Evaluation of Pharmacokinetics, Safety, and Drug‐Drug Interactions of an Oral Suspension of Edaravone in Healthy Adults

Shimizu, H.; Nishimura, Yukiko; Shiide, Yoichi; Matsuda, Hideaki; Akimoto, Mami; Matsuda, Munetomo; Nakamaru, Yoshinobu; Kato, Yuichiro; Kondo, Kazuoki

doi:10.1002/cpdd.925

Cited by 21 publications

(36 citation statements)

References 23 publications

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“…As one of the factors contributing to the equivalent exposures between 2 formulations, edaravone was considered to remain sufficiently soluble to be orally absorbed using the 105‐mg oral suspension formulation used in this study, followed by rapid absorption from the gastrointestinal tract to systemic blood. The dose of oral edaravone was planned appropriately for the equivalent plasma exposures considering the nonlinearity of the PK of oral edaravone based on the statistically meaningful calculations, which was previously determined 21 …”

Section: Discussionmentioning

confidence: 99%

“…The AUC 0‐∞ and C max of 60‐mg IV edaravone were calculated to be 1738 ng·h/mL and 1195 ng/mL, respectively 18 . The AUC 0‐∞ and C max of 105‐mg edaravone oral suspension were estimated to be 1828 ng·h/mL and 1661 ng/mL, respectively 21 . Therefore, subjects under fasted conditions in group 1 received the 105‐mg edaravone oral suspension in period I and the 60 mg/60 min edaravone IV formulation in period II.…”

Section: Methodsmentioning

confidence: 99%

“…The calculation was performed so that for AUC 0‐∞ , the 2‐sided 90%CI of the mean ratio of edaravone oral suspension to edaravone IV would fall within the bioequivalence criterion of 0.80 to 1.25; and for C max , the lower limit of the 2‐sided 90%CI would exceed 0.80. The intraindividual standard deviations of log‐transformed AUC 0‐∞ and C max were assumed to be 0.232 and 0.706, respectively, from the previous study 21 . Assuming that the expected ratios of AUC 0‐∞ and C max of edaravone oral suspension to edaravone IV were 1.06 and 1.40 from the 4‐parameter logistic model, the necessary total numbers of subjects calculated on the basis of 2 one‐sided tests with a significance level of 5% and power ≥90% were 36 and 24, respectively.…”

Section: Methodsmentioning

confidence: 99%

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Bioequivalence Study of Oral Suspension and Intravenous Formulation of Edaravone in Healthy Adult Subjects

Shimizu¹,

Nishimura²,

Shiide³

et al. 2021

Clinical Pharm in Drug Dev

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The neuroprotective agent edaravone is an intravenous treatment for amyotrophic lateral sclerosis. As intravenous administration burdens patients, orally administered treatments are needed. This phase 1, open‐label, single‐dose crossover study in 42 healthy adults evaluated bioequivalence of a 105‐mg edaravone oral suspension and intravenous edaravone (60 mg/60 min). The evaluation was whether the 90% confidence intervals (CIs) for the ratio of the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from time 0 to the last quantifiable time point and to infinity of unchanged edaravone were between the bioequivalence limit of 0.80 and 1.25. Metabolic profiles and elimination pathways were also compared between the 2 routes. Geometric mean ratios and 90%CIs of area under the plasma concentration–time curve from time 0 to the last quantifiable time point and to infinity for unchanged edaravone satisfied bioequivalence limits. The geometric mean ratio and its lower limit of 90%CI of Cmax of the 105‐mg oral suspension compared with 60‐mg intravenous formulations for unchanged edaravone fell within bioequivalence limits. Both formulations showed triphasic plasma concentration–time profiles of unchanged edaravone after reaching Cmax. Plasma concentrations of edaravone inactive metabolites after oral administration were higher than with intravenous administration. Edaravone in both routes underwent urinary excretion, mainly as the glucuronide conjugate and, to a lesser extent, as the sulfate conjugate. Urinary excretion of unchanged edaravone was low, and urinary relative composition ratios of unchanged edaravone and metabolites were similar for both formulations. These findings showed equivalent exposure of the 105‐mg oral suspension of edaravone to the 60‐mg intravenous formulation, supporting further investigation of the oral suspension for treating amyotrophic lateral sclerosis.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Bioequivalence Study of Oral Suspension and Intravenous Formulation of Edaravone in Healthy Adult Subjects

