A Randomized, Single‐Blind, Placebo‐Controlled, 3‐Way Crossover Study to Evaluate the Effect of Therapeutic and Supratherapeutic Doses of Edaravone on QT/QTc Interval in Healthy Subjects

Abstract

This randomized, single‐blind, 3‐way crossover study assessed the effect of edaravone on QT interval, including an exposure‐response analysis. Twenty‐seven healthy Japanese male volunteers, aged 20 to 49 years, were randomly assigned to receive a single intravenous dose of each treatment in 1 of 3 sequences (n = 9 each): ACB, BAC, and CBA, where A was edaravone 60 mg (therapeutic dose), B was edaravone 300 mg (supratherapeutic dose), and C was normal saline (placebo). Electrocardiographs were collected to assess treatment effects. In an exposure‐response analysis, a linear model was determined to be valid and indicated no statistically significant positive slope for the relationship between change from baseline in QTcF (ΔQTcF) and edaravone concentration (0.000155 ms/(ng/mL); P = .1478); upper bounds of 2‐sided 90% confidence intervals after placebo adjustment (ΔΔQTcF) were <10 milliseconds at the geometric mean maximum concentration for each edaravone dose. Overall estimated values by time point of ΔΔQTcF ≤0.9 milliseconds, no outlier values, and no morphologic changes suggestive of repolarization abnormalities were observed. Analysis of heart rate, PR interval, and QRS duration also revealed no adverse findings. These data indicate that edaravone, even at supratherapeutic doses, does not produce clinically meaningful QT prolongation and has no clinically relevant cardiac effects.

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

“…Overall, by comparing the data from our study of oral edaravone and a prior study of the IV formulation, 18 we can see that following C max , oral edaravone elimination was triphasic, as was observed for IV edaravone. Sulfate and glucuronide conjugates of oral edaravone were the main metabolites observed, which is consistent with the observation after IV infusion 15 .…”

“…Racial differences in the PK of unchanged edaravone and its metabolites were examined at oral edaravone doses of 200 mg and 100 mg, the latter of which is closer to the dose that provides equivalent plasma exposures to approved IV edaravone of 60 mg 18 . Notably, there were no remarkable differences in the PK profile of unchanged edaravone, or the sulfate and glucuronide conjugates between healthy Japanese and White subjects.…”

“…Bioequivalent doses of the edaravone oral suspension to the edaravone IV formulation were estimated with a 4‐parameter logistic model, using log‐transformed C max or AUC 0‐∞ obtained in the oral dose range of 30 to 300 mg in study 1 and study 2 using the following nonlinear regression equation: ln ( Y ) = δ + (α−δ) / [1 + ( X / γ) β ], where Y is the PK parameter and X is the dose. These were calculated to yield C max or AUC 0‐∞ equivalent to those after infusion of the approved 60 mg/60 min edaravone IV formulation (ie, 1195 ng/mL or 1738 ng·h/mL, respectively) obtained in a previous study of the edaravone IV formulation in healthy Japanese subjects at the therapeutic dose 18 …”

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

“…The composition of the edaravone oral suspension is summarized in Table 1. A 105‐mg dose of edaravone oral suspension was selected for assessment so it would provide an AUC corresponding to those of the approved 60‐minute IV infusion of edaravone 60 mg, 18 as predicted in previous studies 21 . Specifically, using a 4‐parameter logistic model developed with the relationship between the AUC from time 0 to infinity (AUC 0‐∞ ) with extrapolation of the terminal phase values and oral doses with the range of 30 to 300 mg of edaravone, the predicted AUC 0‐∞ values after administration of 100‐ and 105‐mg oral doses would be 0.97‐fold (90% confidence interval [CI], 0.84‐1.11) and 1.06‐fold (90%CI, 0.91‐1.20), respectively, compared with that of 60‐mg IV edaravone 21 .…”

“…To achieve sufficient exposures of edaravone in plasma for subsequent treatment effects and to prevent the AUC and C max of the oral suspension from falling short of respective values of IV edaravone, the 105‐mg dose was considered preferable, based on the AUC and C max values and their 90%CI of oral doses estimated from model analysis. 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 .…”