Effect of recombinant granulocyte colony-stimulating factor on neutrophil kinetics in normal young and elderly humans

Abstract

Recombinant granulocyte colony-stimulating factor (G-CSF) was administered to healthy young (n = 32) and elderly (n = 19) volunteers (0 microgram/d, 30 microgram/d, or 300 microgram/d) to determine its effect on neutrophil production, blood kinetics, and tissue migration. Measurements included blood counts (daily), marrow neutrophil pool sizes and neutrophil tissue migration (baseline and day 5), blood kinetics (day 6), and marrow transit time while on drug (days 6 to 14). G-CSF markedly expanded the marrow neutrophil mitotic pool and shortened the transit time of the postmitotic pool (control, mean = 6.4 days; 300 microgram/d, mean = 2.9 d). G-CSF increased neutrophil production without significantly altering blood neutrophil half-life or margination. Compared to control, neutrophil accumulation in skin chambers decreased by about 50% in the 300 microgram/d group in both young and elderly subjects. G-CSF induced neutrophilia by stimulating proliferation of marrow neutrophil precursors and accelerating neutrophil entry into the blood. Decreased neutrophil inflammatory responses measured with the skin chamber technique may be because of the relative immaturity of the circulating cells or to alterations in neutrophil phenotype induced by G-CSF.

Duffy (Fy), DARC, and neutropenia among women from the United States, Europe and the Caribbean

“…The association observed in the current study between higher G-CSF and the DARC rs2814778 null homozygous genotype may reflect a feedback mechanism stimulated by low ANC (Semerad et al, 2002). G-CSF has been shown both to increase neutrophil production and to accelerate neutrophil entry into the blood (Price et al, 1996).…”

Pharmacokinetic/Pharmacodynamic Modeling of Pegfilgrastim in Healthy Subjects

“…Elimination of neutrophils from blood was modeled as a first-order loss, as numerous kinetic studies of labeled autologous neutrophils have demonstrated that neutrophils are eliminated randomly from circulation and not by senescence; the model estimate of segmented neutrophil half-life was consistent with these published results. 13,25 The modeling-derived EC 50 (9.86 ng/mL) and EC 90 (88.7 ng/mL) for the mitotic, mobilization, and maturational effects of pegfilgrastim in healthy subjects agree with exposure-response data collected in patients receiving chemotherapy. In patients with nonsmall-cell lung cancer who received carboplatin and paclitaxel, patients receiving 30 µg/kg pegfilgrastim experienced a lower ANC nadir and a slower ANC recovery compared to patients receiving 100-and 300-µg/kg doses.…”

“…Daily filgrastim doses of 30 and 300 µg in healthy subjects have been demonstrated to shorten the neutrophil marrow transit time to 4.3 ± 0.2 days and 2.9 ± 0.1 days, respectively, compared with a 6.3 ± 0.3-day transit time in subjects in the control group, as determined by a flash labeling study with 3 H-TdR. 25 As suggested by the model, this decreased transit time may be due, in part, to the early release of band cells and segmented neutrophils from bone marrow. The early release of neutrophils and accelerated precursor maturation may be important contributors to accelerated ANC recovery after myelosuppressive chemotherapy.…”

“…Consistent with the modeling results, neutrophil kinetic studies of filgrastim in healthy subjects have shown that filgrastim exerts mitotic effects primarily on promyelocytes and myelocytes, with a 2-to 3-fold amplification of mitosis and a minimal delay before influx of metamyelocytes. 24,25 Differential effects of pegfilgrastim on blood neutrophil populations were modeled as a pegfilgrastimdependent flux of younger neutrophils, including band cells and segmented neutrophils through early release from marrow and a decrease in maturation time. Band cells are juvenile neutrophils and differ from mature, segmented neutrophils primarily by the shape of the nucleus.…”

What's your age again? Determination of human neutrophil half-lives revisited

“…Ex vivo-labeled neutrophils showed an increased circulatory half-life compared with healthy volunteers in patients suffering from CML, sarcoidosis or liver cirrhosis, in splenectomized individuals, and when healthy volunteers received prednisolone ( Table 2) [54,55]. No difference was seen in patients suffering from rheumatoid arthritis and active inflammation or in healthy volunteers receiving G-CSF [26,35,57]. One study suggested that G-CSF and GM-CSF administration lead to increased neutrophil counts in peripheral blood by increasing the production rate rather than the circulatory half-life of neutrophils [58], whereas another study found evidence for an increased neutrophil half-life after GM-CSF administration.…”