Mahmood Iftekhar, Green Martin D
Clinical Pharmacology and Toxicology Branch, Office of Drug Evaluation VI, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20852, USA.
Clin Pharmacokinet. 2005;44(4):331-47. doi: 10.2165/00003088-200544040-00001.
With an increasing number of therapeutic proteins moving into preclinical and clinical development, pharmacokinetic factors play an important role in the development of these macromolecules. It is also important that the pharmacokinetic evaluation of these compounds be done as accurately as possible. For macromolecules, evaluation of pharmacokinetic parameters is often complicated by a number of factors. Bioanalytical methods are essential for any pharmacokinetic study, but for many therapeutic proteins the immunoassay and bioassay methodologies are often nonspecific and sometimes the estimation of pharmacokinetic parameters becomes assay dependent. In vivo binding proteins, metabolites and antibody formation may also interfere with bioanalytical methodologies and thus may have significant impact on the pharmacokinetics of therapeutic proteins. There are also difficulties in identifying and quantifying metabolites as well as the binding of therapeutic proteins to endogenous proteins. Some macromolecules exhibit species specificity that complicates the preclinical pharmacological and toxicological evaluation of these compounds. Antibody formation is a particular problem in the preclinical evaluation of therapeutic proteins. Changes in structure or sequence of protein molecules (glycosylation or pegylation) may cause changes in the pharmacokinetics of these compounds. The size of therapeutic proteins may become a hindrance for absorption. Low absorption of intact molecules across biological membranes frequently occurs. Other factors that may affect the pharmacokinetics of a therapeutic protein are immunogenicity, presence of endogenous protein, time of drug administration, and rate and site of drug delivery. The relationship between pharmacokinetics and pharmacodynamics of therapeutic proteins is complex and in most cases is unclear. In many cases the mechanism and site of action are unknown for these compounds.
随着越来越多的治疗性蛋白质进入临床前和临床开发阶段，药代动力学因素在这些大分子的开发中发挥着重要作用。同样重要的是，要尽可能准确地对这些化合物进行药代动力学评估。对于大分子而言，药代动力学参数的评估常常受到多种因素的困扰。生物分析方法对于任何药代动力学研究都是必不可少的，但对于许多治疗性蛋白质来说，免疫测定和生物测定方法往往缺乏特异性，有时药代动力学参数的估计会依赖于测定方法。体内结合蛋白、代谢产物和抗体形成也可能干扰生物分析方法，从而可能对治疗性蛋白质的药代动力学产生重大影响。在鉴定和定量代谢产物以及治疗性蛋白质与内源性蛋白质的结合方面也存在困难。一些大分子表现出物种特异性，这使得对这些化合物的临床前药理和毒理学评估变得复杂。抗体形成是治疗性蛋白质临床前评估中的一个特殊问题。蛋白质分子结构或序列的变化（糖基化或聚乙二醇化）可能导致这些化合物药代动力学的改变。治疗性蛋白质的大小可能会成为吸收的障碍。完整分子跨生物膜的低吸收经常发生。其他可能影响治疗性蛋白质药代动力学的因素包括免疫原性、内源性蛋白质的存在、给药时间以及药物递送的速率和部位。治疗性蛋白质的药代动力学和药效学之间的关系很复杂，在大多数情况下尚不清楚。在许多情况下，这些化合物的作用机制和作用部位尚不清楚。
