A Phase I Study To Evaluate The Clinical Pharmacokinetics And Pharmacodynamics Of Long Acting Recombinant Human Granulocyte Colony-stimulating Factor

Part1:A phase I study to evaluate the clinical pharmacokinetics and pharmacodynamics of pegylated recombinant human granulocyte colony-stimulating factor[Objective] To evaluate the pharmacokinetics, pharmacodynamics and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in the prevention of chemotherapy-induced neutropenia, as the basis for phase II clinical study.[Methods] Twenty-seven untreated patients received two cycles of the same chemotherapy regimen(paclitaxel and carboplatin). In cycle1, patients were just treated with chemotherapy. In cycle2, patients would receive a single subcutaneous injection of PEG-rhG-CSF (dose levels of30,60,100, or150μg·kg-1)48hours after chemotherapy. There are3patients in30μg·kg-1group, and8patients in each of60μg·kg-1,100μg·kg-1and150μg·kg-1group. The concentration of PEG-rhG-CSF was detected in the serum by ELISA, meanwhile pharmacodynamic analysis was performed.[Results] Twenty-four patients can be evaluated the pharmacokinetics, pharmacodynamics and safety,30μg·kg-1was pre-experimental group. The main pharmacokinetic parameters of PEG-rhG-CSF after three single dose injection were as follows:t1/2were (37.5±7),(40.8±12),(80.7±48) h; CL were (17±9),(9±4),(7±2) L·h-1·g-1; AUC0-t were (5,593.6±5,435),(14,651.3±12,183),(23,002.5±6,655) mg·h·L-1. The mean ANC nadirs in cycle2were higher than those in cycle1. The utilization of PEG-rhG-CSF may prevent the incidence of grade4neutropenia, meanwhile the incidence of adverse reactions in cycle2was the same with cycle1.[Conclusion] The pharmacokinetics of PEG-rhG-CSF were a non-linear profile in60μg·kg-1to150μg·kg-1range. It has a potential of once-per-cycle administration. The recommended dose of YPEG-rHuG-CSF for phase Ⅱ trail is100μg·kg-1. Part2:A phase I study to evaluate the clinical pharmacokinetics and pharmacodynamics of Y-pegylated recombinant human granulocyte-colony stimulating factor[Objective] To evaluate the pharmacokinetics, pharmacodynamics and safety of Y-pegylated recombinant human granulocyte-colony stimulating factor (YPEG-rHuG-CSF) in the prevention of chemotherapy-induced neutropenia and compare the pharmacodynamics of YPEG-rHuG-CSF and rHuG-CSF.[Methods] Thirty patients received three cycles of the same chemotherapy regimen. In cycle1, patients were just treated with chemotherapy. In cycle2, when ANC<1.5×109cells·L-1, patients would receive a single subcutaneous injection of YPEG-rHuG-CSF (dose levels of10,20,30,45or60μg-kg-1)48hours after chemotherapy. In cycle3,48hours after chemotherapy, patients would receive a subcutaneous injection of rHuG-CSF every day until ANC≥5.0×109cells·L-1. The safety, efficacy and pharmacokinetics were analyzed.[Results] Twenty-seven patients can be evaluated the pharmacokinetics, pharmacodynamics and safety,10μg·kg-1was pre-experimental group. The main pharmacokinetic parameters of YPEG-rHuG-CSF were as follows:t1/2were (56.9±11),(71.7±23),(73.9±23),(77.4±14) h; CL were:(19.7±5),(19.5±9),(21.6±9),(12.4±4) mL·h-1·kg-1; AUC0-t were (1,009.8±245),(1,844.8±1,111),(2,342.2±1,029),(5,332.6±2,120) ng·h·ml-1. Anti-G-CSF antibody was not detected in this study. The mean ANC nadirs were3.43×109,3.0×109,2.96×109,3.0×109cells·L-1in cycle2, higher than those in cycle1and cycle3.[Conclusion] The pharmacokinetics of YPEG-rHuG-CSF were a linear profile in20μg·kg-1to45μg·kg-1range and was a non-linear profile at60μg·kg-1. It has a potential of once-per-cycle administration to prevent the chemotherapy-induced neutropenia. The recommended dose of YPEG-rHuG-CSF for phase II clinical trail is45μg·kg-1, it should be administrated once per cycle.