Shimizu¹,

Nishimura²,

Shiide³

et al. 2021

Clinical Pharm in Drug Dev

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“…Amyotrophic lateral sclerosis (ALS) is a disorder that causes degeneration of cerebral and spinal cord motor neurons. Although its disease progression rate greatly differs depending on individuals, death occurs within 3–5 years after its diagnosis without ventilator support [ 1 ]. The underlying cause of ALS remains unclear.…”

Section: Introductionmentioning

confidence: 99%

“…According to the US FDA drug label, the initial treatment cycle requires daily dosing of edaravone 60 mg for 14 days followed by a 14-day drug-free period with subsequent treatment cycles of daily dosing of edaravone 60 mg for 10 days out of a 14-day period, followed by a 14-day drug-free period. As its approved route of administration and treatment cycle greatly burden ALS patients and caregivers, an edaravone oral formulation is needed [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Pre-Clinical Pharmacokinetic Characterization, Tissue Distribution, and Excretion Studies of Novel Edaravone Oral Prodrug, TEJ-1704

Kang

Kim

et al. 2021

Pharmaceutics

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Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a free radical scavenger approved for the treatment of amyotrophic lateral sclerosis, a fatal neuromuscular disease. Edaravone is administered as an intravenous infusion over 60 min for several treatment cycles. To ease the burden of patients and caregivers, the oral formulation of edaravone has been developed. The purpose of this study was to evaluate pharmacokinetics and tissue distribution of TEJ-1704, an edaravone oral prodrug, in male Sprague Dawley rats and beagle dogs. Animal experiments were conducted using Sprague Dawley rats and beagle dogs to evaluate pharmacokinetics, tissue distribution, and excretion of TEJ-1704. Blood, tissues, cerebrospinal fluid, urine, and feces samples were collected at designated sampling time after intravenous (IV) or oral (PO) administration of edaravone or TEJ-1704. A modified bioanalysis method was developed to quantify edaravone in samples including plasma, tissues, cerebrospinal fluid, urine, and feces. The bioanalysis method was validated and successfully applied to pharmacokinetics, tissue distribution, and excretion studies of the novel edaravone prodrug. Although plasma Cmax of TEJ-1704 was low, groups administered with TEJ-1704 had high AUCinf, suggesting continuous metabolism of TEJ-1704 into edaravone. Groups treated with TEJ-1704 also showed lower CSF distribution than the control groups. After the administration of TEJ-1704, the majority of edaravone was distributed to the heart, lung, and kidney. It was excreted equally via urine and feces. The pharmacokinetics, tissue distribution, and excretion of TEJ-1704, a novel edaravone oral prodrug, were successfully characterized. Additional studies are needed to fully understand the difference between TEJ-1704 and edaravone and determine the potency of TEJ-1704.

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

Shimizu

Nishimura

Shiide

et al. 2022

Clinical Pharm in Drug Dev

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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.

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Evaluation of Pharmacokinetics, Safety, and Drug‐Drug Interactions of an Oral Suspension of Edaravone in Healthy Adults

Cited by 21 publications

References 23 publications

Bioequivalence Study of Oral Suspension and Intravenous Formulation of Edaravone in Healthy Adult Subjects

Bioequivalence Study of Oral Suspension and Intravenous Formulation of Edaravone in Healthy Adult Subjects

Pre-Clinical Pharmacokinetic Characterization, Tissue Distribution, and Excretion Studies of Novel Edaravone Oral Prodrug, TEJ-1704

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

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