Fishburn C Simone
Nektar Therapeutics, 150 Industrial Road, San Carlos, California 94070, USA.
J Pharm Sci. 2008 Oct;97(10):4167-83. doi: 10.1002/jps.21278.
Conjugation of macromolecules to polyethylene glycol (PEG) has emerged recently as an effective strategy to alter the pharmacokinetic (PK) profiles of a variety of drugs, and thereby to improve their therapeutic potential. PEG conjugation increases retention of drugs in the circulation by protecting against enzymatic digestion, slowing filtration by the kidneys and reducing the generation of neutralizing antibodies. Often, PEGylation leads to a loss in binding affinity due to steric interference with the drug-target binding interaction. This loss in potency is offset by the longer circulating half-life of the drugs, and the resulting change in PK-PD profile has led in some cases to enabling of drugs that otherwise could not be developed, and in others to improvements in existing drugs. Thus, whereas most approaches to drug development seek to increase the activity of drugs directly, the creation of PEGylated drugs seeks to balance the pharmacodynamic (PD) and pharmacokinetic properties to produce novel therapies that will meet with both increased efficacy and greater compliance in the clinical setting. This review examines some of the PEGylated drugs developed in recent years, and highlights some of the different strategies taken to employ PEG to maximize the overall PK-PD profiles of these compounds.
大分子与聚乙二醇（PEG）的缀合最近已成为一种有效的策略，可改变多种药物的药代动力学（PK）特征，从而提高其治疗潜力。PEG缀合通过防止酶消化、减缓肾脏过滤和减少中和抗体的产生，增加药物在循环中的保留时间。通常，聚乙二醇化由于对药物-靶点结合相互作用的空间干扰而导致结合亲和力丧失。这种效力的损失被药物更长的循环半衰期所抵消，并且PK-PD曲线的变化在某些情况下使得原本无法开发的药物得以开发，而在其他情况下则改进了现有药物。因此，虽然大多数药物开发方法旨在直接提高药物活性，但聚乙二醇化药物的研发旨在平衡药效学（PD）和药代动力学特性，以产生在临床环境中既能提高疗效又能提高依从性的新型疗法。本综述考察了近年来开发的一些聚乙二醇化药物，并强调了为利用PEG使这些化合物的整体PK-PD曲线最大化而采取的一些不同策略。
