Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
Clin Ther. 2020 Sep;42(9):1699-1714. doi: 10.1016/j.clinthera.2020.06.020. Epub 2020 Aug 28.
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 m), moderate renal impairment (30-59 mL/min/1.73 m), or normal renal function (≥90 mL/min/1.73 m).
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 C and AUC 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 (C and AUC) to edaravone were noted between the 3 groups (P > 0.05). The geometric least-squares mean values for C and AUC 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 (C 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.
本研究旨在比较轻度肾功能损害（肾小球滤过率 60-89mL/min/1.73m）、中度肾功能损害（30-59mL/min/1.73m）和肾功能正常（≥90mL/min/1.73m）受试者单次静脉输注 30mg 依达拉奉 60 分钟后依达拉奉的药代动力学（PK）变量和耐受性。
这是一项在日本进行的开放标签、单次剂量研究。在筛选期最长达 3 周后，所有受试者于第 1 天接受依达拉奉 30mg/h 单次静脉滴注。在给药后 48 小时内采集血样进行依达拉奉及其硫酸结合物的 PK 分析。
本研究共纳入 30 名受试者：11 名轻度肾功能损害（第 1 组）、8 名中度肾功能损害（第 2 组）和 11 名肾功能正常（第 3 组）。尽管第 1 组中未改变的依达拉奉 C 和 AUC 的几何均数最小二乘均值分别比第 3 组高 1.15 倍和 1.20 倍，第 2 组比第 3 组高 1.25 倍和 1.30 倍，但 3 组间依达拉奉暴露量（C 和 AUC）无统计学差异（P>0.05）。第 1 组中硫酸结合物的 C 和 AUC 的几何均数最小二乘均值分别比第 3 组高 1.41 倍和 1.50 倍，第 2 组比第 3 组高 1.41 倍和 1.97 倍。依达拉奉硫酸结合物的暴露量（C 和 AUC）在 3 个研究组间有统计学差异（P<0.0001）。第 1 组中 3 名受试者的 5 种治疗出现的不良事件被研究者认为与依达拉奉合理相关：头痛（2 例/2 名受试者）、呕吐（2 例/1 名受试者）和胆红素水平升高（n=1）。这些治疗出现的不良事件均为轻度，且无后遗症恢复。
与肾功能正常者相比，轻度至中度肾功能损害对日本受试者依达拉奉的 PK 特征无临床意义影响，且无明显安全性担忧。因此，轻度至中度肾功能损害患者可能不需要调整依达拉奉剂量。临床试验.gov 标识符：NCT03289208。
