Edaravone Administered Orally and Via Nasogastric Tube in Healthy Adults: A Comparative Bioavailability Phase 1 Study

Abstract

Intravenous edaravone is used to treat patients with amyotrophic lateral sclerosis. This randomized, open‐label, two‐way crossover, single‐dose phase 1 study compared the relative bioavailability of a newly developed edaravone oral suspension when administered orally and via a nasogastric tube (NGT) as a model of percutaneous endoscopic gastrostomy tube administration in healthy adult subjects. Thirty‐six subjects were randomly assigned to one of two groups, with 18 per group. Blood was collected pre‐ and post‐dose for pharmacokinetic assessments; safety was evaluated. Plasma concentration–time profiles of unchanged edaravone were similar between administration routes. Comparative bioavailability analysis revealed that geometric least squares mean ratios (NGT/oral) for maximum plasma concentration and area under the plasma concentration–time curve from time zero to infinity of unchanged edaravone were 1.052 and 0.981, respectively. No serious adverse events or adverse drug reactions were reported. These results suggest that oral edaravone suspension can be administered directly to the stomach without dose adjustment via feeding tubes; both oral and NGT administration are well tolerated.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by upper and lower motor neuron loss, with a median time from onset to death in patients of 20–48 months. ¹ Edaravone is a free‐radical scavenger that works as a neuroprotective agent and may also protect against oxidative stress, one of the mechanisms involved in the etiology of ALS. ² The intravenous formulation of edaravone is currently used for the treatment of ALS. The safety and efficacy of intravenous edaravone have been confirmed in previous phase 2 and 3 clinical trials, in which it has been shown to slow the rate of physical functional decline. ³ , ⁴ , ⁵ As repeated intravenous administrations are conducted in hospitals or at home and can burden patients, caregivers, and medical personnel, orally administered treatments are needed.

An oral suspension of edaravone has been developed, and clinical trials have been conducted to characterize the pharmacokinetics (PKs) of edaravone oral suspension formulation in healthy subjects and patients with ALS (NCT04176224) and to confirm the equivalent plasma exposures of edaravone administered orally and intravenously. ⁶ , ⁷ Considering that the fraction of the dose absorbed was >77% and the time to reach maximum plasma concentration (t_max) was within 1 hour, orally administered edaravone showed a good and rapid absorption, a triphasic elimination after reaching maximum plasma concentration (C_max), nonlinear PKs over the dose range of 30–300 mg, and no accumulation after repeated doses. The plasma exposure (area under the plasma concentration–time curve [AUC]) of 105 mg of edaravone oral suspension was equivalent to that of intravenous edaravone (60‐minute infusion at a dose of 60 mg), and the C_max and plasma concentrations were not lower than those of intravenous edaravone. Elimination pathways were similar regardless of the administration route. In addition, the PK profile of the edaravone oral suspension was similar between ALS patients and healthy volunteers, and no safety concerns were raised (NCT04176224).

Dysphagia is one of the symptoms of ALS. ⁸ In advanced dysphagia, the oral transfer becomes difficult because of impaired tongue movement and atrophy, and the risk of transfer from the pharynx to the esophagus and aspiration increases. In such cases, enteral nutrition and parenteral nutrition are the main routes of nutrition, ⁹ and gastrostomy is generally used for enteral nutrition. In addition to deleteriously affecting nutrition intake, dysphagia can also seriously affect the administration of beneficial medications. ¹⁰ Gastrostomy can be used to deliver drugs as well as nutrition. Some patients with ALS may undergo a percutaneous endoscopic gastrostomy (PEG) for required nutritional and medical support because of dysphagia as ALS progresses. The possibility of administering drugs to patients with ALS via a PEG tube should be considered.

