Chen Yuancheng, Li Size, Hedrich William, Wu Xiaojie, Li Shanshan, Qiu Chao, Lin Ke, Bian Xingchen, He Jinjie, Zhou He, Adrian Francisco, Schweizer Liang, Zhang Jing
Clinical Pharmacology Research Centre, Huashan Hospital, Fudan University, Shanghai, China; National Clinical Research Centre for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China; Research Ward, Huashan Hospital, Fudan University, Shanghai, China.
HiFiBiO (Hang Zhou) Ltd, Hang Zhou, China.
Int J Antimicrob Agents. 2025 Mar;65(3):107439. doi: 10.1016/j.ijantimicag.2024.107439. Epub 2025 Jan 9.
Development of neutralizing monoclonal antibodies (nAbs) is a strategy for treatment of infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of HFB30132A, a fully human nAb targeting the SARS-CoV-2 spike protein receptor binding domain in healthy subjects. A randomized, double-blind, placebo-controlled phase I trial was performed in healthy Chinese and US subjects. The subjects (n=44) received a single ascending dose (400, 1000, 2000 mg) or placebo. Safety and PK data were analysed. PD were evaluated with a pseudovirus neutralization test in vitro using serum samples of Chinese subjects. A population PK/PD model was developed using non-linear mixed effects modelling. The effects of covariates were evaluated via covariate screening, Monte Carlo simulation and randomization tests. The PK profile was consistent with a three-compartment model. Clearance and V1 were 0.38 mL/h and 2.9 L, respectively. Ethnicity and body weight were factors affecting PK. Compared with subjects who were not Hispanic or Latino, area under the curve increased by 64% in subjects of Han nationality. PD were consistent with the effect-compartment model when 50% of neutralization dilution titre was used as the PD index. Maximal effect (E) reduced with time, consistent with the exponential model. The concentration of HFB30132A exerting 50% of E was 4590 mg/L. The half-life for reduction of E was 133 days. Albumin, lymphocytes, neutrophils and monocytes affected PD. Ethnic differences in PK and tolerance of PD were found for HFB30132A. The population PK/PD model characterized the dose-exposure-response relationship of HFB30132A in healthy subjects. These findings are useful for drug development in the future. Clinical trial registration: ClinicalTrial.gov NCT04590430, NCT05275660.
开发中和单克隆抗体（nAbs）是治疗由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的感染的一种策略。本研究评估了HFB30132A在健康受试者中的药代动力学（PK）和药效学（PD），HFB30132A是一种靶向SARS-CoV-2刺突蛋白受体结合域的全人源nAb。在中国和美国的健康受试者中进行了一项随机、双盲、安慰剂对照的I期试验。受试者（n = 44）接受单剂量递增（400、1000、2000 mg）或安慰剂。分析了安全性和PK数据。使用中国受试者的血清样本通过体外假病毒中和试验评估PD。使用非线性混合效应模型建立了群体PK/PD模型。通过协变量筛选、蒙特卡罗模拟和随机化检验评估协变量的影响。PK曲线与三室模型一致。清除率和V1分别为0.38 mL/h和2.9 L。种族和体重是影响PK的因素。与非西班牙裔或拉丁裔受试者相比，汉族受试者的曲线下面积增加了64%。当使用50%的中和稀释滴度作为PD指标时，PD与效应室模型一致。最大效应（E）随时间降低，与指数模型一致。发挥50% E的HFB30132A浓度为4590 mg/L。E降低的半衰期为133天。白蛋白、淋巴细胞、中性粒细胞和单核细胞影响PD。发现HFB30132A在PK和PD耐受性方面存在种族差异。群体PK/PD模型表征了HFB30132A在健康受试者中的剂量-暴露-反应关系。这些发现对未来的药物开发有用。临床试验注册：ClinicalTrial.gov NCT04590430，NCT05275660。
