聚乙二醇化新型集成干扰素生物处置过程研究
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摘要
聚乙二醇化（PEG）新型集成干扰素（PEG-IFN-SA）属生物技术创新药物，临床用于治疗慢性丙型肝炎病毒感染。本文首次研究PEG-IFN-SA的非临床和临床药代动力学（PK）/药效动力学（PD）的生物处置过程。
本研究基于生物技术药物特点，建立并采用多种定量分析方法，即放射免疫、酶联免疫、生物活性和~(125)I标记同位素示踪等，研究动物和健康志愿者单次皮下注射（s.c.）PEG-IFN-SA的药代动力学、药效动力学、组织分布与排泄，体内抗病毒活性及PK/PD作用关系。研究包括：猕猴和大鼠PK特征；食蟹猴体内抗病毒活性；豚鼠组织分布和尿、粪及胆汁排泄模式；健康人体剂量-浓度-效应间的PK/PD相关性分析。
非临床研究表明，与非PEG化IFN-SA相比，PEG-IFN-SA在猕猴和大鼠体内平均消除半衰期t1/2分别延长12倍和15倍；清除率CL降低100倍和10倍；达峰时间T_(max)增加100倍和10倍。大鼠s.c. PEG-IFN-SA（7,14和28μg/kg）后，峰浓度C_(max)和药时曲线下面积AUC随剂量增加呈更大比例增大，CL随剂量增大而降低；T_(max)和t_(1/2β)与剂量呈非相关；相同剂量下的PEG-IFN-SA较IFN-SA的AUC增加8倍，C_(max)降低近1倍。食蟹猴体内血清PEG-IFN-SA（10,30和90μg/kg）抗病毒活性呈剂量依赖性增加，且能维持一周。~(125)I-PEG-IFN-SA在豚鼠体内被分布到大多数受检脏器组织中，并呈靶向特异性分布，以脾和肾脏的含药量最高；尿排泄是PEG-IFN-SA的主要排泄途径。
临床研究显示，健康志愿者皮下给予PEG-IFN-SA的PK参数t_(1/2β)为51h；与阳性对照药派罗欣比，PEG-IFN-SA的T_(max)提前和CL增大；PEG-IFN-SA诱导的3个生物标志物（2’,5’-OAS，新碟呤和β2微球蛋白）的PD参数T_(max)均滞后于PK参数的T_(max)。PK/PD特征分析提示，随血药浓度升高，体内药效学作用也随之增强，且体内有效药物浓度和其诱导的抗病毒作用至少持续一周。另外，PEG-IFN-SA（1,1.5和2μg/kg）诱导体内2’,5’-OAS的Cmax(2,5-A)和AUC(2,5-A)与剂量呈依赖性增加。
根据本文研究结果，可以得到如下结论：PEG化后的IFN-SA确实能改善和提高PK/PD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。
A novel pegylated consensus interferon (PEG-IFN-SA), investigated in thispaper, is a biotech drug for the treatment of chronic hepatitis C virus infections.Thisstudy first evaluated the biological disposition of non-clinical and clinical pharmaco-kinetics (PK)/pharmacodynamics (PD) of PEG-IFN-SA
In this study, based on characteristic of biotech drugs, multiple quantitativebioanalytical methods, including radioimmunoassay (RIA), enzyme linkedimmunosorbent assay (ELISA), bioassay, and radioactive isotope trace assay, wereestablished and employed. The purpose of this series of studies was to characterize thepharmacokinetic, pharmacodynamic, tissue distribution, excretion, and antiviralefficacy properties, and PK-PD relationship of PEG-IFN-SA following a singlesubcutaneous administration to monkeys, rat, guinea pigs and healthy volunteers,thereby providing critical information for human health risk assessment. Studiesincluded:(1) pharmacokinetic properties of PEG-IFN-SA and comparison with thoseof non-pegylated consensus interferon (IFN-SA) in rhesus monkeys and rats;(2)antiviral activity assessment of PEG-IFN-SA in cynomolgus monkeys;(3) tissuedistribution and urinary, fecal, and biliary excretion patterns of~(125)I-PEG-IFN-SA inguinea pigs; and (4) pharmacokinetic and pharmacodynamic profiles of PEG-IFN-SAin healthy volunteers.
