Chen Rui, Zhao Qian, Wu Ni, Zhong Wen, Jin Xin, Liu Chunyan, Zhu Zhenyu, Hu Pei
Int J Clin Pharmacol Ther. 2019 Dec;57(12):596-602. doi: 10.5414/CP203550.
To evaluate the pharmacokinetics of PC-SOD after single intravenous administration and its safety profile in healthy Chinese subjects.
This was a phase 1, randomized, double-blind, placebo-controlled, sequential, single-dose, and dose-escalation study. The study was done in 4 cohorts and a total of 40 subjects received a single dose of PC-SOD (from 20 to 160 mg). There were 12 subjects in each dose group (10 active treatments and 2 placebos), except a 20-mg group, in which all 4 subjects were given active treatment. Serial venous blood samples were collected up to 168 hours after dosing. Serum samples were analyzed using an enzyme-linked immunosorbent assay. Pharmacokinetic parameters of PC-SOD were calculated via noncompartmental analysis using the WinNonlin.
After intravenous administration, PC-SOD reached the peak concentration quickly with a median t of 0.5 - 1.3 hours across all dose cohorts. After reaching C, the mean T was 35.9 - 42.3 hours, which was independent of dose. The CL and V were 0.13 L/h and 6.72 L, 0.13 L/h and 7.33 L, and 0.11 L/h and 6.88 L for the 40, 80, and 160 mg dose cohorts, respectively. Over the dose range of 20 - 160 mg, the mean C increased from 5,546.6 to 44,145.2 h×ng/mL and AUC increased from 117,464.5 to 1,348,209.4 h×ng/mL. The 90% CI for β of AUC or C slightly exceeded the criterion, indicating that there was approximate dose proportionality over the range of 20 - 160 mg or 40 - 160 mg of PC-SOD. Generally, PC-SOD was well tolerated in doses up to 160 mg in healthy Chinese subjects. Reversible elevated blood triglyceride levels were reported in 2 subjects as moderate adverse events, and all other reported adverse events were considered to be mild. The possibility of a drug hypersensitivity syndrome was not high for PC-SOD in Chinese subjects based on current data.
Single intravenous administrations of PC-SOD in doses up to 160 mg were well tolerated in healthy Chinese subjects. The prolonged half-life of PC-SOD was confirmed and independent of dose. Over the range of 20 - 160 mg, PC-SOD showed approximate dose proportionality. These findings suggest that it is worthwhile to investigate PC-SOD in clinical conditions characterized by a high radical overload.
评估聚乙二醇化超氧化物歧化酶（PC-SOD）单次静脉给药后的药代动力学及其在健康中国受试者中的安全性。
这是一项1期、随机、双盲、安慰剂对照、序贯、单剂量和剂量递增研究。该研究分为4个队列，共有40名受试者接受了单剂量的PC-SOD（20至160毫克）。每个剂量组有12名受试者（10名接受活性治疗，2名接受安慰剂），但20毫克组的4名受试者均接受活性治疗。给药后长达168小时内采集系列静脉血样。血清样本采用酶联免疫吸附测定法进行分析。PC-SOD的药代动力学参数通过使用WinNonlin进行非房室分析来计算。
静脉给药后，PC-SOD在所有剂量队列中均迅速达到峰值浓度，中位达峰时间为0.5至1.3小时。达到峰浓度后，平均消除半衰期为35.9至42.3小时，与剂量无关。40毫克、80毫克和160毫克剂量队列的清除率（CL）和分布容积（V）分别为0.13升/小时和6.72升、0.13升/小时和7.33升以及0.11升/小时和6.88升。在20至160毫克的剂量范围内，平均峰浓度（Cmax）从5546.6升高至44145.2小时×纳克/毫升，曲线下面积（AUC）从117464.5升高至1348209.4小时×纳克/毫升。AUC或Cmax的β值的90%置信区间略超过标准，表明在20至160毫克或40至160毫克的PC-SOD剂量范围内存在近似剂量比例关系。总体而言，健康中国受试者中高达160毫克剂量的PC-SOD耐受性良好。有2名受试者报告了可逆性的血液甘油三酯水平升高，为中度不良事件，所有其他报告的不良事件均被认为是轻度的。根据现有数据，PC-SOD在中国受试者中发生药物超敏反应综合征的可能性不高。
健康中国受试者中单次静脉给予高达160毫克剂量的PC-SOD耐受性良好。PC-SOD的半衰期延长得到证实且与剂量无关。在20至160毫克的范围内，PC-SOD显示出近似剂量比例关系。这些发现表明，在以高自由基负荷为特征的临床情况下研究PC-SOD是值得的。
