An assessment of the pharmacokinetics, pharmacodynamics, and tolerability of GCPGC, a novel pegylated granulocyte colony-stimulating factor (G-CSF), in healthy subjects.
BACKGROUND
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.
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine & Hospital, 103 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea.
Kwang-Hee
KH
Shin
Kyoung Soo
KS
Lim
Howard
H
Lee
In-Jin
IJ
Jang
Kyung-Sang
KS
Yu
D000328:Adult; D018952:Antigens, CD34 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006801:Humans; D007279:Injections, Subcutaneous / Q000379:methods; D007958:Leukocyte Count / Q000379:methods; D008297:Male; D009503:Neutropenia / Q000188:drug therapy; D009504:Neutrophils / Q000187:drug effects; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
D018952:Antigens, CD34; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; C423652:pegylated granulocyte colony-stimulating factor; D000069585:Filgrastim