Cao Guoying, Wang Jingjing, He Jinjie, Hu Yingying, Yang Haijing, Que Linling, Gu Xianghong, Yu Jicheng, Wu Xiaojie, Wu Jufang, Fang Wei, He Qing, Zhang Jing
Phase I Clinical Research Center, Huashan Hospital of Fudan University, Shanghai, China.
Drug Clinical Trial Institution, The Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China.
Front Pharmacol. 2023 Apr 4;14:1111893. doi: 10.3389/fphar.2023.1111893. eCollection 2023.
This study aimed to investigate the pharmacokinetics, safety, and immunogenicity of recombinant humanized anti-human IL-6R monoclonal antibody injection, LZM008, and evaluate the pharmacokinetic similarity between LZM008 and tocilizumab (ACTEMRA) in Chinese healthy male subjects. In this randomized, double-blinded, paralleled, two-center Phase I clinical trial, 96 subjects were randomized with a 1:1 ratio to receive 4 mg/kg intravenous dose of LZM008 or ACTEMRA and evaluated for 28 days. The pharmacokinetic bioequivalence was assessed by the maximum serum concentration (C), the area under the serum concentration-time curve (AUC) from time 0 to the last detectable drug concentration (AUC), and AUC. The statistical analysis was conducted using SAS Enterprise Guide statistical software. Safety was assessed by physical examinations, vital signs, laboratory tests, and electrocardiograms. Anti-drug antibodies (ADAs) were measured by a bridged electrochemiluminescence immunoassay. LZM008 (N = 49) and ACTEMRA (N = 47) groups showed similar pharmacokinetic properties. After a single intravenous infusion of 4 mg/kg LZM008, the C and AUC values of LZM008 reached 87.99 μg/mL and 11,526.70 h*μg/mL, respectively, with T 1.98 h, and the half-life (t) was 83.45 h. The 90% confidence intervals of ratios for C, AUC, and AUC were within the range of 80.00%-125.00%. After infusion, one (2.0%) subject in the LZM008 group and three (6.4%) subjects in the ACTEMRA group showed positive ADA test results. The incidence of treatment emergent adverse events (TEAEs) was comparable in LZM008 and ACTEMRA groups (98.0% 100%), with the decrease in blood fibrinogen and neutrophil counts being the most common TEAEs. The pharmacokinetic characteristics and immunogenicity exhibited by LZM008 were similar to those of the reference product, ACTEMRA. The safety profiles of LZM008 were similar in the two groups with mild-moderate adverse effects. The trial is registered at www.chinadrugtrials.org.cn (CTR20190889).
本研究旨在探讨重组人源化抗人IL-6R单克隆抗体注射液LZM008的药代动力学、安全性和免疫原性，并评估LZM008与托珠单抗（雅美罗）在中国健康男性受试者中的药代动力学相似性。在这项随机、双盲、平行、两中心的I期临床试验中，96名受试者按1:1比例随机分组，接受4mg/kg静脉注射剂量的LZM008或雅美罗，并进行28天的评估。通过最大血清浓度（Cmax）、从时间0至最后可检测药物浓度的血清浓度-时间曲线下面积（AUC0-t）以及AUC0-∞评估药代动力学生物等效性。使用SAS Enterprise Guide统计软件进行统计分析。通过体格检查、生命体征、实验室检查和心电图评估安全性。采用桥接电化学发光免疫分析法检测抗药物抗体（ADA）。LZM008组（N = 49）和雅美罗组（N = 47）显示出相似的药代动力学特性。单次静脉输注4mg/kg LZM008后，LZM008的Cmax和AUC0-t值分别达到87.99μg/mL和11,526.70h*μg/mL，Tmax为1.98h，半衰期（t1/2）为83.45h。Cmax、AUC0-t和AUC0-∞比值的90%置信区间在80.00%-125.00%范围内。输注后，LZM008组有1名（2.0%）受试者和雅美罗组有3名（6.4%）受试者ADA检测结果呈阳性。治疗期间出现的不良事件（TEAE）发生率在LZM008组和雅美罗组中相当（分别为98.0%和100%），最常见的TEAE是血纤维蛋白原和中性粒细胞计数降低。LZM008表现出的药代动力学特征和免疫原性与参比产品雅美罗相似。LZM008在两组中的安全性概况相似，不良反应为轻至中度。该试验已在中国药物临床试验登记与信息公示平台（www.chinadrugtrials.org.cn，登记号：CTR20190889）注册。