The pegylated protein exhibited improved pharmacokinetic properties comparedto IFN-SA in both monkeys and rats, with a12-fold and15-fold increase inelimination half life, and a100-fold and10-fold decrease in serum clearance (CL), aswell as a2.5-fold and10-fold increase in the time to reach peak serum concentration(T_(max)), respectively. In rats treated with PEG-IFN-SA following single s.c.administration at doses of7,14, and28μg/kg, a greater than proportional increase inboth Cmaxand AUC for PEG-IFN-SA was observed with increasing dose, while therate of clearance decreased. Both T_(max)and t_(1/2β)did not display markedly dosedependence. Compared with IFN-SA at an identical dose, AUC of PEG-IFN-SA wasapproximately8-fold greater, while Cmaxwas approximately half that of IFN-SA.Serum sample analysis from PEG-IFN-SA-treated monkeys at doses of10,30, and90μg/kg showed dose dependent antiviral activity for at least one week. ~(125)I-PEG-IFN-SA was found to be distributed to most of the tissues examined and hascharacter of targeting special distribution. The highest radioactivity levels weredetected in the spleen and kidney. Urinary appeared to be a major route for theexcretion of PEG-IFN-SA in guinea pigs.
In healthy volunteers, the mean serum PEG-IFN-SA elimination half-life was51h. T_(max)of PEG-IFN-SA occurred at a earlier time and clearance was greater relativeto Pegasys. The characteristic analysis of PK/PD suggested PEG-IFN-SA-inducedserum2’,5’-oligoadenylate synthetase (2’,5’-OAS) activity, Neopterin and β2microglobulin concentration, three classic biomarkers for PEG-IFN-SA pharmaco-dynamics, were enhanced with increasing drug concentration, and sustained-efficacyof in vivo antiviral action for at least one week. T_(max)(2,5-A)，T_(max)(Neopterin)and T_(max)(β2M)ofthree classic biomarkers were achieved much later in comparison with T_(max)of serumdrugs concentration. In additon, PEG-IFN-SA induced dose-depended increases inhuman serum2’,5’-OAS activity.
These findings demonstrate that pegylation of IFN-SA results in more desirablepharmacokinetic and pharmacodynamic properties, prolonged biological half-life,decreased system clearance, enhanced drug exposure, reduced serum peak-to-troughconcentration ratio and increased in vivo duration of antiviral efficacy compared tounmodified IFN-SA.
本研究基于生物技术药物特点，建立并采用多种定量分析方法，即放射免疫、酶联免疫、生物活性和~(125)I标记同位素示踪等，研究动物和健康志愿者单次皮下注射（s.c.）PEG-IFN-SA的药代动力学、药效动力学、组织分布与排泄，体内抗病毒活性及PK/PD作用关系。研究包括：猕猴和大鼠PK特征；食蟹猴体内抗病毒活性；豚鼠组织分布和尿、粪及胆汁排泄模式；健康人体剂量-浓度-效应间的PK/PD相关性分析。
非临床研究表明，与非PEG化IFN-SA相比，PEG-IFN-SA在猕猴和大鼠体内平均消除半衰期t1/2分别延长12倍和15倍；清除率CL降低100倍和10倍；达峰时间T_(max)增加100倍和10倍。大鼠s.c. PEG-IFN-SA（7,14和28μg/kg）后，峰浓度C_(max)和药时曲线下面积AUC随剂量增加呈更大比例增大，CL随剂量增大而降低；T_(max)和t_(1/2β)与剂量呈非相关；相同剂量下的PEG-IFN-SA较IFN-SA的AUC增加8倍，C_(max)降低近1倍。食蟹猴体内血清PEG-IFN-SA（10,30和90μg/kg）抗病毒活性呈剂量依赖性增加，且能维持一周。~(125)I-PEG-IFN-SA在豚鼠体内被分布到大多数受检脏器组织中，并呈靶向特异性分布，以脾和肾脏的含药量最高；尿排泄是PEG-IFN-SA的主要排泄途径。
临床研究显示，健康志愿者皮下给予PEG-IFN-SA的PK参数t_(1/2β)为51h；与阳性对照药派罗欣比，PEG-IFN-SA的T_(max)提前和CL增大；PEG-IFN-SA诱导的3个生物标志物（2’,5’-OAS，新碟呤和β2微球蛋白）的PD参数T_(max)均滞后于PK参数的T_(max)。PK/PD特征分析提示，随血药浓度升高，体内药效学作用也随之增强，且体内有效药物浓度和其诱导的抗病毒作用至少持续一周。另外，PEG-IFN-SA（1,1.5和2μg/kg）诱导体内2’,5’-OAS的Cmax(2,5-A)和AUC(2,5-A)与剂量呈依赖性增加。
根据本文研究结果，可以得到如下结论：PEG化后的IFN-SA确实能改善和提高PK/PD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。
A novel pegylated consensus interferon (PEG-IFN-SA), investigated in thispaper, is a biotech drug for the treatment of chronic hepatitis C virus infections.Thisstudy first evaluated the biological disposition of non-clinical and clinical pharmaco-kinetics (PK)/pharmacodynamics (PD) of PEG-IFN-SA