The PKs of edaravone oral suspension after administration via PEG feeding tube has not been fully evaluated in a sufficient number of subjects. The feasibility of administration of edaravone oral suspension via PEG feeding tube with a specific procedure, including water flush, is also unknown. In the present study, a nasogastric tube (NGT) was used as a model for PEG tubes in healthy subjects. The objective of this study was to compare the relative bioavailability of edaravone oral suspension administered orally and via an NGT in healthy adult subjects by assessing the PKs after administration via NGT. This study also assessed the safety and feasibility of the administration of edaravone oral suspension via NGT in healthy adult subjects.

Subjects and Methods

Study Design

This was a randomized, open‐label, crossover, single‐dose phase 1 study (Figure 1) conducted at Houeikai Medical Corporation, Sekino Clinical Pharmacology Clinic, Tokyo, Japan. The study was carried out in a two‐period, two‐sequence crossover, and subjects were hospitalized for 7 days (6 nights). Periods I and II each lasted 48 hours with a 24‐hour washout period between them. Subjects were randomly assigned to two groups based on the administration sequence: one group received edaravone orally and then by NGT (oral–NGT administration group), and the other group received edaravone by NGT and then orally (NGT–oral administration group).

Figure 1.

Study design. Administration of edaravone oral suspension 105 mg (105 mg/5 mL) for both oral and NGT administrations. NGT, nasogastric tube.

The protocol was approved by the institutional review board at the study site, and the study was conducted in accordance with the Declaration of Helsinki and adhered to Good Clinical Practice guidelines and the Law on Securing Quality, Efficacy, and Safety of Products Including Pharmaceuticals and Medical Devices. All study subjects provided written informed consent. This study was registered at ClinicalTrials.gov under the identifier number NCT04776135.

Subjects

Key inclusion criteria were healthy Japanese men or women aged between 20 and 45 years at the time of informed consent. Subjects who met any of the exclusion criteria between screening and administration of the study drug were excluded. Key exclusion criteria were current or previous history of cardiac, hepatic, renal, gastrointestinal, respiratory, psychiatric/nervous, hematopoietic, or endocrine diseases; body mass index (BMI) <18.0 or >30.0 kg/m² or body weight <50 kg; positive test for hepatitis B surface antigen, serological test for syphilis, hepatitis C virus antibody, or human immunodeficiency virus antigen/antibody at screening, or for SARS‐CoV‐2 at day −1; use of any nutritional supplement(s) or any drugs other than acetylsalicylic acid (single use) within 7 days before the initiation of the study drug; use of alcohol, any products containing xanthines or caffeine, grapefruit or grapefruit juice, any processed food(s) containing grapefruit substances, or any tobacco or nicotine‐containing product(s) within 24 hours before screening and visit on day −1; subjects with any nasal abnormality, symptoms, or history that would prevent an adequate NGT insertion; subjects who had undergone any surgery known to affect the gastrointestinal absorption of drugs; and subjects judged by the investigator or subinvestigator to be unsuitable for the study for any other reason.

Intervention

The edaravone oral suspension contained 105 mg of edaravone powder in 5 mL of an aqueous suspension. Details of the composition of the edaravone oral suspension have been described previously. ⁷

The NGT was selected to model the intragastric administration of medication in patients with PEG. The compatibility of edaravone oral suspension with the NGT was confirmed before conducting the study by checking that there was no adsorption and that the oral suspension of 105 mg of edaravone would pass through the NGT completely with 30 mL of water flush using silicone rubber tubes of 12, 14, and 16 Fr, and a total length of 1250 mm. The specifications of the NGT used in the present study were a silicone rubber tube, 12 Fr (outer diameter 4.0 mm, inner diameter 2.4 mm), total length 1250 mm, with a funnel and connector made of acrylonitrile‐butadiene‐styrene resin (Create Medic Co., Ltd, Yokohama, Japan).

