Pharmacokinetics and pharmacodynamics of subcutaneous single doses of pegylated human G-CSF mutant (PEG30-rhG-CSF) in beagle dogs

Objective To compare the pharmacokinetics and pharmacodynamics of PEG30-rhG-CSF administered to beagle dogs at three diff erent dosages with PEG20-rhG-CSF administered at one dosage, and to provide an experimental basis for clinical trials. Methods Beagle dogs received single, subcutaneous doses of PEG30-rhG-CSF at 100, 200 and 400 μg/kg or PEG20-rhG-CSF at 200 μg/kg. PEG30-rhG-CSF and PEG20-rhG-CSF concentrations in serum were analyzed using an enzyme-linked immunosorbent assay (ELISA). WBC, ANC and PLT counts of whole blood samples were measured using fully automated analytic instrumentation. Pharmacokinetic and pharmacodynamic parameters were calculated using DAS 2.0 statistical analysis so ware. Results The pharmacokinetic parameters of PEG30-rhG-CSF calculated from the serum concentration data determined by ELISA were as follows: the mean elimination half-life (t 1/2ke ) was 40.6 h (33.5∼45.4 h); the mean time to reach peak concentration (T max ) was 19.2 h (11.7∼24.0 h); the drug clearance from the serum (CL) was decreased with increasing doses; the peak concentration (C max ) and the area under the serum concentration-time curve (AUC) were increased with increasing doses. For PEG20-rhG-CSF, the half-life was shorter (12 h) and T max was achieved much earlier (10 h) relative to PEG30-rhG-CSF. The AUC of PEG30-rhG-CSF was much greater than that of PEG20-rhG-CSF, and the relative bioavailability with a subcutaneous injection was 158.7%. Administration of single doses of PEG30-rhG-CSF resulted in substantial increases in the absolute neutrophil count (ANC). The time to reach ANC max (ANCT max ) was 72 h. The maximum observed absolute neutrophil counts (ANC max ) and the area over the baseline effect curve (AOBEC) was increased with increasing doses. The effect-elimination half-life (t 1/2E ) ranged from 60 h to 80 h after subcutaneous administration. The PLT count was slightly elevated 8∼12 h after s.c. injection, and declined after 24 h. Conclusion The mean elimination half-life of PEG30-rhG-CSF was longer than that of PEG20-rhG-CSF at the same dose, and the other main pharmacokinetic and pharmacodynamic parameters of PEG30-rhG-CSF, including Cmax, ANCmax, AUC and AOBEC were much greater than those following PEG20-rhG-CSF injection.