聚乙二醇化新型集成干扰素注射液大鼠药物代谢动力学研究

Pharmacokinetics of a novel pegylated consensus interferon in rats

目的研究聚乙二醇化新型集成干扰素(pegylated consensus interferon,PEG-cIFN)注射液在大鼠体内的药代动力学特征,并与非聚乙二醇化的集成干扰素(consensus interferon,cIFN)进行比较。方法大鼠分别单次皮下注射不同剂量PEG-cIFN(7、14和28μg/kg)和cIFN(7μg/kg),采用酶联免疫分析法测定不同时间血清药物浓度,实验数据以DAS 3.0药动程序拟合并计算药动参数。结果大鼠分别单次皮下注射PEG-cIFN低、中和高3个剂量组后,峰浓度(the peak concentration,Cmax)和药时曲线下面积(the area under the serum concentration-time curve,AUC)随剂量增加呈更大比例增大,清除率(clearance,CL)随剂量增大而降低;达峰时间(the time to reach peak concentration,Tmax)和消除半衰期(elimination half life,t1/2β)与剂量呈非相关,且较为恒定(10～20 h);相同剂量下的PEG-cIFN较cIFN t1/2β延长15倍;CL降低10倍;Tmax滞后约10倍;AUC增加8倍,而Cmax降低近1倍。结论上述研究结果表明,PEG化后的IFN确实能改善和提高药代动力学/药效动力学特性,延长半衰期,降低清除率,增加暴露量,减小血清峰-谷浓度比率,延缓药物体内作用时间,具有长效作用。

Objective To characterize the parmacokinetics of a novel pegylated consensus interferon（PEG-IFN-SA） following a single subcutaneous administration to rat,compared with those of non-PEG modified IFN-SA.Methods The rats were randomly assigned into four groups in which the rats were given PEG-IFN-SA at doses of 7,14 and 28 μg/kg,and IFN-SA at a dose of 7 μg/kg,respectively.The serum concentrations of PEG-IFN-SA and IFN-SA were determined using an enzyme-linked immunosorbent assay（ELISA）.The pharmacokinetic parameters were calculated by DAS 3.0 software.Results The rats treated with PEG-IFN-SA following single s.c.administration at doses of 7,14,and 28 μg/kg,a greater than proportional increase in both the peak concentration（Cmax） and the area under the concentration-time curve（AUC） for PEG-IFN-SA was observed with increasing dose,while the rate of clearance decreased.Both the time to reach peak concentration（Tmax） and serum elimination half life（t1/2β） did not display markedly dose-dependence and were relatively consistent in the range of 10~20 h.The pegylated protein exhibited improved pharmacokinetic properties compared to IFN-SA at an identical dose,with a 15-fold increase in t1/2β,and a 10-fold decrease in serum clearance（CL）,as well as a 10-fold increase in Tmax,respectively.In addition,AUC of PEG-IFN-SA was approximately 8-fold greater,while Cmax was approximately half that of IFN-SA.Conclusion These findings demonstrate that pegylation of IFN-SA results in more desirable pharmacokinetic properties,prolonged biological half-life,decreased system clearance,enhanced drug exposure,reduced serum peak-to-trough concentration ratio and increased in vivo duration of antiviral efficacy compared to unmodified IFN-SA.