In both the oral–NGT and NGT–oral administration groups, after fasting for at least 10 hours subjects received the edaravone oral suspension at a dose of 105 mg/5 mL, which was administered either orally or via NGT in each administration period in a different sequence. During the NGT administration period, in both groups, an NGT was inserted in the morning on the day of administration and the proper placement of the NGT was confirmed by auscultation and X‐ray. To verify the absence of rising gastric contents and NGT blockage, 100 mL of lukewarm water was flushed through the NGT after insertion and before edaravone administration using 50‐mL polypropylene catheter syringes (Syringe DS 50‐mL Catheter Yellow NCAP; Nipro Corporation, Osaka, Japan). The same volume of water was given orally to subjects during the oral administration period. Just before NGT administration, 30 mL of lukewarm water was injected through the NGT to confirm that the tube was not clogged. The study drug was administered through the NGT using a 5‐mL polypropylene catheter syringe (Syringe DS 5‐mL Catheter Yellow NCAP, Nipro Corporation) and the tube was flushed with 30 mL of lukewarm water as soon as possible after administration. Subjects were then given 40 mL of water to drink orally to balance the total water intake at the time of administration with that after receiving edaravone orally. During the oral administration period, the study drug was administered orally directly. Subjects were then given 100 mL of water in portions so that no suspension was left in the mouth. For PK assessment, all subjects were prohibited from drinking water for up to 1 hour after administration of the study drug except for the water given at the time of administration. All subjects were requested to stay in a sitting position from 1 hour before to 2 hours after administration for PK assessment.

Pharmacokinetic Endpoints

The plasma drug concentration of unchanged edaravone was measured. The PK parameters were t_max, C_max, AUC from time zero to the last measurable concentration (AUC_0–t), AUC from time zero to infinity (AUC_0–∞), elimination half‐life (t_1/2), and apparent total clearance (CL/F). Blood samples for PK assessments were taken pre‐dose and at 5, 15, 30, and 45 minutes and 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36, and 48 hours after the study drug administration in both periods. For each sample, 4 mL of blood was obtained using 4‐mL vacuum blood collection tubes containing heparin sodium (128 mL of total blood volume taken during the study). The processing of blood samples and the bioanalytical assays for the determination of the PKs of unchanged edaravone in plasma with validated methodology has been described previously. ⁶ , ⁷ Briefly, collected blood samples were processed by adding a stabilizer, separating the plasma and mixing with an internal standard on ice. The conditions of the bioanalytical assays are shown in Supporting Information Table S1.

Safety Endpoints

The safety endpoints included the incidence of adverse events (AEs) and adverse drug reactions (ADRs), as well as the results of a 12‐lead electrocardiogram, laboratory tests, and vital signs. AEs were coded according to system organ class and preferred term using the Medical Dictionary for Regulatory Activities, version 23.1.

Statistical Methods

A sample size of 36 subjects was set to ensure that at least 30 subjects completed the study and to allow for six dropouts based on practical experience in preceding studies and in reference to the results of a bioavailability study of riluzole suspension administered orally versus via NGT. ¹¹ The sample size was not determined based on the conventional equivalence criteria (least squares [LS] mean ratio of PK parameters [C_max and AUCs] and 90% confidence intervals [CIs] within 0.8–1.25) for edaravone PKs when compared between oral administration and that via NGT. However, the calculations based on intra‐individual variability after repeated administrations of edaravone oral suspension in a previous study ⁶ confirm a certain degree of power. Based on the calculated intra‐individual variability of C_max and AUC_0–∞ (36.3% and 23.5%, respectively), assuming the ratios of PK parameters after administration via NGT against oral administration were both 1, the power to meet the equivalence criteria would be 55% for C_max and 95% for AUC_0–∞.

The PK analysis was performed on all subjects who received at least one dose of the study drug and had evaluable PK data. The safety analysis was performed on all subjects who received at least one dose of the study drug. PK parameters were calculated for each subject and each period using a noncompartmental model using WinNonlin software version 6.3 or later (Certara, Princeton, New Jersey).

