Pepinsky R B, LePage D J, Gill A, Chakraborty A, Vaidyanathan S, Green M, Baker D P, Whalley E, Hochman P S, Martin P
Biogen, Inc., Cambridge, Massachusetts, USA.
J Pharmacol Exp Ther. 2001 Jun;297(3):1059-66.
Interferon therapies suffer from a relatively short half-life of the products in circulation. To address this issue we investigated the effects of polyethylene glycol modification (PEGylation) on the pharmacokinetic properties of human interferon (IFN)-beta-1a. PEGylation with a linear 20-kDa PEG targeted at a single site on the N-terminal amine had no deleterious effect on its specific activity in an in vitro antiviral assay. In monkeys, PEG IFN-beta-1a treatment induced neopterin and beta2-microglobulin expression (pharmacodynamic markers of activity). Systemic clearance values in monkeys, rats, and mice decreased, respectively, from 232, 261, and 247 ml/h/kg for the unmodified IFN-beta-1a to 30.5, 19.2, and 18.7 ml/h/kg for the PEGylated form, while volume of distribution values decreased from 427, 280, and 328 ml/kg to 284, 173, and 150 ml/kg. The decreased clearance and volume of distribution resulted in higher serum antiviral activity in the PEG IFN-beta-1a-treated animals. In the rat, a more extensive set of dosing routes was investigated, including intraperitoneal, intratracheal, and oral administration. Bioavailability for the PEG IFN-beta-1a was similar to the unmodified protein for each of the extravascular routes examined. For the intraperitoneal route, bioavailability was almost 100%, whereas for the oral and intratracheal routes absorption was low (<5%). In rats, subcutaneous bioavailability was moderate (28%), whereas in monkeys it was approximately 100%. In all instances an improved pharmacokinetic profile for the PEGylated IFN-beta-1a was observed. These findings demonstrate that PEGylation greatly alters the pharmacokinetic properties of IFN-beta-1a, resulting in an increase in systemic exposure following diverse routes of administration.
干扰素疗法存在循环中产品半衰期相对较短的问题。为解决这一问题，我们研究了聚乙二醇修饰（聚乙二醇化）对人干扰素（IFN）-β-1a药代动力学特性的影响。用线性20 kDa聚乙二醇靶向N端胺上的单个位点进行聚乙二醇化，在体外抗病毒试验中对其比活性没有有害影响。在猴子中，聚乙二醇化干扰素β-1a治疗可诱导新蝶呤和β2-微球蛋白表达（活性的药效学标志物）。在猴子、大鼠和小鼠中，未修饰的干扰素β-1a的全身清除率值分别从232、261和247 ml/h/kg降至聚乙二醇化形式的30.5、19.2和18.7 ml/h/kg，而分布容积值从427、280和328 ml/kg降至284、173和150 ml/kg。清除率和分布容积的降低导致聚乙二醇化干扰素β-1a治疗的动物血清抗病毒活性更高。在大鼠中，研究了更广泛的给药途径，包括腹腔内、气管内和口服给药。对于所研究的每种血管外途径，聚乙二醇化干扰素β-1a的生物利用度与未修饰的蛋白相似。对于腹腔内途径，生物利用度几乎为100%，而对于口服和气管内途径，吸收较低（<5%）。在大鼠中，皮下生物利用度适中（28%），而在猴子中约为100%。在所有情况下，均观察到聚乙二醇化干扰素β-1a的药代动力学特征得到改善。这些发现表明，聚乙二醇化极大地改变了干扰素β-1a的药代动力学特性，导致不同给药途径后全身暴露增加。
