Relationship between absolute neutrophil count profiles and pharmacokinetics of DA-3031, a pegylated granulocyte colony-stimulating factor (pegylated-G-CSF): a dose block-randomized, double-blind, dose-escalation study in healthy subjects.
BACKGROUND
DA-3031 is a newly developed pegylated filgrastim, a recombinant human granulocyte colony-stimulating factor, that is expected to have an extended duration of action compared with non-modified filgrastim.


OBJECTIVE
This study evaluated the tolerability, pharmacokinetics, and pharmacodynamics of DA-3031 in humans, and compared them with filgrastim.


METHODS
The study was conducted in 48 healthy male Korean subjects. Forty subjects received subcutaneous single doses of 1.8, 3.6, 6, or 18 mg of DA-3031 or placebo in a dose block-randomized, double-blind, dose-escalation design. The remaining eight subjects were given subcutaneous doses of 100 μg/m² of filgrastim daily for 5 days. Serial blood samples were collected for pharmacokinetic and pharmacodynamic analyses up to 312 h after the administration of DA-3031 and up to 264 h following the first administration of filgrastim.


RESULTS
DA-3031 reached its peak plasma concentration at 6.0-48.0 h and was eliminated mono-exponentially. The pharmacokinetic parameters of DA-3031 increased with dose in a non-linear fashion. Absolute neutrophil count (ANC) levels increased with the dose of DA-3031, although the extent of the increase in ANC decreased at higher dose levels. DA-3031 resulted in similar ANC changes in the 3.6 to 6 mg dose range as 100 μg/m² of filgrastim. The most frequent adverse event was back pain, which was observed after both DA-3031 and filgrastim administration.


CONCLUSIONS
DA-3031 showed non-linear pharmacodynamic and pharmacokinetic profiles and an extended duration of action compared with non-modified filgrastim, without unexpected toxicities in healthy subjects.
Li Young
LY
Ahn
Kwang-Hee
KH
Shin
Kyoung Soo
KS
Lim
Tae-Eun
TE
Kim
Hyewon
H
Jeon
Seo Hyun
SH
Yoon
Joo-Youn
JY
Cho
Sang-Goo
SG
Shin
In-Jin
IJ
Jang
Kyung-Sang
KS
Yu
D000328:Adult; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D064368:Healthy Volunteers; D006801:Humans; D007958:Leukocyte Count; D057230:Limit of Detection; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D010919:Placebos; D011092:Polyethylene Glycols / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
D010919:Placebos; C486981:pegylated granulocyte colony-stimulating factor, human; D016179:Granulocyte Colony-Stimulating Factor; D011092:Polyethylene Glycols