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

Abstract

Intravenous (IV) edaravone is approved as an amyotrophic lateral sclerosis (ALS) treatment. Because IV administration places a burden on patients, development of orally administered ALS treatments is needed. Therefore, 2 phase 1 studies of oral formulations of edaravone in healthy subjects examined the pharmacokinetics (PK), safety, racial differences, and drug-drug interactions (DDIs) and investigated the dose of the oral formulation considered to be bioequivalent to the approved dose of the IV formulation. Study 1 was a placebo-controlled, randomized, single-blind study of single-ascending-dose oral edaravone with the dose range of 30 to 300 mg (n = 56). Study 2 was conducted in 2 cohorts (n = 84); the first assessed DDIs with multiple-dose edaravone 120 mg/day given over 5 or 8 days (coadministered with single-dose rosuvastatin, sildenafil, or furosemide), and the second evaluated PK and racial (Japanese/White) differences in PK parameters with doses of 100-mg edaravone. The oral formulation of edaravone was well absorbed, and plasma concentrations of unchanged edaravone increased more than dose proportionally within the dose range of 30 to 300 mg. No effect of race on oral edaravone PK and no notable DDI effects possibly caused by orally administered edaravone were observed. The oral edaravone formulations were safe and tolerable under the assessed conditions. Mathematical modeling determined that equivalent exposures in plasma with the approved dose of the IV edaravone formulation, as reported previously, could be achieved when the oral edaravone formulation was administered at a dose of ≈100 mg, with an absolute bioavailability of ≈60%.

Trial registration: ClinicalTrials.gov NCT04481750 NCT04481789.

Keywords: clinical pharmacology; drug-drug interactions; edaravone; oral formulation; phase 1 study; racial difference.

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

Mean plasma concentrations of unchanged edaravone over time after single‐dose administration of edaravone in study 1 (A) and cohort 2 in study 2 (B). Data are shown as mean ± standard deviation. The number of subjects in each cohort is denoted by N. In (A), Japanese subjects were included in all cohorts apart from cohort 7, which included White subjects. aWith xanthan gum.

Figure 2

Mean plasma concentrations of sildenafil alone and in combination with edaravone (A), furosemide alone and in combination with edaravone (B), and rosuvastatin alone and in combination with edaravone (C) in study 2. Data are shown as mean ± standard deviation. Each panel includes data for 0 to 24 or 48 hours as well as 0 to 4 or 12 hours.

Figure 3

Plasma concentration profiles of unchanged edaravone over time after multiple administrations of edaravone in groups 1 and 2 of cohort 1 in study 2. In group 1, edaravone was administered once daily for 8 days from days 6 to 13 with coadministration of 10 mg of rosuvastatin on day 9 (fourth edaravone dosing) and 50 mg of sildenafil on day 12 (seventh edaravone dosing). In group 2, edaravone was administered once daily for 5 days from days 3 to 7 with coadministration of 40 mg of furosemide on day 6 (fourth edaravone dosing). aOne subject withdrew from the study before the administration of sildenafil and edaravone.

Figure 4

Mathematical 4‐parameter logistic modeling of area under the curve (AUC) vs edaravone dose (A, B) and maximum plasma concentration (Cmax) vs edaravone dose (C) obtained in pharmacokinetic studies in healthy subjects. (B) shows data magnified from (A). The x‐axis in (C) is also magnified. AUC0‐∞ and Cmax of IV edaravone are the values for the IV formulation of edaravone at a dose of 60 mg/60 min. (A and B) AUC0‐∞ of IV edaravone = 1738 ng·h/mL. (C) Cmax of IV edaravone = 1195 ng/mL. AUC, area under plasma concentration–time curve; AUC0‐∞, AUC from time 0 to infinity; Cmax, maximum plasma concentration; IV, intravenous.