A Randomized, Double-Blind, Placebo- and Active-Controlled, Escalating Single-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Profiles of Subcutaneous Eflapegrastim in Healthy Japanese and Caucasian Subjects

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).