Department of Applied Biomedical Engineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea.
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea.
Drugs R D. 2022 Mar;22(1):71-87. doi: 10.1007/s40268-021-00379-8. Epub 2022 Jan 6.
Eflapegrastim (Rolontis) is a novel long-acting pegylated recombinant human granulocyte colony-stimulating factor (G-CSF). Eflapegrastim has been developed to reduce the duration and incidence of chemotherapy-induced neutropenia in cancer patients using patient-friendly, less-frequent administration.
This phase I study aimed to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and immunogenicity of eflapegrastim following a single subcutaneous administration to healthy Japanese and Caucasian subjects.
A randomized, double-blind, placebo- and active-controlled, dose-escalation study was conducted in healthy Japanese and Caucasian subjects. Eligible subjects randomly received a single subcutaneous administration of eflapegrastim (1.1, 3.3, 10, 45, 135, and 270 μg/kg), pegfilgrastim 6 mg, or placebo in a ratio of 6:2:2 (Cohorts 1-2, Caucasian subjects only) or 12:2:2 (Cohorts 3-6, Japanese and Caucasian subjects). Safety and tolerability were assessed throughout the study. Serial blood samples were collected predose and up to day 22 postdose for PK and PD analyses. PK assessments were performed in the 45, 135, and 270 µg/kg dose groups. Antidrug antibodies to eflapegrastim were determined at baseline up to day 42 after the first dose for immunogenicity.
A total of 84 subjects (42 males and 42 females) were enrolled, and 78 (31 Japanese and 47 Caucasian subjects) completed the study as planned. Japanese and Caucasian subjects showed similar PK and PD profiles. In the 45, 135, and 270 µg/kg dose groups, the maximum serum concentration (C) of eflapegrastim exhibited a dose-proportional increase, whereas its exposure increased greater than dose proportional in both ethnic groups. The mean area under the effect-time curve (AUEC) and maximum serum concentration of both absolute neutrophil count (ANC) and CD34 cell count (CD34) increased in a dose-dependent manner. There were no significant adverse events attributable to eflapegrastim or pegfilgrastim in both Japanese and Caucasian subjects. No neutralizing antibodies against G-CSF were detected.
Eflapegrastim was safe and well tolerated at doses up to 270 μg/kg in healthy Japanese and Caucasian subjects. In both ethnic groups, eflapegrastim showed dose-dependent PK and the exposure to eflapegrastim was positively correlated with ANC and CD34 cell count. The comparable PK and PD profiles of eflapegrastim in Japanese and Caucasian subjects may indicate the same dosage regimen is acceptable.
ClinicalTrials.gov: NCT01037543 (23 December 2009).
依福拉滨（Rolontis）是一种新型长效聚乙二醇化重组人粒细胞集落刺激因子（G-CSF）。依福拉滨的开发目的是通过使用患者友好、更频繁的给药方式，减少癌症患者化疗引起的中性粒细胞减少症的持续时间和发生率。
本Ⅰ期研究旨在评估单次皮下给予健康的日本和白种人受试者后依福拉滨的安全性、耐受性、药代动力学（PK）、药效学（PD）和免疫原性。
在健康的日本和白种人受试者中进行了一项随机、双盲、安慰剂和活性对照、剂量递增研究。合格的受试者随机接受单次皮下注射依福拉滨（1.1、3.3、10、45、135 和 270 μg/kg）、培非格司亭 6 mg 或安慰剂，按 6:2:2（Cohorts 1-2，仅白种人受试者）或 12:2:2（Cohorts 3-6，日本和白种人受试者）的比例给药。在整个研究过程中评估安全性和耐受性。在给药前和给药后第 22 天之前采集连续血样，进行 PK 和 PD 分析。在 45、135 和 270 μg/kg 剂量组中进行 PK 评估。在第一次给药后第 42 天之前测定针对依福拉滨的抗体。
共纳入 84 名受试者（42 名男性和 42 名女性），78 名（31 名日本人和 47 名白种人）按计划完成了研究。日本和白种人受试者表现出相似的 PK 和 PD 特征。在 45、135 和 270 μg/kg 剂量组中，依福拉滨的最大血清浓度（C）呈剂量比例增加，而在两个种族群体中，其暴露量均呈大于剂量比例的增加。绝对中性粒细胞计数（ANC）和 CD34 细胞计数（CD34）的效应时间曲线下面积（AUEC）和最大血清浓度均呈剂量依赖性增加。在日本和白种人受试者中，均未观察到与依福拉滨或培非格司亭相关的严重不良事件。未检测到针对 G-CSF 的中和抗体。
依福拉滨在健康的日本和白种人受试者中最高剂量达 270 μg/kg 时安全且耐受良好。在两个种族群体中，依福拉滨均表现出剂量依赖性 PK，依福拉滨的暴露量与 ANC 和 CD34 细胞计数呈正相关。依福拉滨在日本和白种人受试者中的 PK 和 PD 特征相似，可能表明相同的剂量方案是可以接受的。
ClinicalTrials.gov：NCT01037543（2009 年 12 月 23 日）。
