Crossover study of the haematological effects and pharmacokinetics of glycosylated and non‐glycosylated G‐CSF in healthy volunteers

Abstract

Summary.A cross-over study of glycosylated and nonglycosylated G-CSF was performed in 20 healthy male volunteers to compare the effects of the different forms of G-CSF, the extent of inter-individual progenitor cell mobilization and to determine whether any differences observed were related to the serum concentrations of G-CSF attained. The peak WBC achieved during 6 d of G-CSF administration at a dose of 5 mg/kg/d was significantly higher with the glycosylated than the non-glycosylated product (P ¼ 0 . 02) as was the peak level of granulocyte-monocyte colony forming cells (GM-CFC) (P ¼ 0 . 03). The average GM-CFC count on days 5, 6 and 7 was 28% higher with the glycosylated product (P ¼ 0 . 003). Serum concentrations of G-CSF achieved were significantly higher with the nonglycosylated G-CSF, however, suggesting that the difference in bio-efficacy was not due to a difference in G-CSF stability. Marked inter-individual variation in progenitor mobilization was observed, but this was not related to serum G-CSF levels. The G-CSF concentrations on day 6 were approximately one third of those on day 1, with both forms of G-CSF.

Glycosylated vs non-glycosylated granulocyte colony-stimulating factor (G-CSF) – results of a prospective randomised monocentre study

“…In a group of healthy volunteers, Høglund et al 27 found lenograstim to be 25% superior to filgrastim in terms of CD34 + cell and CFU-GM mobilization. The same study design was used by Watts et al 28 However, in their study there was no difference in CD34 + cell mobilisation, but the number of GM-CFC was higher in the lenograstim-treated subjects. Watts et al 28 also compared day-1 G-CSF plasma levels and found filgrastim levels to be significantly higher than lenograstim levels.…”

“…19,35 However, while the effect of the presence of neutrophils increases daily, the pharmacokinetic studies were only done on day 1 of G-CSF treatment. 28 If glycosylated rhG-CSF was neutralised less effectively by neutrophils, this could explain better CD34 + or GM-CFC harvest and higher maximum WBC in probationers with very high neutrophil counts. 25,27,28 During neutropenia, this difference would not come into play, which might explain why, even if there were a difference between the two G-CSF preparations in terms of receptor binding, in neutroBone Marrow Transplantation penic hosts consistently no difference was found between glycosylated and non-glycosylated G-CSF.…”

“…28 If glycosylated rhG-CSF was neutralised less effectively by neutrophils, this could explain better CD34 + or GM-CFC harvest and higher maximum WBC in probationers with very high neutrophil counts. 25,27,28 During neutropenia, this difference would not come into play, which might explain why, even if there were a difference between the two G-CSF preparations in terms of receptor binding, in neutroBone Marrow Transplantation penic hosts consistently no difference was found between glycosylated and non-glycosylated G-CSF. 29,30 As was mentioned above, the greater physical stability of the glycosylated molecule 17 appears to confer to lenograstim an advantage in the in vitro system.…”

“…In randomised cross-over studies with healthy individuals, lenograstim was reported to be more potent as a mobiliser of CD34 + cells 27 and/or of GM-CFC. 27,28 For all four studies, it must be said that the very subtle kinetics of G-CSF-induced stem cell mobilisation 33 are probably not sufficiently reflected by once daily determination of CD34 + count or progenitor cell culture. The data available at present are thus not sufficient to justify any general statement about differences in potency of the two G-CSF preparations.…”

A randomised study of 10 μg/kg/day (single dose) vs 2 × 5 μg/kg/day (split dose) G-CSF as stem cell mobilisation regimen in high-risk breast cancer patients

“…Therefore, randomised clinical trials with an original (cross-over) design have been reported. 4,5 High-dose chemotherapy followed by autologous PBPC transplantation was a widely used procedure to treat metastatic and high-risk breast cancer patients. Since reported randomised clinical trials were negative and fraudulent studies were audited, 6 this indication is decreasing.…”