximum; Min, minimum; NA, not applicable; PK, pharmacokinetic; ratio to C_max,po, ratio of C_max after IV infusion to C_max,po; SD, standard deviation.

^an = 4 (Days 2-4).

^bn = 20 (Days 2-4).

^cIndividual C_max values were dose-normalized to 8 mg and summarized.

The plots of individual plasma concentrations of perampanel showed no change in C_trough before and after transitioning from oral dosing to 30-minute IV infusions across perampanel doses (Figure 2A). The C_max tended to be lower in the EIASM subgroup than in the non-EIASM subgroup after both oral and IV dosing. No substantial differences were observed in the changes in C_max before and after transitioning from oral tablets to 30-minute IV infusions across perampanel doses, irrespective of the concomitant use of EIASM (Figure 2B and C).

Maintenance of efficacy Study 240

The plots of individual daily seizure frequency for patients enrolled in Study 240 who had FOS are presented by EIASM status in Figure 2D and E; no meaningful changes associated with transitioning from oral tablets to IV perampanel and back to oral tablets were observed except in two patients. The daily seizure frequency in these two patients was higher during the Treatment Phase (IV perampanel) than that reported during the Pretreatment Phase (oral perampanel). However, the increases in seizure frequency were deemed not related to the transition from oral dosing to IV perampanel. In one patient (Figure 2D), the number of seizures increased on Day 1 (seven events per day) of the Treatment Phase but was similar to Day −3 of the Pretreatment Phase and Day 9 of the Follow-up Phase (five events per day, each). Thus, the worsening of seizures was not considered as a TEAE per the investigator's discretion. In the other patient (Figure 2E), increased number of focal aware seizures on Day 3 was reported as a TEAE which was mild in severity and considered not related to study drug by the investigator because the seizures were controlled on other days during the Treatment Phase. Only one patient with a medical history of GTCS had no generalized-onset seizures throughout the study. There were no notable differences in changes in the seizure frequency between the EIASM and non-EIASM subgroups.

DISCUSSION

In Study 050, the bioavailability of a single 12-mg IV perampanel infusion (30-, 60-, or 90-minute) relative to a single administration of 12-mg oral perampanel tablet was evaluated in healthy subjects including Japanese subjects.¹⁷ The 90% confidence intervals for the geometric mean ratio of AUC from zero time extrapolated to infinite time (AUC_[0-inf]) following the 30- and 60-minute IV infusion vs the oral tablet were within the bioequivalence criteria of 80%-125%; however, the mean C_max values for the 30- and 60-minute IV infusions were 1.61- and 1.35-fold higher than those reported for oral tablets, respectively. The PK profiles following switch from maintenance treatment with 12-mg oral tablet to 12-mg IV infusion were simulated using the PK data following the administration of a single oral or IV dose of perampanel. The simulation results suggested that perampanel exposure would remain steady immediately after formulation change and supported the interchangeability of oral and IV formulations at the same dose during maintenance treatment.¹⁷ Comparable PK profiles between Japanese and non-Japanese healthy subjects in Study 050 presented in this analysis further support the interchangeability of oral and IV formulations of perampanel in Japanese patients with epilepsy.

Results from Study 240 in Japanese patients with epilepsy showed the safety of 30-minute infusion of IV perampanel (8-12 mg), a ≤1.4-fold increase in the mean change in C_max of perampanel before and after transitioning from oral dosing to IV infusions, and the efficacy was maintained before, during, and after IV dosing of perampanel. Patients experienced TEAEs more frequently during the transition from oral tablets to IV formulation, but the majority of events were mild and recovered without sequelae. The increased frequency of TEAEs can be attributed to the increased probability of AEs occurring during hospitalization than at home, and the earlier timing of IV infusions (see Section 3.1) versus administration of oral perampanel at bedtime. No clinically meaningful differences in the safety outcomes of IV perampanel were observed compared with oral perampanel. Consistent with the approved indication of oral perampanel, safety, and tolerability of IV perampanel should be carefully monitored following the formulation transition. As previous results showed that the incidence of TEAEs with oral perampanel is dose-dependent,^20,21 we consider that there are no new safety concerns for low-dose (<8 mg) IV perampanel, including the starting dose and the minimum maintenance dose, even though higher doses of 8, 10, or 12 mg were used in Study 240. Taken together, these results demonstrated that IV perampanel was safe, well tolerated, and efficacious in Japanese patients with epilepsy who had received oral perampanel. These findings support the potential use of IV perampanel as a short-term alternative treatment to oral formulation of perampanel, although the estimates are sensitive to variation and should be interpreted with caution, due to the small sample size.

IV perampanel contains the solubilizing agent, SBECD, which is renally cleared and has been reported to be potentially associated with renal impairment. Luke et al. reported that the renal tubular vacuolation was observed in animal models exposed to voriconazole, which is an antifungal medication including SBECD, at a dose of 300 mg/kg as SBECD.¹⁸ Yasu et al. reported that the retrospective analysis of IV voriconazole suggested that a higher cumulative dose of IV voriconazole (400 mg/kg and more; 6400 mg/kg and more as SBECD) is a risk factor for renal dysfunction.²² These SBECD doses are higher than those of IV perampanel at maximum daily dose (6000 mg as SBECD; 100 mg/kg in adults weighting 60 kg). Furthermore, there is also evidence that SBECD did not lead to worsening renal function in subjects who administered remdesivir including SBECD, and a systematic review by Turner et al. concluded that there is no strong evidence indicating that SBECD increased the risk of worsening renal function.^19,23 Our results indicated that there were no clinically relevant changes in renal function markers leading to renal dysfunction following short-term IV perampanel in both studies. Given the small sample size in these studies, interpretation of the effect of IV perampanel on renal function may be limited; hence, renal function should be carefully monitored during and after IV infusions, particularly in patients with renal dysfunction, and further investigation to establish the evidence for an association between SBECD and worsening renal function is needed.