To compare the relative bioavailability of edaravone administered orally versus via NGT, the AUC_0–∞, AUC_0–t, and C_max of unchanged edaravone in plasma were log‐transformed and analyzed by analysis of variance using administration groups, the administration route (oral or NGT), study periods, and subjects (nested in administration group) as factors. Estimates of the mean values on the log scale, the mean difference between administration routes (via NGT minus orally) on the log scale, and 90%CIs for the difference were back‐transformed to present mean ratios and their 90%CIs for administration via NGT to oral administration. The analysis was performed using SAS software version 9.4 (SAS Institute Inc., Cary, North Carolina).

Results

Subjects

In total, 36 subjects were included in the present study and 18 subjects were randomly assigned to each of the oral–NGT and NGT–oral administration groups. Each group included 12 male and six female subjects. All subjects were included in the PK and safety analyses. All subjects completed the study. The background characteristics of the study subjects are summarized in Table 1. The mean age of the subjects was 27.7 years and their mean BMI was 22.5 kg/m².

Table 1.

Background Characteristics

	Total (N = 36)
Sex
Male	24 (66.7)
Female	12 (33.3)
Age, years	27.7 ± 7.6
Height, cm	166.6 ± 7.4
Weight, kg	62.5 ± 6.5
BMI, kg/m2	22.5 ± 2.2

Data are n (%) or mean ± SD.

BMI, body mass index; SD, standard deviation.

Pharmacokinetics

Mean plasma concentration–time profiles of unchanged edaravone following a single administration of 105 mg of oral suspension orally and via NGT are shown in Figure 2. Edaravone suspension administered orally and via NGT showed similar plasma concentration–time profiles of unchanged edaravone regardless of the administration route. Plasma PK parameters of unchanged edaravone are shown in Table 2. The median t_max values of unchanged edaravone administered orally and via NGT were 0.500 and 0.250 hours, respectively. The mean C_max, AUC_0–t, and AUC_0–∞ of unchanged edaravone were similar between the two administration routes. There were also no notable differences in other PK parameters between the two administration routes.

Figure 2.

Mean plasma concentration–time profile of unchanged edaravone after oral administration and administration via NGT for (a) 0–48 hours (log‐linear plot) and (b) 0–12 hours (linear plot). The error bars show SDs. NGT, nasogastric tube; SD, standard deviation.

Table 2.

Plasma Pharmacokinetic Parameters of Unchanged Edaravone

		tmax a (h)	Cmax (ng/mL)	AUC0–t (ng · h/mL)	AUC0–∞ (ng · h/mL)	t1/2 (h)	CL/F (L/h)
Oral (N = 36)	Mean	0.50	2470	2612	2657	21.52	42.8
	CV%	0.25, 0.50	34.0	30.1	30.1	157.2	28.8
NGT (N = 36)	Mean	0.25	2775	2592	2617	13.53	43.8
	CV%	0.08, 1.00	52.1	33.4	33.2	102.1	28.7

AUC, area under the plasma concentration–time curve; CL/F, apparent total clearance; C_max, maximum plasma concentration; CV, coefficient of variation; NGT, nasogastric tube; t_1/2, elimination half‐life; t_max, time to reach C_max.

^a Median, range.

The results of statistical analysis for the comparative bioavailability of C_max, AUC_0–t, and AUC_0–∞ of unchanged edaravone between oral and NGT administration are summarized in Table 3. The geometric LS mean ratios between the two administration routes and 90%CIs for C_max, AUC_0–t, and AUC_0–∞ of unchanged edaravone were 1.052 (90%CI, 0.903–1.227), 0.987 (90%CI, 0.936–1.041), and 0.981 (90%CI, 0.931–1.033), respectively.

Table 3.

Comparative Bioavailability of Plasma Pharmacokinetic Parameters of Unchanged Edaravone

	Geometric LS Mean
	Oral	NGT	Ratio (NGT/Oral) (90%CI)
Cmax (ng/mL)	2310	2431	1.052 (0.903–1.227)
AUC0–t (ng · h/mL)	2508	2476	0.987 (0.936–1.041)
AUC0–∞ (ng · h/mL)	2551	2501	0.981 (0.931–1.033)

AUC, area under the plasma concentration–time curve; CI, confidence interval; C_max, maximum plasma concentration; LS, least‐squares; NGT, nasogastric tube.

