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

Abstract Purpose Edaravone is a free-radical scavenger. Edaravone 30 mg 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 30 mg 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 30 mg, followed by edaravone 30 mg IV infusion given over 30 minutes; or (2) edaravone 30 mg IV infusion given over 30 minutes, followed by SL edaravone 30 mg. The washout period between the 2 dosing periods was at least 24 hours. 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. A mean (SD) C max of 2030.2 (517.2) ng/mL was reached within a median T max of 0.875 hour, 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.