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

Hidetoshi Shimizu, Yukiko Nishimura, Youichi Shiide, Kaori Yoshida, Manabu Hirai, Munetomo Matsuda, Yoshinobu Nakamaru, Yuichiro Kato, Kazuoki Kondo, Hidetoshi Shimizu, Yukiko Nishimura, Youichi Shiide, Kaori Yoshida, Manabu Hirai, Munetomo Matsuda, Yoshinobu Nakamaru, Yuichiro Kato, Kazuoki Kondo

Abstract

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.

Trial registration: ClinicalTrials.gov NCT04493281.

Keywords: ALS; amyotrophic lateral sclerosis; bioequivalence study; clinical pharmacology; edaravone; oral formulation.

Conflict of interest statement

All authors are employees of Mitsubishi Tanabe Pharma Corporation, which manufactures and markets edaravone.

© 2021 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Mean plasma concentration–time profiles of unchanged edaravone for the 105‐mg oral suspension and the 60‐mg IV formulation (log‐linear plot). Data are shown as mean + standard deviation. IV, intravenous.
Figure 2
Figure 2
Mean plasma concentration‐time profiles of sulfate conjugate (A) and glucuronide conjugate (B) for the 105‐mg oral suspension or the 60‐mg IV formulation (log‐linear plot). Data are shown as mean + standard deviation. IV, intravenous.

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Source: PubMed

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