Background: Edaravone is used for the treatment of amyotrophic lateral sclerosis (ALS) in intravenous (IV) and oral formulations in several countries. Although the pharmacokinetics (PK) of edaravone has been investigated in several clinical pharmacology studies, there are limited data to directly compare the PK of edaravone in Japanese and non-Japanese subjects at the dosage for ALS (60 mg IV in 60 minutes or 105 mg orally). We compared the PK profiles of edaravone by population PK (PPK) analysis, which integrates PK data from different dosing regimens, and explored factors affecting PK. Methods: PK data from clinical studies of edaravone administered intravenously and orally in Japanese and non-Japanese subjects were combined and evaluated by PPK analysis using a nonlinear mixed effects model. First, PPK model was developed using a 3-compartment model incorporating the saturated elimination based on PK data after IV administration. PK data after oral administration were then added to datasets, and the model was modified with a first-order absorption process to the final model. Covariates of intrinsic and extrinsic factors on the PK of edaravone were explored, and the effects of the covariates on PK were investigated by simulation. Results: lasma edaravone concentrations at a total of 7534 time points from 415 subjects after IV and oral administration were used in the PPK analysis, and edaravone PK could be described by a common final model. Although body weight, subject population (ALS patients and healthy subjects), formulation composition, and concomitant medications were included as significant covariates in the final model, factors other than body weight did not appear to affect the PK of the IV and oral edaravone formulations. The AUC and Cmax,ss ratios of non- Japanese to Japanese were 74.3% (90%CI: 69.8-79.2%) and 76.9% (90%CI: 71.3-83.0%), respectively, indicating that the AUC of non-Japanese was significantly lower than that of Japanese. However, the upper limit of the CI for the AUC ratio was very close to 80%, and the upper limit of the CI for Cmax,ss exceeded 80%, suggesting no clinically meaningful effect and no racial difference between non-Japanese and Japanese. Conclusion: PPK analysis of edaravone showed no clinically meaningful differences in exposure between Japanese and non-Japanese.
