Bioavailability of Edaravone Sublingual Tablet Versus Intravenous Infusion in Healthy Male Volunteers

Purpose

Edaravone is a free-radical scavenger. Edaravone 30mg IV has been approved for use in the treatment of acute ischemic stroke in Japan and China, and for amyotrophic lateral sclerosis in Japan and the United States. Considering the inconvenience of IV infusion in clinical practice, an oral tablet formulation of edaravone was developed but failed in 2011 due to poor bioavailability. More recently, a sublingual (SL) tablet formulation of edaravone 30mg was developed by a Good Manufacturing Practices–compliant manufacturer in China. This study explored the bioavailability of the SL tablet of edaravone and aimed to provide evidence to support decision making in future clinical development.

Methods

This 2-way crossover study was conducted in 10 healthy male volunteers. Eligible subjects were randomized, in a 1:1 ratio, to 1 of 2 dosing sequences: (1) SL edaravone 30mg, followed by edaravone 30mg IV infusion given over 30 minutes; or (2) edaravone 30mg IV infusion given over 30 minutes, followed by SL edaravone 30mg. The washout period between the 2 dosing periods was at least 24hours. Serial blood samples were collected in each dosing period. The bioavailability of the SL tablet was assessed using bioavailability analysis. Tolerability was evaluated throughout the study.

Findings

The plasma concentration–time profile of the SL tablet was similar to that with the IV infusion. Amean (SD) C_max of 2030.2 (517.2) ng/mL was reached within a median T_max of 0.875hour, which was statistically significantly longer than the median T_max with IV administration (0.5 hour). The C_max with SL administration corresponded to 83.92% (90% CI, 73.22%–96.18%) of the C_max with the start of IV infusion (2354.0 [336.6] ng/mL). The mean AUC_0–t with SL dosing was 5420.07 (1429.75) h · ng/mL, which corresponded to 91.94% (90% CI, 86.81%–97.39%) of the AUC_0–t with IV administration (5824.42 [1338.48] h · ng/mL). Two cases of adverse events were reported during the study; both were considered by the investigator to have been possibly not related to the study treatment.

Implications

The bioavailability of the SL tablet of edaravone was 91.94%. Compared with IV administration, C_max with SL administration was ～17% lower and T_max was statistically significantly longer. The exposure differences can be addressed by modifying the strength of the SL tablet, and then conducting a second study to demonstrate the pharmacokinetic bioavailability of the sublingually administered new strength versus IV infusion of edaravone.