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Investigational New Drugs

, Volume 32, Issue 4, pp 636–643 | Cite as

An assessment of the pharmacokinetics, pharmacodynamics, and tolerability of GCPGC, a novel pegylated granulocyte colony-stimulating factor (G-CSF), in healthy subjects

  • Kwang-Hee Shin
  • Kyoung Soo Lim
  • Howard Lee
  • In-Jin Jang
  • Kyung-Sang YuEmail author
PHASE I STUDIES

Summary

Introduction A pegylated recombinant human granulocyte colony-stimulating factor (G-CSF) is effective in reducing the severity and duration of neutropenia. This study was performed to investigate the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of GCPGC, a new formulation of pegylated G-CSF, in healthy volunteers and to compare them with those of pegfilgrastim (Neulasta®). Methods Twenty-five healthy Korean male volunteers randomly received a single subcutaneous (SC) GCPGC injection at a dose of 30 (n = 10), 100 (n = 10), or 300 (n = 5) μg/kg or placebo in a 4:1 ratio in a double-blind manner. Additionally, 8 subjects received a SC dose of pegfilgrastim at 100 μg/kg. Blood samples were collected up to 14 days after both therapies. The absolute neutrophil count (ANC) and CD34+ cell counts were the PD markers. Results After GCPGC administration, 4 different pharmacokinetic phases were identified, indicating target-mediated drug disposition (TMDD) for the elimination of GCPGC, which was slowed down as the dose was increased, resulting in a higher than proportional dose-normalized exposure to GCPGC. Although GCPGC was cleared faster than pegfilgrastim, leading to a 19 % lower systemic exposure to pegylated G-CSF, the increase in ANC and CD34+ were ~20 % greater by GCPGC at 100 μg/kg than pegfilgrastim. Thrombocytopenia, splenomegaly, and hemoperitoneum occurred in one subject in the 300 μg/kg GCPGC group, which resolved completely with appropriate care. Conclusions GCPGC showed a non-linear TMDD. The PK-PD characteristics of GCPGC at 30–100 μg/kg were comparable to those of pegfilgrastim at 100 μg/kg. GCPGC at 30–100 μg/kg was well tolerated in healthy Korean males.

Keywords

Pegylated G-CSF Pharmacokinetics Pharmacodynamics Tolerability Healthy subjects 

Notes

Acknowledgments

Dr. K-H Shin was supported by a training program grant of the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A070001). This study was performed by staff members of the Clinical Trials Center, Seoul National University Hospital, under the supervision of the authors. This study was supported by a grant of the Korean Health Technology R & D Project, Ministry of Health & Welfare, Republic of Korea (A091128).

Declaration of Funding

This study was supported by a research grant from Green Cross Co., Ltd, Korea.

Declaration of Financial/Other Relationships

The sponsor was not involved in the design, conduct, or analysis of the present study. The authors have nothing to declare in terms of conflict of interest.

Ethical Standards

The Institutional Review Board (IRB) at Seoul National University Hospital approved the study protocol, and the study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. (ClinicalTrials.gov registry number: NCT00969826).

Financial disclosure

This study was supported by a research grant from Green Cross Co., Ltd, Korea.

None of the authors have any conflicts of interest to disclose.

The investigational site was the Clinical Trials Center at Seoul National University Hospital.

Previous publications

This manuscript has not been previously published or simultaneously submitted for publication elsewhere. It has been read and approved by all of the authors.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Kwang-Hee Shin
    • 1
    • 3
  • Kyoung Soo Lim
    • 1
  • Howard Lee
    • 1
    • 2
  • In-Jin Jang
    • 1
  • Kyung-Sang Yu
    • 1
    Email author
  1. 1.Department of Clinical Pharmacology and TherapeuticsSeoul National University College of Medicine & HospitalSeoulKorea
  2. 2.Clinical Trials CenterSeoul National University HospitalSeoulRepublic of Korea
  3. 3.College of PharmacyResearch Institute of Pharmaceutical Sciences, Kyungpook National UniversityDaeguRepublic of Korea

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