Safety

One AE was reported in one subject (2.8%) after oral administration (blood creatinine increase) and five AEs were reported in three subjects (8.3%) after NGT administration (two events of alanine aminotransferase increase and one event each of aspartate aminotransferase increase, blood creatine phosphokinase increase, and C‐reactive protein increase). All of these AEs were mild and resolved without medication. One subject (2.8%) in the NGT administration period experienced two ADRs (alanine aminotransferase increase and aspartate aminotransferase increase). ADRs of gait disturbance, headache, and fatigue were not reported in this study. No serious AEs, serious ADRs, or AEs leading to discontinuation or death were reported during the study. No notable trends were observed in 12‐lead electrocardiogram parameters, most safety laboratory parameters, or vital signs in any of the two administration routes during this study.

Discussion

The present study was conducted to compare the relative bioavailability of edaravone oral suspension administered orally and via NGT in healthy adult Japanese subjects. A total of 36 subjects (24 male and 12 female) were included in this study, which demonstrated that edaravone oral suspension administered orally and via NGT had similar C_max, AUC_0–t, and AUC_0–∞. Furthermore, there were no distinct differences in other PK parameters. The plasma concentration–time profiles were similar between oral and NGT administration. The geometric LS mean ratios between administration routes (NGT to oral) and 90%CIs for C_max, AUC_0–t, and AUC_0–∞ of unchanged edaravone support the similarity in plasma concentrations between the two administration routes. These comparative bioavailability results suggest that oral edaravone suspension can be administered directly to the stomach via a feeding tube without the need for dose adjustment. The two administration routes for edaravone 105‐mg oral suspension were well tolerated and no safety concerns were raised. Gait disturbance, headache, and fatigue, which are known ADRs of edaravone (NCT04165824), ⁵ were not observed in this study.

The difference in median t_max between the two administration routes (oral 0.500 hours, NGT 0.250 hours) was probably due to the slight difference in time required to reach the stomach and the subsequent time of absorption with oral administration versus administration via NGT. However, the difference in t_max was not considered clinically meaningful because of the slight difference in, and overlapped ranges of, individual values. The difference in mean t_1/2 between oral administration and administration via NGT (21.52 hours vs 13.53 hours) was due to one of the subjects in the oral administration group having a t_1/2 of 204 hours. The concentration almost reached the lower limit of quantitation in the terminal elimination phase of the t_1/2 calculation, which would have been calculated as 204 hours for this subject. Excluding the subject for whom the t_1/2 was 204 hours, the t_1/2 after oral and NGT administration for the other subjects was distributed in the range of 4.76–56.8 hours and 5.20–75.5 hours, respectively, and the mean t_1/2 when this one subject was excluded was 16.32 and 13.69 hours, respectively. Therefore, this slight difference in the t_1/2 was not considered to be clinically meaningful. This finding suggests that the elimination of edaravone is similar to oral administration and administration via NGT.

Of note, the t_1/2 in the present study was longer than that previously reported for intravenously administered edaravone (4.5–6.0 hours). ¹² The t_1/2 of edaravone is greatly affected by the time point of evaluation for plasma concentration because edaravone showed triphasic elimination in the plasma concentration–time profile. The previously reported t_1/2 of 4.5–6.0 hours was calculated up to 24 hours after intravenous administration, and in the present study the t_1/2 was calculated up to 48 hours after, which may explain the difference in values.

