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/m ² 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.