In this study, based on characteristic of biotech drugs, multiple quantitativebioanalytical methods, including radioimmunoassay (RIA), enzyme linkedimmunosorbent assay (ELISA), bioassay, and radioactive isotope trace assay, wereestablished and employed. The purpose of this series of studies was to characterize thepharmacokinetic, pharmacodynamic, tissue distribution, excretion, and antiviralefficacy properties, and PK-PD relationship of PEG-IFN-SA following a singlesubcutaneous administration to monkeys, rat, guinea pigs and healthy volunteers,thereby providing critical information for human health risk assessment. Studiesincluded:(1) pharmacokinetic properties of PEG-IFN-SA and comparison with thoseof non-pegylated consensus interferon (IFN-SA) in rhesus monkeys and rats;(2)antiviral activity assessment of PEG-IFN-SA in cynomolgus monkeys;(3) tissuedistribution and urinary, fecal, and biliary excretion patterns of~(125)I-PEG-IFN-SA inguinea pigs; and (4) pharmacokinetic and pharmacodynamic profiles of PEG-IFN-SAin healthy volunteers.
The pegylated protein exhibited improved pharmacokinetic properties comparedto IFN-SA in both monkeys and rats, with a12-fold and15-fold increase inelimination half life, and a100-fold and10-fold decrease in serum clearance (CL), aswell as a2.5-fold and10-fold increase in the time to reach peak serum concentration(T_(max)), respectively. In rats treated with PEG-IFN-SA following single s.c.administration at doses of7,14, and28μg/kg, a greater than proportional increase inboth Cmaxand AUC for PEG-IFN-SA was observed with increasing dose, while therate of clearance decreased. Both T_(max)and t_(1/2β)did not display markedly dosedependence. Compared with IFN-SA at an identical dose, AUC of PEG-IFN-SA wasapproximately8-fold greater, while Cmaxwas approximately half that of IFN-SA.Serum sample analysis from PEG-IFN-SA-treated monkeys at doses of10,30, and90μg/kg showed dose dependent antiviral activity for at least one week. ~(125)I-PEG-IFN-SA was found to be distributed to most of the tissues examined and hascharacter of targeting special distribution. The highest radioactivity levels weredetected in the spleen and kidney. Urinary appeared to be a major route for theexcretion of PEG-IFN-SA in guinea pigs.
In healthy volunteers, the mean serum PEG-IFN-SA elimination half-life was51h. T_(max)of PEG-IFN-SA occurred at a earlier time and clearance was greater relativeto Pegasys. The characteristic analysis of PK/PD suggested PEG-IFN-SA-inducedserum2’,5’-oligoadenylate synthetase (2’,5’-OAS) activity, Neopterin and β2microglobulin concentration, three classic biomarkers for PEG-IFN-SA pharmaco-dynamics, were enhanced with increasing drug concentration, and sustained-efficacyof in vivo antiviral action for at least one week. T_(max)(2,5-A)，T_(max)(Neopterin)and T_(max)(β2M)ofthree classic biomarkers were achieved much later in comparison with T_(max)of serumdrugs concentration. In additon, PEG-IFN-SA induced dose-depended increases inhuman serum2’,5’-OAS activity.
These findings demonstrate that pegylation of IFN-SA results in more desirablepharmacokinetic and pharmacodynamic properties, prolonged biological half-life,decreased system clearance, enhanced drug exposure, reduced serum peak-to-troughconcentration ratio and increased in vivo duration of antiviral efficacy compared tounmodified IFN-SA.
引文
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