There were no substantial changes in the plasma concentrations of perampanel before and after transitioning from oral dosing to IV infusions in Study 240 although the plasma concentration after transition back to oral dosing was not assessed. Although the adolescent patients aged 12 to <18 years were not enrolled in Study 240, PK following the IV dosing is anticipated to be similar between adolescent and adult patients since no substantial age-dependent PK differences were observed with oral perampanel.²⁴ Seizure control was observed with IV perampanel when administered via infusions for up to 4 days and then transitioned into oral perampanel in Study 240. In the two subjects who experienced increasing number of seizures on 1 day during the Treatment Phase (Day 1 and Day 3, respectively, see in Section 3.4), plasma concentrations of perampanel showed no obvious change before and after transition to IV infusion. Typically, the efficacy of ASMs should be evaluated in average seizure frequency over several weeks, as seizure frequency is influenced by the change in circumstances and may change daily.^25–27 Considering the limitation, we need further investigation on the efficacy maintenance with IV perampanel, but our findings supported that the seizure control could be maintained with IV perampanel of same dose as oral perampanel when used as short-term alternative treatment, here 4 days. Patients with epilepsy often experience scenarios in which oral dosing of ASMs is not feasible. For example, among patients who cannot take tablets when undergoing surgery or experiencing gastrointestinal disorders, continuous dosing of ASMs is recommended under these conditions because the abrupt withdrawal from ASMs can precipitate severe rebound seizures and status epilepticus.^10–16 As our findings suggest that IV perampanel could be an alternative treatment to be used, patients who are receiving oral perampanel and experiencing difficulties in taking oral tablets could be transitioned to IV perampanel for the maintenance of seizure control to avoid the risk of seizure recurrence due to abrupt withdrawal or shift to other ASMs. Moreover, a 30-minute infusion of IV perampanel is acceptable based on results from Studies 050 and 240, and IV infusion over a brief duration is desirable from a clinical care perspective.

CLINICAL RELEVANCE

Overall, these results support that IV perampanel of 8 to 12 mg/day is safe and well tolerated in patients with epilepsy, and the efficacy of perampanel could be maintained throughout the transition between IV infusion and oral dosing, though the duration of infusion was limited to only 4 days and the sample size was small. Our findings suggest that a 30-minute IV infusion of perampanel may be a potential option as a short-term alternative treatment to tablets when oral dosing is temporarily infeasible.

AUTHOR CONTRIBUTIONS

Ryosuke Hanaya, Yuichi Kubota, Masahiro Mizobuchi, Koji Iida, Tomonori Ono, Hiromichi Motooka, Naoki Nakano, Ayataka Fujimoto, Masaki Iwasaki, Masafumi Fukuda, Akihiko Kondo, Katsuhisa Uruno, and Yushi Inoue contributed to patient recruitment and enrollment, and contributed to the acquisition of the data. Shintaro Yamamuro, Kohei Yamaguchi, Kisaki Onishi, Leock Y. Ngo, and Yushi Inoue contributed to the conception and design of the study. Shintaro Yamamuro, Kohei Yamaguchi, and Kisaki Onishi conducted the analysis of the data. All authors were involved in data interpretation, reviewing, and approval of the manuscript, and the decision to submit the article for publication.

ACKNOWLEDGMENTS

This study was funded by Eisai Inc. The authors acknowledge the contributions made by patients and their caregivers, and the members of the Study 050 and Study 240 Group who assisted in the preparation of this manuscript by taking care of patients according to the approved trial protocol and helping gather the data generated for this trial. Editorial support, under the direction of the authors, was provided by Can Huang, PhD, of CMC AFFINITY, a division IPG Health Medical Communications, funded by Eisai Inc., in accordance with Good Publication Practice (GPP 2022) guidelines.

CONFLICT OF INTEREST STATEMENT

Yuichi Kubota has received speaker's honoraria from Daiichi-Sankyo and Eisai. Koji Iida has received advisor fee from Eisai, and speaker's honoraria from Daiichi-Sankyo, Eisai, and UCB Japan. Tomonori Ono is an editorial board member of Epilepsia Open. Masaki Iwasaki has received consultation fees from LivaNova Japan K.K. and Zimmer Biomet G.K.; honoraria from Daiichi-Sankyo, Eisai, LivaNova Japan K.K., Novartis Pharma K.K., and UCB Japan. Masafumi Fukuda has received research support from Eisai. Shintaro Yamamuro, Kohei Yamaguchi, and Kisaki Onishi are employees of Eisai Co., Ltd. Leock Y Ngo is an employee of Eisai Inc. Yushi Inoue has received consultation fees from Eisai Co., Ltd., GW Pharmaceuticals, and UCB Japan Co., Ltd. The remaining authors have no conflicts of interest.

DATA AVAILABILITY STATEMENT

Data generated during and/or analyzed during the current study are owned by the authors and available based on the authors' decisions upon reasonable request.

ETHICS STATEMENT

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

IRB STATEMENT

The protocol, informed consent form (ICF), and any appropriate related documents were submitted to the Institutional Review Board (IRB) for approval. The study was initiated after Eisai (the sponsor) received IRB approval of the protocol and ICF.

In Study 050, the investigator submitted periodic reports and informed the IRB of any reportable adverse events (AEs) as per The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines and local IRB standards of practice.

In Study 240, the sponsor submitted periodic reports and informed the investigator, the head of the medical institution, and the relevant IRB (directly or via the head of the medical institution) of any reportable AEs per Japan's Good Clinical Practice (J-GCP) guidelines and local IRB standards of practice.