Pharmacokinetic and pharmacodynamic properties of a new long-acting granulocyte colony-stimulating factor (HM10460A) in healthy volunteers.
BACKGROUND
HM10460A is a newly developed recombinant human granulocyte colony-stimulating factor with long-lasting characteristics. This factor is expected to be used for chemotherapy-related neutropenic conditions.


OBJECTIVE
The aim of the present study was to evaluate the pharmacokinetics and pharmacodynamics of HM10460A following subcutaneous administration to healthy Korean subjects.


METHODS
A randomized, double-blind, placebo-controlled, escalating single-dose study was conducted in 40 healthy Korean subjects. The subjects were allocated to single-dose groups of 5, 15, 45, 135 or 350 μg/kg, or placebo. Serial blood samples for pharmacokinetic/pharmacodynamic analyses were collected up to 22 days, and urine samples for pharmacokinetic analysis were collected up to 3 days after subcutaneous administration of HM10460A. The serum and urine concentrations were analyzed by enzyme-linked immunosorbent assay.


RESULTS
Most of the serum concentrations in the 5 and 15 μg/kg dosing groups were below the lower limit of quantification (LLOQ). The median times to the peak concentration (T(max)) of HM10460A in the 45, 135, and 350 μg/kg dosing groups were 8.0, 14.0, and 24.0 h, respectively. The mean ± standard deviation values of the dose-normalized maximum concentration (C(max)) and dose-normalized area under the concentration-time curve (AUC(last)) for the 45, 135, and 350 μg/kg dosing groups were 14.13 ± 6.37, 66.19 ± 38.71, and 34.65 ± 19.69 μg/L/mg, respectively, and 265.0 ± 124.1, 2144 ± 1232, and 1386 ± 701.2 μg h/L/mg, respectively. The concentrations of HM10460A in the urine were below the LLOQ in all of the subjects. In all of the dosing groups, the area under the effect-time curve (AUEC(last)) of both the absolute neutrophil count (ANC) and the CD34(+) cell count increased as the dose increased.


CONCLUSIONS
HM10460A showed dose-dependent pharmacokinetic characteristics, and the systemic exposure of HM10460A was positively correlated with the ANC and CD34(+) cell counts.
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101 Daehak-ro, Seoul 110-744, Korea.
Kwang-Hee
KH
Shin
Tae-Eun
TE
Kim
Kyoung Soo
KS
Lim
Seo-Hyun
SH
Yoon
Joo-Youn
JY
Cho
Sei-Eun
SE
Kim
Kyung-Mi
KM
Park
Sang-Goo
SG
Shin
In-Jin
IJ
Jang
Kyung-Sang
KS
Yu
D000328:Adult; D018952:Antigens, CD34 / Q000096:biosynthesis; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D007958:Leukocyte Count; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D013997:Time Factors; D055815:Young Adult
D018952:Antigens, CD34; D003692:Delayed-Action Preparations; D007141:Immunoglobulin Fc Fragments; D016179:Granulocyte Colony-Stimulating Factor; C583329:eflapegrastim