To conduct this comparative bioavailability study with a sufficient sample size, the study was performed using healthy adult subjects rather than ALS patients with PEG. Because it is not practical to enroll many patients with ALS with PEG and not possible to administer via a PEG tube in healthy adults, NGT in healthy subjects was used as an alternative administration model for PEG. The NGT is similar to the PEG tube in that they are both positioned in the stomach, have a similar composition (generally made of silicone, silicone rubber, polyurethane, polyvinyl chloride, and polyacetal), and are compatible with edaravone oral suspension; therefore the NGT is a suitable model for PEG administration. It is suggested that the effect of administration via a PEG tube on the PKs of edaravone can be well estimated using the present study model, and our findings suggest that administration of edaravone oral suspension via a PEG tube is feasible. Although PEG is commonly used for enteral nutrition and drug administration in ALS patients after the progression of dysphagia, this study also shows that edaravone oral suspension can be administered via a feeding tube such as NGT when feeding tubes other than a PEG tube are used.

Dysphagia, a common symptom of ALS, represents a difficult challenge for providing nutrition and administering medications, therefore most patients with ALS will eventually require the insertion of a PEG tube. ¹³ The inability of a patient to swallow drugs may lead to poor treatment adherence and early discontinuation of necessary treatment. PEG tubes pose significant difficulties, especially for administering medications. Thus, changing or modifying medications, such as administering drugs via PEG or feeding tube with crushed drugs and drug suspensions in fluid, is routinely carried out to manage patients who are unable to swallow drugs. ¹⁴ , ¹⁵ However, there are limited data on whether such medication changes/modifications lead to dosage errors, changes in PKs, and subsequent alterations in the tolerability and efficacy of medications. Although there are some reports to guide caregivers and medical personnel in administering drugs via PEG or feeding tube and prevent complications related to PEG or feeding tube use, such as administering drugs that are incompatible with PEG tube administration and not preparing the medications properly, ¹⁶ , ¹⁷ , ¹⁸ the PKs of drugs after administration via PEG tube are rarely reported and confirmed. The present study findings show that plasma exposure (drug concentration) after administration via a PEG tube is sufficient and comparable to that after oral administration. Combined with the fact that edaravone plasma exposure after oral administration has been shown to be equivalent to that after intravenous administration (60 mg), these results suggest that the administration of edaravone oral suspension via PEG tube in ALS patients will have similar efficacy and safety as that of intravenous edaravone, as discussed in a previous report. ⁷

The limitations of this study include that it was conducted with healthy subjects with NGT to obtain a sufficient sample size to compare the relative bioavailability of edaravone oral suspension using two administration routes. Although the PKs of edaravone have been shown to be identical between healthy subjects and patients with ALS (NCT04176224), the PKs, safety, and tolerability in patients with ALS after administration via PEG or feeding tube was not directly investigated in this study. A separate phase 1 study investigating the PKs, safety, and tolerability of edaravone oral suspension after administration via a PEG tube in patients with ALS is being conducted to compensate for this limitation (NCT04254913). This study assessed only single dosing via NGT, so assessment after repeated administrations via PEG or feeding tubes in patients with ALS in the same dosing regimens as intravenous edaravone is also necessary. The effects in patients with ALS after administration via PEG tube are being investigated separately in clinical trials that include a large number of patients with ALS (NCT04165824, NCT04569084, and NCT04577404).

This comparative bioavailability study of 36 healthy subjects indicated that an edaravone suspension administered orally and via NGT had similar C_max and AUC_0–∞, and similar plasma concentration–time profiles. There were no clinically meaningful differences in other PK parameters. The geometric LS mean ratios and 90%CIs of C_max and AUC_0–∞ suggest a similarity in plasma concentrations between the two administration routes. The two administration routes for edaravone 105‐mg oral suspension were well tolerated, and no safety concerns were raised. These comparative bioavailability results suggest that edaravone oral suspension formulation can be administered directly to the stomach with a feeding tube (via PEG tube) without the need for dose adjustment.

Conflicts of Interest

H.S., Y.N., Y.S., M.U., S.Y., Y.K., and M.H. are employees of Mitsubishi Tanabe Pharma Corporation.

Supporting information

Supporting Information

Additional supporting information may be found in the online version of this article at the publisher's website.