Nestorov Ivan
ZymoGenetics, Seattle, WA 98102, USA.
Semin Arthritis Rheum. 2005 Apr;34(5 Suppl1):12-8. doi: 10.1016/j.semarthrit.2005.01.004.
The relationship between the dose administered and the observed beneficial or adverse effects of a drug is one of the basic concepts of clinical pharmacology. The broad term "exposure" usually refers to the dose and the various acute or integrated measures of the resulting concentrations in blood (plasma, serum) and/or tissues/fluids. The term "response" refers to any direct measure of the pharmacologic effect (beneficial or otherwise) of the drug. Thus, as specified in a recent US Food and Drug Administration (FDA) Guidance for Industry (2004), "... a drug can be determined to be safe and effective only when the relationship of beneficial and adverse effect to a defined exposure is known." Consequently, there has been a recent strong academic, industrial, and regulatory interest in exploring and characterizing the exposure-response relationships of existing and developed drugs. The first part of the cascade exposure, response cascade, is the relationship between the administered dose and the observed concentration-time profiles in the organism of interest, often referred to as pharmacokinetics (PK). The second part is the relationship between the concentration levels and the observed pharmacodynamic (PD) responses, often called PK-PD relationship. Within the causal chain of events after a drug is administered, the exposure (or PK) precedes the effect (or PD). Therefore, whenever any differentiation in the beneficial and/or adverse effects between drugs with similar mechanisms of action is observed, the underlying clinical PK is among the first considerations. The purpose of the current article is to review the PK properties of the 3 existing marketed tumor necrosis factor (TNF) antagonists, adalimumab (Abbott Laboratories), etanercept (Amgen Inc.), and infliximab (Centocor, Inc.), and to discuss the potential clinical implications of any PK differences.
给药剂量与药物所观察到的有益或不良反应之间的关系是临床药理学的基本概念之一。广义的“暴露”通常指剂量以及血液（血浆、血清）和/或组织/体液中所产生浓度的各种急性或综合测量值。“反应”一词指药物药理作用（有益或其他）的任何直接测量值。因此，正如美国食品药品监督管理局（FDA）最近发布的行业指南（2004年）所规定的，“……只有当有益和不良反应与确定的暴露之间的关系已知时，才能确定一种药物是安全有效的。”因此，近期学术界、产业界和监管机构对探索和描述现有及已研发药物的暴露-反应关系产生了浓厚兴趣。暴露-反应级联的第一部分是给药剂量与在目标生物体中观察到的浓度-时间曲线之间的关系，通常称为药代动力学（PK）。第二部分是浓度水平与观察到的药效学（PD）反应之间的关系，通常称为PK-PD关系。在药物给药后的因果事件链中，暴露（或PK）先于效应（或PD）。因此，每当观察到作用机制相似的药物在有益和/或不良反应方面存在任何差异时，潜在的临床PK是首先要考虑的因素之一。本文的目的是综述三种现有的上市肿瘤坏死因子（TNF）拮抗剂，即阿达木单抗（雅培实验室）、依那西普（安进公司）和英夫利昔单抗（先灵葆雅公司）的PK特性，并讨论任何PK差异的潜在临床意义。
