Abstract：Objective To examine the pharmacodynamics, pharmacology and toxicology of recombinant serum human albumin/granulocyte colony-stimulating factor fusion protein (rHSA/GCSF), and to obtain the pharmacokinetics and toxicokinetics data for directing the ongoing human clinical trials.
Methods The rhesus monkey bone marrow cells were used for in vitro pharmacodynamics studies and the colony form unit-granulocyte macrophage (CFU-GM) numbers were counted to evaluate the influence of rHSA/GCSF. The therapeutic efficacy of rHSA/GCSF on leucopenia in mice and monkeys caused by radiation or injection of fluorouracil were evaluated. For pharmacologic study. The influence of rHSA/GCSF on central nervous system of mice and respiratory and cardiovascular systems of dogs were observed. Through acute and chronic toxicity studies, safety evaluation about rHSA/GCSF was performed in mice, rats and cynomolgus monkeys. The pharmacokinetics /toxicokinetics studies were performed to examine the PK parameters and the tissue distributions in above indicated animals.
Results rHSA/GCSF stimulated the proliferation in granulocytic series of bone marrow and increased the neutrophile granulocytes. rHSA/GCSF had obvious effects on leucopenia in mice caused by fluorouracil. In the early stage of chemotherapy, it slowed down the reduction of white blood cells (WBC), and brought the peripheral neutrophils back the normal level. rHSA/GCSF reduced the duration of absolute neutrophil count (ANC) nadir in leucopenia model caused by radiation in mice and accelerated the recovery of the peripheral WBC. Meanwhile, it had less influence on red blood cell (RBC) and platelet (PLT). Results in mice and monkeys showed that rHSA/GCSF had long-lasting effect. PD/PK data showed that the half-life of rHSA/GCSF was approximately 38.6 hours; single dose of rHSA/GCSF (500, 1500 and 3000 μg/kg) had no effect on nervous system of mice and no synergistic effect with pentobarbital sodium. Furthermore, single dose of rHSA/GCSF (50 and 200 μg/kg) had no effect on respiratory and cardiovascular systems of dogs. In single-dose toxicity studies, the maximum tolerated dose (MTD) in mice was≥ 37.5 mg/kg (i.v. or s.c.) and the MTD in monkeys was 11.6 mg/kg (s.c.). In repeated-dose toxicity studies, the basic safety dose in rats and monkeys was 300 μg/kgand≥ 150 μg/kg, respectively.
Conclusion Single dose every 4 days of rHSA/GCSF administered subcutaneously (s.c.) to the leucopenia on monkeys and mice were caused by radiation, caused by chemical therapeutic on mice, has comparable effect to the merchant rhG-CSF administered a single dose once a day. The study shows that rHSA/GCSF has a long-acting therapeutic function in all of the tested animals. The data obtained from the studies on pharmacodynamics, pharmacokinetics, toxicity and toxicokinetics provide reference and guidance for ongoing clinical trials on cancer patients.
2012, Vol. 7 
