Investigational new drugs · 2014
An assessment of the pharmacokinetics, pharmacodynamics, and tolerability of GCPGC, a novel pegylated granulocyte colony-stimulating factor (G-CSF), in healthy subjects.
СтатьяРандомизированное исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Shin Kwang-Hee, Lim Kyoung Soo, Lee Howard, Jang In-Jin, Yu Kyung-Sang
Аннотация
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.
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.