Plasma Concentrations and AUC of Pegfilgrastim Have No Impact on Its Efficacy in Peripheral Blood Progenitor Cell Mobilization.
Authors: Kroschinsky Frank P. , Schleyer Eberhard , Hoelig Kristina , Oelschlaegel Uta , Ordemann Rainer , Poppe-Thiede Kirsten , Schaich Markus A. , Rutt Claudia , Ehninger Gerhard 
Published: April 2020

Abstract
The use of pegfilgrastim (Neulasta™, Amgen Inc., Thousand Oaks, USA) in mobilization of CD34+ peripheral blood progenitor cells (PBPC) is promising because a continuously increased G-CSF level is suspected to exert a higher biological activity than pulsatile elevations after intermittent injections of unconjugated G-CSF. In clinical phase I/II trials we evaluated the agent both in combination with chemotherapy to mobilize autologous PBPC in 40 cancer patients and as growth factor treatment alone in a small pilot study with 25 allogeneic stem cell donors. The results were reported recently (Kroschinsky et al., Blood2004; 104: 2922 abstr.).
To investigate the impact of growth factor pharmacokinetics on mobilization efficacy blood samples were taken from 11 patients with lymphoproliferative malignancies and 11 allogeneic stem cell donors. The mobilization regimen in the patients consisted of disease specific chemotherapy and a single subcutaneous injection of 6 mg pegfilgrastim administered 48 hours after the end of cytotoxic treatment (day 0). CD34+ cells in the peripheral blood (PB-CD34) were measured if white blood cells (WBC) exceeded 1.0 x 10^9/L after nadir. PBPC collections started at a PB-CD34 cell count &gt;10/μl. The allogeneic donors received a single subcutaneous injection of 12 mg PEGFIL on day 1, leukaphereses started on day 5. All procedures were performed as large-volume apheresis (4x blood volume) using a Cobe Spectra (Gambro BCT Inc.). EDTA blood samples for pharmacokinetic analyses were taken before pegfilgrastim administration and 30 and 60 min, 4, 8 and 12 hours after injection, followed by daily (in allogeneic donors) or twice daily (in patients) sampling. The samples were centrifuged immediately at 5°C for 15 min, and the plasma was aliquoted into cryo vials and stored at −20°C until assayed. G-CSF plasma levels were measured using a solid phase sandwich ELISA (BioSource International, Nivelles, Belgium) and pharmacokinetic data were calculated based on the TOPFIT computer program. The results are presented as medians and ranges in the Table #1.
In Pearson’s analysis there were no correlations between the peak of PB-CD34+ cells with cmax or AUC of G-CSF, neither in the autologous mobilized patients, nor in the allogeneic donors. Furthermore we could not detect an influence of the G-CSF levels at the time of PB-CD34 maximum (cP) on the concentration of circulating stem cells. In conclusion, our data do not support the hypothesis of a superior mobilization efficacy of pegfilgrastim due to its specific pharmacologic properties.
Table 1 Patients (n=11) Donors (n=11) * Cp = GCSF concentration at maximum (peak) of PB-CD34+ cells; ** PB = peripheral blood dose of pegfilgrastim [μg/kg] 81 (59–107) 162 (133–203) t1/2 [h] 49 (28–180) 19 (13–48) AUC [μg*h/mL] 21 (11–39) 30 (8–83) Cmax [ng/mL] 130 (69–340) 480 (82–1300) tmax [h] 53 (22–92) 25 (21–51) Cp* [ng/mL] 30 (8–135) 87 (37–728) CL [mL/min] 4.7 (2.6–8.9) 6.2 (2.4–24.0) VD [L] 17 (7–80) 8 (3–100) Peak PB**-CD34 [1/μL] 32 (1–565) 60 (4–113)