An Open-label, Single-dose Study to Evaluate the Pharmacokinetic Variables of Edaravone in Subjects with Mild, Moderate, or No Renal Impairment

• Published in: Clinical therapeutics Vol. 42; no. 9; pp. 1699 - 1714
• Main Authors: Nakamaru, Yoshinobu, Kakubari, Masae, Yoshida, Kaori, Akimoto, Makoto, Kondo, Kazuoki
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2020; Elsevier Limited
• Subjects: Adult; Aged; Alcohol; Amyotrophic lateral sclerosis; Antigens; Area Under Curve; Bilirubin; Biochemistry; Birth control; Complications; Cytochrome; Disease; Dosage; Drug dosages; edaravone; Edaravone - administration & dosage; Edaravone - pharmacokinetics; FDA approval; Female; Food; Glomerular Filtration Rate; Headache; Hematology; Hepatitis; Humans; Internal Medicine; Intravenous administration; Japan; Japanese; Male; Medical Education; Medical laboratories; Metabolites; Middle Aged; Pharmacokinetics; Plasma; Renal function; renal impairment; Renal Insufficiency - physiopathology; Statistical analysis; Sulfates; Urinalysis; Urine; Vital signs; Vomiting; Japan; United States > US; pharmacokinetics; edaravone; Japanese; renal impairment
• DOI: 10.1016/j.clinthera.2020.06.020
• ISSN: 0149-2918; 1879-114X

The goal of this study was to compare edaravone pharmacokinetic (PK) variables and tolerability after a single intravenous (IV) infusion of 30 mg over 60 min in subjects with mild renal impairment (estimated glomerular filtration rate 60–89 mL/min/1.73 m2), moderate renal impairment (30–59 mL/min/1.73 m2), or normal renal function (≥90 mL/min/1.73 m2). This open-label, single-dose study was conducted in Japan. After a screening period of up to 3 weeks, all subjects received a single IV dose of edaravone 30 mg/h on day 1. Blood samples were collected for PK analysis of edaravone and its sulfate conjugate for up to 48 h postdose. Edaravone was administered to 30 subjects: 11 with mild (Group 1), 8 with moderate (Group 2), and 11 with no (Group 3) renal impairment. Although geometric least-squares mean values for Cmax and AUC0–∞ for unchanged edaravone were 1.15- and 1.20-fold greater in Group 1 than in Group 3, and were 1.25- and 1.30-fold greater in Group 2 than in Group 3, no statistically significant differences in exposure (Cmax and AUC) to edaravone were noted between the 3 groups (P > 0.05). The geometric least-squares mean values for Cmax and AUC0–∞ for the sulfate conjugate were 1.41- and 1.50-fold greater in Group 1 than in Group 3, and 1.41- and 1.97-fold greater in Group 2 than in Group 3. Differences in exposure (Cmax and AUC) to the sulfate conjugate of edaravone were statistically significant between the 3 study groups (P < 0.0001). A total of 5 treatment-emergent adverse events in 3 subjects in Group 1 were considered by the investigator to be reasonably related to edaravone: headache (2 events/2 subjects), vomiting (2 events/1 subjects), and increased blood bilirubin level (n = 1). These treatment-emergent adverse events were mild and recovered without sequelae. Mild to moderate renal impairment had no clinically significant effects on the PK profile of edaravone in Japanese subjects, relative to individuals with normal renal function, and there were no significant safety concerns. Thus, edaravone dosage adjustments are unlikely to be needed in patients with mild to moderate renal impairment. Clinicaltrials.gov identifier: NCT03289208. •Renal impairment did not significantly affect edaravone PK in Japanese patients.•Edaravone sulfate conjugate is a substrate for human organic anion transporters.•Reduced transporters may hypothetically increase sulfate conjugate levels.•Edaravone dosage adjustments may not be required in mild to moderate renal impairment.