Background

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.

Objective

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.

Methods

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.

Results

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_max) 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_last) and maximum serum concentration of both absolute neutrophil count (ANC_max) and CD34⁺ cell count (CD34⁺_max) 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.

Conclusions

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.

Clinical Trial Registration

ClinicalTrials.gov: NCT01037543 (23 December 2009).

中文翻译：

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一项随机、双盲、安慰剂和活性对照、逐步升级的单剂量研究，以评估健康日本和白种人受试者皮下注射依拉司亭的安全性、耐受性、药代动力学和药效学特征

背景

Eflapegrastim (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)。Eflapegrastim 已被开发用于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，使用对患者友好、频率较低的给药。

客观的

这项 I 期研究旨在评估对健康日本和高加索受试者单次皮下给药后依拉司亭的安全性、耐受性、药代动力学 (PK)、药效学 (PD) 和免疫原性。

方法

在健康的日本和高加索人受试者中进行了一项随机、双盲、安慰剂和活性药物对照的剂量递增研究。符合条件的受试者以 6:2:2 的比例随机接受单次皮下给药依非格司亭（1.1、3.3、10、45、135 和 270 μg/kg）、培非格司亭或安慰剂（队列 1-2，白种人仅限科目）或 12:2:2（队列 3-6，日语和高加索科目）。在整个研究过程中评估了安全性和耐受性。在给药前和给药后第 22 天收集系列血样用于 PK 和 PD 分析。在 45、135 和 270 µg/kg 剂量组中进行 PK 评估。在基线至第一次给药后第 42 天，测定依弗拉司亭的抗药抗体的免疫原性。

结果

共招募了 84 名受试者（42 名男性和 42 名女性），78 名（31 名日本人和 47 名白种人受试者）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 曲线。在 45、135 和 270 µg/kg 剂量组中，依弗拉司亭的最大血清浓度 ( Cmax ₎表现出与剂量成正比的增加，而在两个种族群体中其暴露增加大于剂量成比例。作用时间曲线下的平均面积 (AUEC _{last ) 和中性粒细胞绝对计数 (ANC max} ) 和 CD34 ⁺细胞计数 (CD34 ⁺ _max ) 的最大血清浓度) 以剂量依赖的方式增加。在日本和高加索受试者中均未发生可归因于依拉司亭或培非格司亭的显着不良事件。未检测到针对 G-CSF 的中和抗体。

结论

在健康的日本和高加索受试者中，Eflapegrastim 在高达 270 μg/kg 的剂量下是安全且耐受良好的。在两个种族组中，依拉司亭显示出剂量依赖性 PK，并且依拉司亭的暴露量与 ANC 和 CD34 ⁺细胞计数呈正相关。在日本和高加索受试者中，依拉司亭的可比 PK 和 PD 曲线可能表明相同的剂量方案是可以接受的。

临床试验注册

ClinicalTrials.gov：NCT01037543（2009 年 12 月 23 日）。