4505 ORAL A population pharmacokinetic/pharmacodynamic (PK/PD) analysis of exposure–response for sunitinib in metastatic renal cell carcinoma (mRCC)

Abstract

To ascertain the pharmacological activity of erythropoietin (EPO) administered by self-dissolving micropiles (SDMP), four kinds of EPO SDMPs were prepared and were administered to rats in 4 consecutive days at 200, 500, 1000 and 2300 IU/kg. After the start of the experiment, blood samples were obtained once a day for 10 days and percent circulating reticulocytes were counted using Miller technique. At the lower doses, 200 and 500 IU/kg, pharmacological activity of EPO was not obtained. By increasing EPO dose to 1000 IU/kg, circulating reticulocytes significantly increased at days 4, 5, 6 and 7 after the start of the experiment and the average value for the change in reticulocyte levels during day 1 and day 5 was 170.9%. With the highest dose, 2300 IU/kg, higher circulating reticulocytes levels started to increase at the 4th day after the start of the experiment and maintained from day 5 to day 10. The average of the changes in reticulocyte from day 5 to day 10 was 251%. Dose-dependent circulating reticulocytes increase was observed at the higher dose range, 1000 and 2300 IU/kg. To study the linearity on the serum EPO level vs. time curves, pharmacokinetic experiment was performed with rats. After the administration of EPO SDMPs to rats, 200, 500, 1000 and 2300 IU/kg, serum EPO levels gradually increased and reached to the maximum level, Cmax, at 18 h after administration. The Cmaxs were 100.4 ± 11.7 mIU/ml (200 IU/kg), 346.6 ± 11.8 mIU/ml (500 IU/kg), 391.6 ± 17.6 mIU/ml (1000 IU/kg), and 1094.9 ± 114.8 mIU/ml (2300 IU/kg), respectively. AUCs were 1407 ± 231, 3843 ± 402, 5363 ± 482 and 15,566 ± 1894 mIU h/ml. Linear relation was obtained between serum EPO level and EPO dose administered as SDMP. With histological study, any adverse effect was not found out on the skin where SDMPs were administered for consecutive 4 days. These results suggest the usefulness of SDMP as a new percutaneous delivery system of EPO.